33. Bacteriology π’ Flashcards
List some common bacterial virulence factors and include their function.
- Flagella β movement and attachment
- Pili β adherence factors
- Capsule β protects against phagocytosis
- Endospores β metabolically dormant forms of bacteria β they are heat, cold, desiccation and chemical resistant
- Biofilms β organised aggregates of bacteria embedded in a polysaccharide matrix β antibiotic resistant
Give examples of bacteria that possess the following virulence factors:
a. Capsule
b. Endospores
c. Biofilms
βa. Capsule
- S. pneumoniae
b. Endospores
- Lysinibacillus sphaericus
- Clostridium sporogenes
c. Biofilms
- Pseudomonas aeruginosa
- S. epidermidis
What are exotoxins?
A toxin released by a living bacterial cell into its surrounding
What are the five different types of exotoxin? Give examples of bacteria that produce such toxins.
- Neurotoxins
- Botulinum toxin
- Tetanus E
- Enterotoxins
- Infectious diarrhoea
- Vibrio cholerae
- E. coli
- Shigella
- Infectious diarrhoea
- Food poisoning
- Bacillus cereus
- S. aureus
- Pyrogenic toxins
- S. aureus
- S. pyogenes
- Tissue invasive toxins
- S. aureus
- S. pyogenes
- C. perfringens
What is an endotoxin?
This is the lipid A part of lipopolysaccharide that is found on the outer membrane of Gram-negative cells NOTE: so ONLY Gram-negative cells can produce endotoxins
Why can treating patients with Gram-negative infection sometimes worsen their condition?
Antibiotics can cause lysis of the bacteria meaning that the endotoxins are released into the circulation in large quantities This can trigger an immune response that leads to SEPTIC SHOCK
What is an outbreak?
A greater than normal or greater than expected number of individuals infected or diagnosed with a particular infection in a given time period, or a particular place, or both
How can an outbreak be identified?
- Surveillance
- Good and timely reporting systems are necessary
What was the 2011 E. coli outbreak in Germany caused by?
Enteroaggregative shiga toxin producing E. coli
What were the symptoms of infection by shigella producing enteroaggregative Escherichia coli?
- Gastroenteritis
- Haemolytic uraemia syndrome
- Acute renal failure
- Haemolytic anaemia
- Thrombocytopenia
What was special about the bacterial strain that caused by outbreak?
- The bacterial strain had acquired the ability to produce shiga toxin (through phagetransfer)
- Shiga toxin production is a feature of Enterohaemorrhagic E. coli(EHEC)
This produced a new strain called Enteroaggregative haemorrhagic E. coli (EAHEC)
- Shiga toxin production is a feature of Enterohaemorrhagic E. coli(EHEC)
Describe the structure of shiga toxin.
There is an A subunit that is non-covalently associated with a pentamer of protein B
Describe the action of shiga toxin.
- Subunit A is the enzymatically active domain
- Subunit B is responsible for binding to the host cell membrane
- Subunit A cleaves 28S ribosomal RNA in eukaryotic cells thus inhibiting protein synthesis
- Bacterial ribosomes are also a substrate for subunit A so it can lead to decreased proliferation of susceptible bacteria (e.g. commensal microflora of the gut)
How was the shiga toxin gene transferred between bacteria?
Bacteriophage
What is the important virulence factor in EAEC?
Aggregative adherence fimbriae (AAF) β this is required for adhesion to enterocytes
What type of bacterium is Legionella pneumophila and what is the route of infection?
- Gram negative rod
- It is transmitted through inhalation of contaminated aerosols
Which cells within the human host does L. pneumophila infect and grow inside?
Alveolar macrophages
What is the important virulence factor for L. pneumophila?
Type IV secretion system
What feature of Mycobacterium tuberculosis makes it more difficult to treat?
It has a mycolic acid outer membrane β this prevents normal antibiotics from getting into the cell
State three bacterial sexually transmitted diseases including the species of bacteria that cause the diseases.
- Chlamydia - Chlamydia trachomatis
- Syphilis β Treponema pallidum
- Gonorrhoea β Neisseria gonorrhoeae
What is a major consequence of Chlamydia in the developing world?
Blindness (due to eye infection)
How does N. gonorrhoeae establish infection in the urogenital tract?
It interacts with non-ciliated epithelial cells
What are the important virulence factors of N. gonorrhoeae?
- Pili
- Antigenic variation escapes detection and clearance by the immune system
What is the most commonly reported infectious GI disease in the EU?
Campylobacter jejuni
What is the route of infection of Campylobacter and Salmonella?
Ingestion of undercooked poultry
State some important virulence factors of Campylobacter jejuni.
- Adhesion and invasion factors
- Type IV secretion system
- Toxin
Which subset of the population has the highest incidence of Salmonella and Campylobacter infection?
Young children (0-4 years)
What is an important virulence determinant of Salmonella sp.?
Type III secretion system NOTE: Salmonella sp. can cause outbreaks whereas Campylobacter tends to be sporadic cases
What are the important virulence factors of Vibrio cholerae?
- Cholera toxin
- Type IV secretion system
- Fimbria
Explain how cholera toxin works.
- It has A and B subunits
- A is the active toxin
- B allows entry of the toxin into the epithelial cell
- The A subunit activates adenylate cyclase, thus increasing the production of cAMP
- The cAMP then binds to CFTR and causes Cl- efflux
- Water follows the ion movement so you get massive movement of water into the lumen of the intestine
Which subsets of the population are at risk of infection by Listeria monocytogenes?
Immunocompromised Elderly Pregnant and their foetus
What are some special features of Listeria?
They can enter non-phagocytic cells and cross tight barriers (e.g. BBB and maternal-foetal barrier)
Name some bacterial vector-borne diseases.
- Q fever
- Plague
- Yersinia pestis
List some vaccine-preventable diseases. Identify which are viral.
- Diphtheria
- Invasive pneumococcal infections
- Invasive meningococcal infections
- Pertussis
- Tetanus I
- Invasive Haemophilus influenzae
- Rabies
Measles * Mumps* Rubella* Polio*
Define the following: a. Antimicrobial b. Antibacterial c. Antibiotic
-
a. Antimicrobial
- Interferes with growth and reproduction of a microbe
-
b. Antibacterial
- Commonly used to describe agents that reduce or eliminate harmful bacteria
-
c. Antibiotic
- Type of antimicrobial that is used as medicine for humans and animals
What is a health-care associated infection?
Infections that occur after exposure to healthcare Infection starts >48 hours after admission to hospital
Why do health-care associated infections cost money to the healthcare system?
They increase the length of stay at hospital
List some medical interventions that can increase the risk of infection.
- Catheterisation
- Intubation
- Lines (e.g. central venous lines)
- Chemotherapy
- Prosthetic material
State some other factors that increase the risk of infection in the hospital setting.
Dissemination by healthcare staff Concentration of ill patients
What are the ESCAPE pathogens? Commonly associated with antimicrobial resistance
- Enterococcus faecium
- Staphylococcus aureus
- Clostridium difficile
- Acinetobacter baumanii
- Pseudomonas aeruginosa
- Enterobacteriaceae
- ESC are Gram-positive
- APE are Gram-negative
What is the main problem with the escape pathogens?
They are antibiotic resistant
What is the most frequent cause of bacteraemia by a Gram-negative bacterium?
E. coli
What does E. coli frequently cause?
UTI
Which antibiotics is E. coli resistant to in many countries?
Cephalosporins
Which antibiotics is E. coli still sensitive to?
Carbapenems
State the target proteins and the method of resistance to the following classes of antibiotics:
a. Cephalosporins
b. Carbapenems
c. Methicillin
d. Vancomycin
- a) Cephalosporins
- Target:
- Penicillin binding proteins (PBP)
- Resistance:
- Extended-Spectrum Beta-Lactamase (ESBL)
-
b. Carbapenems
- Target:
- PBP
- Resistance:
- Carbapenemase enzymes
- Target:
-
c. Methicillin
- Target:
- PBP
- Resistance:
- alternative target (PBP2A)
- which has low affinity for methicillin and can function in its presence
- alternative target (PBP2A)
- Target:
-
d. Vancomycin
- Target: peptidoglycan precursor
- Resistance: synthesis of a different peptidoglycan precursor
What are extended-spectrum beta lactamases encoded on?
Plasmid
What are carbapenemases encoded on?
Transposon
What types of infections does Klebsiella pneumoniae tend to cause?
- UTI
- Respiratory tract
Which group of patients are at risk of Klebsiella infection?
Immunocompromised
Which classes of antibiotics are Klebsiella widely resistant to?
- Cephalosporins, fluoroquinolones and aminoglycosides
- Carbapenem resistance in the US
Which group of patients are at risk of P. aeruginosa infection?
Immunocompromised
Which class of antibiotics is P. aeruginosa widely resistant to?
Carbapenems
What is the most important cause of antimicrobial resistant infection in the world?
MRSA
What is Enterococcus faecium widely resistant to?
Vancomycin NOTE: causes blood stream infections
What is a health-care associated infection?
Infections that occur after exposure to healthcare Infection starts >48 hours after admission to hospital
What is Enterococcus faecium widely resistant to?
Vancomycin NOTE: causes blood stream infections
What is the most important cause of antimicrobial resistant infection in the world?
MRSA
Which class of antibiotics is P. aeruginosa widely resistant to?
Carbapenems
Which group of patients are at risk of P. aeruginosa infection?
Immunocompromised
Which classes of antibiotics are Klebsiella widely resistant to?
Cephalosporins, fluoroquinolones and aminoglycosides Carbapenem resistance in the US
Which group of patients are at risk of Klebsiella infection?
Immunocompromised
What types of infections does Klebsiella pneumoniae tend to cause?
- UTI
- Respiratory tract
What are carbapenemases encoded on?
Transposon
What are extended-spectrum beta lactamses (ESBL) encoded on?
Plasmid
State the target proteins and the method of resistance to the following classes of antibiotics: a. Cephalosporins b. Carbapenems c. Methicillin d. Vancomycin
-
a. Cephalosporins
- Target: Penicillin binding proteins (PBP)
- Resistance: Extended-Spectrum Beta-Lactamase (ESBL)
-
b. Carbapenems
- Target: PBP
- Resistance: Carbapenemase enzymes
-
c. Methicillin
- Target: PBP
- Resistance: alternative target (PBP2A), which has low affinity for methicillin and can function in its presence
-
d. Vancomycin
- Target: peptidoglycan precursor
- Resistance: synthesis of a different peptidoglycan precursor
Which antibiotics is E. coli still sensitive to?
Carbapenems
Which antibiotics is E. coli resistant to in many countries?
Cephalosporins
What does E. coli frequently cause?
UTI
What is the most frequent cause of bacteraemia by a Gram-negative bacterium?
E. coli
What is the main problem with the escape pathogens?
They are antibiotic resistant
What are the ESCAPE pathogens?
Enterococcus faecium Staphylococcus aureus Clostridium difficile Acinetobacter baumanii Pseudomonas aeruginosa Enterobacteriaceae NOTE: ESC are Gram-positive APE are Gram-negative
State some other factors that increase the risk of infection in the hospital setting.
Dissemination by healthcare staff Concentration of ill patients
List some medical interventions that can increase the risk of infection.
Catheterisation Intubation Lines (e.g. central venous lines) Chemotherapy Prosthetic material
Why do health-care associated infections cost money to the healthcare system?
They increase the length of stay at hospital
Describe the distinctive features of:
a. Gram positive bacteria
b. Gram negative bacteria
c. Mycolic bacteria
- a. Gram positive bacteria
- Thick peptidoglycan cell wall
- b. Gram negative bacteria
- Outer membrane that contains lipopolysaccharide (LPS)
- c. Mycolic bacteria
- Outer mycolic acid layer
What is DNA gyrase?
- A type of topoisomerase (topoisomerase II)
- It releases tension in DNA and is important in unwinding DNA to allow protein binding required for DNA replication
What does RNA polymerase do?
Produces RNA from a DNA template
What is the key difference between ribosomes in eukaryotes and prokaryotes?
Eukaryote = 40S + 60S
Prokaryote = 30S + 50S
State two classes of drugs that interfere with nucleic acid synthesis and name the enzymes that they inhibit.
- Sulphonamides β inhibits dihydropterate synthase
- Trimethoprim β inhibits DHF reductase
Trimethoprim and sulfamethoxazole drugs are sometimes used together. What is this preparation called?
Co-trimoxazole
Name a group of drugs that interfere with DNA replication and state its targets.
Fluoroquinolones (e.g. ciprofloxacin) inhibits bacterial DNA gyrase and topoisomerase IV
Name a group of drugs that interfere with RNA synthesis and state its main target.
Rifamycins (e.g. rifampicin) β inhibits RNA polymerase
List 4 groups of drugs that interfere with ribosomes.
- Macrolides
- Aminoglycosides
- Chloramphenicol
- Tetracyclines
Describe how peptidoglycan is synthesized, transported to the cell wall and incorporated into the cell wall.
- A pentapeptide is created on N-acetyl muramic acid (NAM)
- N-acetyl glucosamine (NAG) associates with NAM forming peptidoglycan
- The peptidoglycan is then transported into the cell wall by bactoprenol
- The peptidoglycan is then incorporated into the cell wall by transpeptidase enzyme, which cross-links the peptidoglycan pentapeptides
Which groups of drugs interfere with peptidoglycan synthesis and how do they do this?
- Glycopeptides (e.g. vancomycin) β they bind to the pentapeptides and inhibit peptidoglycan synthesis
- This is used as a last resort for Gram-positive bacteria that are resistant to other antibiotics
Name a drug that interferes with peptidoglycan transport and state its target.
Bacitracin β this inhibits bactoprenol, hence preventing peptidoglycan transport
Name a class of drugs that inhibit peptidoglycan incorporation and explain how they do this.
Beta lactams β they bind covalently to transpeptidase, which inhibits peptidoglycan incorporation into the cell wall
What are the three subsets of beta lactams?
- Carbapenems
- Cephalosporins
- Penicillins
Name two drugs that interfere with cell wall stability and explain how they do this.
- Lipopeptides β disrupt Gram-positive cell walls
- Polymyxins β bind to lipopolysaccharide and disrupt Gram-negative cell membranes
List five mechanisms of antibiotic resistance and give a brief description of each.
-
Additional target
- the bacteria produce another target that is unaffected by the drug
-
Hyperproduction
- the bacteria increase the production of the target so the antibiotics are less effective (this is energy inefficient)
-
Altered target site
- there is an alteration in the drug target so that the drug is no longer effective
-
Alteration in drug permeation
- down regulation of aquaporins (responsible for allowing drugs into cells) or the upregulation of efflux systems
-
Production of destruction enzymes
- beta-lactamases hydrolyse the C-N bond in the beta-lactam ring rendering the beta-lactams inactive
What are penicillins G and V normally used to treat?
Gram-positive bacteria
Name two drugs that are relatively beta lactamase resistant.
Flucloxacillin and temocillin
Name a broad-spectrum antibiotic that must be administered with another drug to become resistant to beta lactamases. What is this other drug?
- Amoxicillin (no antibiotic resistance on its own)
- Clavulanic acid (beta-lactmase inhibitor)
What are the mechanisms of action of isoniazid and rifampicin?
- Isoniazid β inhibits mycolic acid synthesis
- Rifampicin β inhibits RNA polymerase
Why do gram + bacteria stain purple?
Because of the peptidoglycan cell wall, which is impermeable so it retains the blue stain.
Difference between the strep species hemolytic actions?
Beta: hemolyze fully Alpha: incomplete hemolysis, turn green (viridans). gamma: Donβt hemolyze at all
Differentiate between staph and strep presentation?
staph: cluster like grapes strep: chains or diclocci (pair up), donβt clump like staph
What is associated with Corynebacterium Diptheriae?
gray pseudo membrane
How do you differentiate between gram + and - on a gram stain?
gram + = purple gram - = red
Different structures of gram + and - bacteria?
bacillus= rod shaped coccus = sphere shaped spirillum = spiral streptococci -> cocci in chains staphylococci -> cocci in clusters
3 different staph species?
-staph aureus -staph epidermis (foreign bodies - cath, prosthetic valve) -staph saprophyticus (UTIs)
What does staph aureus look like on a gram stain?
It is bright yellow on sheep blood agar, and will coagulate positive with hydrogen peroxide (bubbles) this differentiates it from the other 2 staph species that are negative coagulants.
What are the Streptococcus species?
Strep. pyogenes (group A) strep. agalactiae (group B) strep. pneumoniae (pneumococcus) -> GPdiplococci strep viridans Enterococcus (group D)
Why is strep pneumo so virulent?
Because it is encapsulated so when you have no spleen you are at high risk for strep pneumo infections (also why immunocompromised, children, and elderly are at risk). -> this doesnβt have lancefield antigens either
What are the lancefield antigens
differentiates between the different groups of streptococci species. All have specific antigens -> group A, B Viridans (alpha hemo) and pneumo donβt have lancefield antigens
Where are common places for bacterial infections (staph and strep)?
skin (staph), soft tissue and bone
What are the 2 main classes of infection
local: face -> acne generalized (systemic)
What is a localized infection?
the organism enters the body and reaches the target site of infection -> then adheres to or enters host cells and multiplies at site of infection. Infection spreads within site (resp. tract or intestines). -the sxs of the illness appear - organism doesnβt spread through the lymphatic system or reach the bloodstream. The infection subsides due to host defenses (immunity) -> the agent is eliminated from the body and the infected cells are replaced and pt is cured!!
Explain a generalized infection?
the organism enters the body and reaches the target site of initial infection. The organism then adheres to or enters the host cells and multiplies at initial site of infection. The infection spreads within the site and to other sites via tissues, lymphatic system, bloodstream (bacterimia, viremia) and possibly other routes. -sxs of illness may appear -organisms infect other organs, tissues and cells -> more spread via bloodstream - sxs of illness become severe -host defenses eliminate organisms leading to cure or disease continues, possibly leading to irreversible damage or death.
What are 2 common localized infections?
cellulitis, and erysipelas
What are some potentially lethal infections?
-necrotizing fasciitis (flesh eating) -myonecrosis (gas gangrene or clostridial myonecrosis) -pyomyositis (abscess from bacterial infection of skeletal muscles)
Common staph infections
gram positive cocci, grape like clusters most are harmless and reside normally on the skin and mucous membranes MRSA: resistant to b-lactam antibiotics
What might MRSA be confused with?
a spider bite
How does coagulase differentiate the staph species?
coagulase + species (virulence) -> staph aureus (common nasal flora) coagulase - species - staph epidermidis (universal skin flora)
How might staph present in an infection?
stye (cordeolum) boils, carbuncles, furuncles sinusitis hematogenous spread (IV -epid.) endocarditis pneumonia, emesis, impetigo, diarrhea, TSS, UTI, cystitis, osteomyelitis, SSSS
What are the cutaneous infections of S. aureus?
folliculitis (boils), furuncles, burns and wounds
What are deep infections of S. aureus?
osteomyelitis, abscesses, pneumonia, endocarditis, septicemia
What are the toxic mediated infections of S. aureus?
-staphylococcal scalded skin syndrome (SSSS), TSS, food poisoning
What are the most common skin and soft tissue infections of s. aureus? Who are they most common in?
Most common in immunocompetent host -abscesses (cutaneous -> common) -folliculitis -mastitis -wound infections - infect. IV catheter sites
What are other common staph aureus infections? (more severe)
bacteremia, septicemia, endocarditis, pneumonia, musculoskeletal: septic arthritis (injury)
Differentiate b/t the different associated MRSAβs
HA-MRSA: health care assod, occur in people that have been in hospitals. Usually assod with invasive procedures or devices CA-MRSA: community associated among healthy people. Can begin as a painful skin boil. Spread by skin-skin contact, At risk pop: high school wrestlers, child care workers, and people who live in crowded conditions
Process of MRSA infection
generally start as small red areas that resemble spider bites, boils, pimples that can quickly develop into deep, painful abscess that require surgical draining (Really rapid -> in 24 hours will progress) Sometimes will go deeper into tissue and cause life threatening infections in the bones, joints, blood stream, heart valves and lungs
Treatment process of MRSA
culture and sensitivity - septra or -Doxy
If MRSA + -> what do you do to rid yourself of infection?
Bactroban -> ointment in nose qd full body wash -Hibiclens: rule of 3: 3x a day for 3 days then 3 x a week for 3 weeks
Difference b/t strep cellulitis and staph cellulitis?
Group A strep cellulitis: follows an innocuous or unrecognized injury, inflammation is diffuse, spreading along tissue planes Staph aureus: usually assod w/ wound or penetrating trauma, localized abscess become surrounded by cellulitis
Tx of cellulitis
Donβt use Keflex -> doesnβt cover MRSA -now half of cellulitis infections are resistant to tx with kefex -Current tx: clindamycin, doxycycline, Bactrim, Septra
What is the DOC of cellulitis
Bactrim alt: clindamycin (sulfa allergy) Vanco: MRSA severe cellulitis: IV abx especially if pt has high fever and appears ill - be aggressive with tx!
What is the admission criteria for cellulitis?
animal bite on ptβs face or hand area of skin involvement >50% of limb or torso, or >10% of bod surface -coexisting morbidity (diabetes, Heart failure, renal failure, edema) -compromised host -need for IV Abx
What is an abscess?
when the tissue in the area of cellulitis turns to pus under the surface of the skin, the collection of pus is called an abscess -the pus is just dead, liquified tissue, billions of WBCs - the most common bacteria in the abscess is staph aureus - but many other bacteria can cause abscesses -The organisms kill the local cells resulting in the release of cytokines which trigger an inflammatory response which draws large numbers of WBCS -
What must abscesses be distinguished from?
empyemas -> these are accumulations of pus in a preexisting rather than a newly formed anatomical cavity
Clinical features of superficial, and deep seated infections?
superficial: skin and subcutaneous tissues -> infections of the hand Infections of the head and neck: suppurative parotitis (acute infection of the parotid) -Deep seated infections: hepatic abscess/ splenic abscess/ sub-phrenic abscess/ rectal abscess
When would you I and D? What is other part of tx of this?
Only if you see that there is an obvious abscess - should be drained + abx maybe - if the abscess has a lot of cellulitis around it then an abx is probably needed. -Antibiotics canβt penetrate w/o drainage so they need to be drained.
What is necrotizing fasciitis?
this is caused mostly from strep - it is when the bacteria in a cellulitis or abscess starts spreading quickly between the fat layer and the muscle underneath -necrotizing= living flesh to dead flesh - fasciitis means the infection is spreading along space b/t fat and muscle -the infection cuts off blood supply to the tissue above it and the tissue dies - the bacteria may also enter the bloodstream.
Tx of necrotizing fasciitis
cut all the dead tissue out, and keep cutting until only living tissue is left. -do this over and over again until the infection stops spreading. -Antibiotics help but donβt cure the infection -The open muscle needs to be tx like a burn with skin grafts - empiric abx to cover anaerobes, gram -, streptococci, and staph aureus -abx for min. of 3 weeks
What is myonecrosis?
Gas gangrene - pure clostridium perfringens infection -gas in gangrenous muscle group - incubation hours to days -local edema and pain accompanied by fever and tachycardia -discharge is sero-sanguinous, dirty, and foul, crunchy upon palpation
Tx of myonecrosis
Pen G or chloramphenicol -surgical removal of infected muscle -watch out for diabetics -consider hyperbaric chamber
What is pyomyositis
- mostly caused by staph aureus - a purulent bacterial infection of skeletal muscles which results in pus-filled abscess. - most common in tropical areas, temperate zones - mainly a disease of children 2-5 Tx: must be drained surgically and abx given for min. of 3 weeks
What are the staph toxin disorders?
Gastroenteritis (food poisoning) TSS Toxic epidermal necrolysis (TEN) - this started as rxn to drug -> SJS -> TEN Staph scalded skin syndrome (SSSS)
SSSS
also known as Ritter disease: causes by epidermolytic toxins produced by certain strains of staph. This toxin is distributed systemically and results in dissolution of keratinocyte attachments in only the upper layer of the epidermis. - Usually affects newborns and children, adults less affected b/c of improved renal fxn allows for clearance of toxins from the body (w/ renal failure = more susceptible)
Staph epidermidis infections occur when?
Staph epidermidis is a major component of the skin flora. - it is common in nosocomial infections: device/implant associated infections -> shunts, catheters, artificial heart valves, joints, pacemaker (anything foreign in the body) (endocarditis)
Strep infections
30 species of bacteria - gram + cocci in chains subdivided by ability to lyse RBCS: beta (complete lysis), alpha (partial lysis), gamma (no hemolysis)
What is erysipelas?
acute streptococcus infection of the upper dermis and superficial lymphatics. Caused most by strep. pyogenes (group A Beta hemolytic ) -Rarely caused by beta hero of B, C, G group - pathogen enters through a break in the skin and eventually spreads to the dermis and subcutaneous layer - can remain superficial or become systemic
General features and differences of cellulitis and erysipelas?
Varying degrees of skin or soft-tissue erythema, warmth, edema and pain -associated fever and leukocytosis -hx of trauma, abrasion, or skin ulceration Cellulitis has an ill-defined border that merge smoothy with adjacent skin, usually pinkish to red erysipelas: has an elevated and sharply demarcated border with a fiery-red appearance
Management of Cellulitis and erysipelas
local care: immobilization, elevation to reduce swelling, draw lines on areas to assess response to tx - 2 weeks of abx therapy: PCN or dicloxacillin
Impetigo
(pyoderma) -> superficial lesions that break and form highly contagious crust, often occurs in epidemics in school children, bug bites, poor hygiene, and crowded living situations
Differentiate between non-bullous and bullous impetigo?
Non bullous: strep Group A or it could be staph aureus - see in pre-school and young school age, very thin walled vesicle on erythematous base, transient, yellowish-brain crusts (thick Bullous (blister forming): staph aureus cause, all ages, bull: 1-2 cm, persist for 2-3 days, thin and flat, brownish crust, fluid filled
Predisposing factors to impetigo
malnutrition, diabetes, immuno-compromised status
complications of impetigo
strep infection (pink eye, meningitis, endocarditis) - scarlet fever (strep pyogenes (group A): get strawberry tongue - urtricaria - erythema multiforme: usually follows an infection or drug exposure
Tx of impetigo
usually dx by presentation - no cultures usually needed - first soak affected area in warm water or use wet compress to help remove overlying scabs - abx creams or ointments: bactroban AAA Fusidic acid cream AAA retapamulon ointment consider septra/bactrim if hx of MRSA
Common infections of strep progenies (group A beta hemolytic strep)
- cutaneous infections - pharyngitis (sore throat) - otitis media - sinusitis -pneumonia - streptococcal TSS Complications of GABHS: rheumatic fever glomerulonephritis
Describe the long term complications of Group A infections
rheumatic fever: follows overt or subclinical pharyngitis in children, extensive valve damage possible, arthritis, chorea, fever acute glomerulonephritis: nephritis, increased BP, occasionally heart failure, can become chronic leading to kidney failure
Signs of strep throat?
red, beefy tonsils that are covered in exudate, strawberry tongue, petechiae Differential: mono
Beta hemolytic group B strep
normal flora in lower GIT, female genital tract -pathogenicity: neonatal meningitis and sepsis and pneumonia meningitis in babies: wonβt eat, crabby -> fever, vomiting: Emergency
Strep pneumoniae (pneumococcus)
gram + cocci in pairs: pneumonia, otitis media, sinusitis, meningitis Prevention: vaccination (capsular antigens) immunization!!! sxs of strep pneumonaie pneumonia -> shaking, chills, rust colored sputum, consolidation in lungs
Otitis media
presence of a middle ear infection acute otitis media: occurrence of bacterial infection w/in the middle ear cavity otitis media w/ effusion: presence of non purulent fluid w/in middle ear cavity -> have bulging, taut, inflexible TM (have effusion: add decongestant to abx -> drain better) *OM: is 2nd most common clinical problem in childhood after URI
Epidemiology of otitis media
peak incidence in 1st 2 years
Acute otitis media facts
more common in boys -lower socioeconomic status (smoking) -seasonal disease (peak in Jan, Feb) - corresponds to rhinovirus, RSV, influenza seasons ( secondary infection to virus, donβt get good drainage from initial infection, immunity down)
RFs for acute otitis media
young age, bottle feeding, drinking a bottle in bed, parental hx, sibling hx, second hand smoke, daycare
etiology of acute otitis media
suppurative infection of middle ear cavity, common bacterial pathogens achieve access through blocked eustachian tube (infection, pharyngitis, pr hypertrophied adenoids) - air trapping -> neg. pressure -> bacterial reflux bacterial reflux + obstructed flow = effusion
organisms that cause otitis media
strep. pneumo H. influenza Moraxella catarrhalis Group A strep staph aureus pseudomonas aeruginosa RSV assoc. w/ acute otitis media
Signs and sxs of otitis media
sxs are often nonspecific: fever, irritability, poor feeding, otalgia, otorrhea, signs of common cold
What will you see on the physical exam if pt has otitis media?
erythematic, opaque (not translucent, bulging TM w/ loss of anatomic landmarks including a dull/absent light reflex otoscopy: decreased tympanic membrane motility (pulled tight)
Complications of otitis media
hearing loss, acute mastoiditis, chronic perforation of TM, tympanosclerosis, cholesteatoma, chronic suppurative OM, cholesterol granuloma: blue drum syndrome, facial nerve paralysis even worse: intracranial complications, bacterial meningitis, epidural abscess, brain abscess, subdural empyema, otitic hydrocephalus, lateral sinus thrombosis
Tx guidelines for otitis media
infants 102) observation period is an option
tx of otitis media
amoxicillin for 10-14 days or augmentin + auralgan (analgesic/adjunct for ear pain -> drops) TID
2nd line tx for otitis media
cefzil (2nd gen cephalosporin) 6 months to 12 years pediazole (erythro/sulfisoxazole) bactrim *used as secondary agents if the pt is allergic to pcn or primary abx has failed after 10 days and sxs persist
Streptococci viridans
alpha or gamma hemolytic -common oral/pharyngeal flora (bind to teeth, cavities) infections: endocarditis, bacteremia, and septic shock
Group D streptococci (enterococcus)
-UTI -endocarditis -intraabdominal infections (abscesses) -biliary tract infections -wound infections *resistant to vanco and ampicillin, even becoming resistant to aminoglycosides
Dx of streptococcal infections
- culture - ASO titers/streptozyme (body will develop abs to strep -> streptolysin O) - rapid Group A strep tests -gram stains antistreptolysin O (ASO) titer is a blood test to measure abs against streptolysin O, a substance produced by group A streptococcus bacteria
DOC for streptococcal infections
S. pyogenes: PCN (low incidence of resistant organisms S. pneumoniae: increased PCN resistance Erythromycin for both in PCN allergic pt Ampicillin for enterococcus
What is anthrax?
gram positive spore forming bacterium Bacillus anthracis (special capsule to avoid phagocytosis) - anthrax spores are easily found in nature, and can be produced in the lab, can last a long time in the environment - anthrax has been used before as bioterrorism agent - can be released into powders, sprays, food and water - primarily disease of herbivores which are infected by ingesting spores in the soil -natural transmission to humans by contact with infected animals or contaminated animal products
epidemiology of anthrax
reservoir: herbivores (cattle, goats, sheep), capable of surviving in enviro for prolonged periods Transmission: contact, ingestion, or inhalation of infective spores sources of infection: contaminated hides, wool, hair, bone, meat, or other animal products
Clinical features of anthrax
incubation period: 1-7 days (1-60 days) - clinical syndromes: cutaneous ulcer, respiratory, gi, oropharyngeal - inhalation anthrax= main threat spores may germinate up to 60 days after exposure - bronchopneumonia not a component -> hemorrhagic lymphadenitis and mediastinitis - hard to early dx
Cutaneous anthrax
stays local, necrotic center
inhalation anthrax epidemiology and clinical sxs
epidemiology: sudden appearance of multiple cases of severe flu illnesses with fulminant course and high mortality non-specific prodrome of flu-like sxs -possible brief interim improvement -abrupt onset of resp failure and hemodynamic collapse 2-4 days after initial sxs, possible accompanied by thoracic edema and widened mediastinum on CxR (from bleeding)
Diagnostic studies, microbe and pathology of inhalation anthrax
dx studies: chest radiograph w/ widened mediastinum, periph blood smear w/ gm + bacilli on unspun smear Micro: blood culture growth of large gm + bacilli with preliminary identification of Bacillus sp. patho: hemorrhagic medistinitis (death), hemorrhagic thoracic lymphadenitis, hemorrhagic meningitis
prophylaxis anthrax control
prophylaxis: pre-exposure: vaccine (not available?) post exposure: cipro or other quinolone or doxy (vaccine if available) CDC isolation: standard contact isolation if cutaneous lesions present
treatment of anthrax
prophylaxis: cipro or doxy x 60 days tx for cutaneous: cipro or doxy x 60 days tx for inhalation: cipro or doxy plus vanco, imipenem (initial rx= IV then switch to PO for total 60 days) same tx for children and pregos
Diphtheria
gram + rod -acute bacterial respiratory infxn caused by Corynebacterium diphtheria -may involve any mucous membrane: will see gray pseudomembrane - classified based on site of infection (laryngeal, cutaneous, ocular, genital) -very rare in 1st world countries
Most common complications of diphtheria
myocarditis and neuritis - death occurs in 5-10% from respiratory disease
symptoms and findings of Diphtheria
sxs: sore throat, malaise, cervical lymphadenopathy, and low grade fever - earliest pharyngeal finding is mild erythema, which can progress to isolated spots of gray and white exudate. In 1/3 of pts - elaboration of toxin induces formation of coalescing pseudomembrane. This membrane adheres tightly to underlying tissue and bleeds with scraping but doesnβt scrape off.
Tx of diphtheria
abxs: erythro or PCN G diphtheria antitoxin for severe cases - careful airway management -serial electrocardiograms and cardiac enzymes - neuro status should also be monitored carefully
What type of bacteria do you find in the small intestine?
Gram-negative
Give some examples of bacteria and viruses that use the upper respiratory tract as a portal of entry.
Neisseria meningitidis Influenza Parainfluenza Streptococcus pneumoniae Streptococcus pyogenes Staphylococcus aureus
Give some examples of intrinsic bacteria that can infect via the urogenital tract.
E. coli Klebsiella Candida
Give some examples of extrinsic bacteria that can infect via the urogenital tract.
Chlamydia Syphillis Neisseria gonorrheae
Give examples of bacteria that can infect via broken skin.
Staphylococcus aureus Streptococcus pyogenes
State some consequences of infection via broken skin.
Abscess formation Bacteraemia Necrotic infection
Give some examples of bacteria and viruses that infect via the gastrointestinal tract.
Vibrio cholera Salmonella Listeria Shigella E. coli Campylobacter jejuni
What are some consequences of infection via the gastro-intestinal tract?
Diarrhoea Bacteraemia/systemic infections
What two main factors affect pathogenecity?
Infectivity and Virulence
Define infectivity.
The ability of a pathogen to establish infection
Define virulence.
The ability of a pathogen to cause disease
Define infectious dose.
Number of bacteria needed to cause infection
Describe how vibrio cholerae causes disease.
It uses its flagella to propel itself into the mucosal membrane of the intestines. It then begins producing toxins A and B, which bind to GM gangliosides and triggers production of cAMP This leads to chloride efflux and hence movement of water into the lumen from the cells
State whether each of the following are Gram-positive or Gram-negative:
Shigella - negative Streptococcus - positive Listeria - positive Clostridium - positive Vibrio cholerae - negative E. coli - negative Salmonella - negative Staphylococcus - positive Neisseria - negative Haemophilus influenzae - negative
Give two examples of Gram-negative opportunistic bacteria.
Pseudomonas aeruginosa Acinetobacter baumanii
Give two examples of Gram-positive opportunistic bacteria.
E. faecalis Staphylococcus epidermidis
What is the difference between Gram-negative and Gram-positive bacteria?
Gram-negative bacteria have a thin peptidoglycan layer with two membranes (cytoplasmic and outer membranes) Gram-positive bacteria have a thick peptidoglycan layer, which retains the dye well. It only has one membrane
Give examples of some Gram-negative pathogenic bacteria and the diseases they cause.
E. coli β diarrhoea, dysentery, kidney failure Salmonella - food poisoning, typhoid Shigella β dysentery Neisseria β meningitis + gonorrhoea Vibrio cholerae - cholera
What feature is found only on Gram-negative cell walls?
Lipopolysaccharide
Give examples of some Gram-positive pathogenic bacteria and the diseases they cause.
Staphylococcus aureus β skin infections, endocarditis, bacteraemia, pneumonia Streptococcus pneumoniae β pneumonia, meningitis, otitis media Streptococcus pyogenes β tonsillitis, necrotising fasciitis, scarlet fever
Give examples of some Mycobaceria and the diseases they cause
Mycobacterium tuberculosis β TB Mycobacterius leprae - leprosy
What is another way of classifying bacteria?
Intracellular and Extracellular pathogens
Give examples of some extracellular pathogens.
Staphylococcus Streptococcus Neisseria Yersinia
What are the three methods by which bacteria survive in the host cell?
Escape Preventing fusion with lysosome Surviving in the phagolysosome
Give examples of bacteria that survive using each of the above methods.
Escape β Listeria, Shigella Prevent fusion of lysosome β Salmonella, Mycobacteria, Chlamydia Survive in phagolysosome - Coxiella
Motility and Invasion require which two multi-protein machines?
Flagella Type III Secretion system
Describe the role of the type III secretion system.
A protein machine assembles which provides a channel through which virulence proteins can be injected into the host cell The virulence proteins then stimulate actin polymerisation and membrane ruffling which allows bacterial internalisation Gram-positive bacteria donβt have the type III secretion system
Describe another way in which actin is manipulated by bacteria.
Bacteria (such as listeria and shigella) can polymerise actin at one pole of the bacterium forming comet tails This polymerisation propels the bacterium through the cytoplasm
What are the three mechanisms of horizontal gene transmission?
Transformation, Transduction and Conjugation
Explain each of the three mechanisms of horizontal gene transmission.
Transformation β the uptake of naked DNA from the environment Transduction β bacteriophages infect a bacterium and take up some of the bacterial DNA. The bacteriophage then carries the bacterial DNA to another bacterium. Conjugation β transfer of genetic material in the form of a plasmid via a conjugation tube
What is a Pathogenicity Island?
Horizontally acquired genes that contribute to the virulence
Why are cultures performed?
- confirm a dx - exclude a dx - screening - monitor the course of a disease - monitor response to therapy - stage the severity of the disease - provide a prognosis
How can results of a culture be altered?
- Collection methods: swab, aspirate, expectorant - physiologic variables transient bacteremia - meds: especially abx
General culture interpretation guidelines
- as a general rule: infection considered if >10^5 organisms found -
How long does it take cultures to grow?
1 full day to grow the organism and then part or all of 1 day to ID it. It may take an add. day to isolate it b/f ID if there is a mix of organisms. - a preliminary report for most cultures may be issued in 24 hours
What is important to ID from the infectious organisms?
- normal flora from the infection - normal flora and pathogens vary dependent on anatomic location
What is normal flora on the skin?
staph epiermidis, S. aureus, micrococcus, few gram - bacilli moist skin, corynebacterium, propionibacterium acnes
Pathogenic organisms on the skin?
strep. pyogenes pseudomonas proteus
Pathogens in the mouth?
strep pneumoniae, strep pyogenes, Neisseria meningitidis, H. influenza, N. gonorrheae
Potential pathogens and pathogens of oropharynx?
potentials: mycoplasma, bordatella pertussis, many others pathogens: staph aureus, pseudomonas
normal flora in conjunctiva?
corynebacterium, Neisseria, moraxellae, staph, strep, occasional Haemophilus and parainfluenza
Pathogens of the conjunctiva?
pneumococcus, pseudomonas, strep
pathogens of the GI tract?
C. diff, salmonella, toxic strains of E. coli, Helicobactor pylori (in duodenum)
Pathogens of anterior urthera?
chlamydia, gonorrhea, syphilis
What does the normal flora of the vagina depend on?
- varies with hormonal state
Pathogens of the vagina?
candida, trichomonas
What are important steps to collecting a specimen and achieving the highest diagnostic yield?
- obtain specimen before abx - use strict aseptic technique - minimize contamination by skin and mucous membranes (be careful with swabbing) - collect an adequate volume and send tissue or fluid rather then a swab when possible (culture when possible) - label appropriately - fill out requisition slips completely and precisely - call microbio dept if you have any ???s
within how many hours of collection should samples arrive in the lab?
within 1-2 hours of collection, but if delay is unavoidable most specimens (except blood, CSF
Culture turnaround times?
blood cultures: 48-96 hours most routine cultures (urine, throat, sputum): 24-48 hrs unless looking for unusual bacteria - anaerobes: can take 48-72 hours * almost always get gram stain with culture in most settings
appropriate culture media?
-routine: blood agar -chocolate agar -> gram negatives (GC & Haemophilus) -anaerobic blood agar: needs to be fresh -sabourad agar: fungi - GPS -> gram + selective media -> allows isolation of strep and staph and inhibits most gram - rods - MacConkey or eosin methylene blue agars: anaerobic gram - rods - Thioglycollate media: liquid media, enrichment broth used as supplement to plated media
Process of wound culture?
- usually pus present - round up some pus on an applicator - culture of specimens from the skin edge is less accurate than culturing the suppurative material - if anaerobic organism suspected -> get anaerobic culturette from lab
Culture of abscess/boil/furuncle
- incised and any fluid or material swabbed with culture swab and sent to lab - important to get pus/exudate from deep in the wound to avoid surface contamination
Culture of the eye-> conjunctiva
- gently swab to collect drainage - place in approp. container and send to lab at 25 degrees C
How to obtain throat cultures? when are these done?
- done to rule out strep pharyngitis (GABS) - sore throat, inflamed tonsils - inform lab if trying to ID something else such as N. gonorrheae (this reqrs Thayer-Martin agar) - swab posterior pharynx and tonsils - avoid touching any other part of mouth - send to lab at 25 degrees C - often indicated if the in office rapid strep screen is negative
Sputum culture indications
-HAP - hosp patients with pneumonia (CAP) and any of the following criteria: -ICU admission - failure of output abx therapy - cavitary lesion - active alcohol use (aspiration pneumonia) - severe obstructive of structural lung disease - + urine antigen test for pneumococcus - + urine antigen test for Legionella - pleural effusion
Sputum cultures are not indicated when:
- for most outpatient CAPs - management of bronchitis - initial management of acute exacerbations of COPD
How to obtain a sputum collection for optimal yield?
- obtain prior to abx tx - have the pt rinse their mouth prior to expectoration - no food 1-2 hours prior to expectoration - inoculation of culture media immediately after specimen is obtained or immediately after prompt transport to microbio lab - bronchoscopy: sampling of lower airway is another potential dx method in patients w/ suspected pneumonia
What may make a sputum culture inaccurate? When would you suspect a pathogen? When is the best time to get a sputum culture?
- may be inaccurate due to mouth flora - suspect a pathogen if WBCs are present along with an overabundance pf 1 type of organism -first morning sputum will represent deeper pulmonary secretions - induce cough with nebs, pulmonary PT, aspiration, bronchoscopy
What should you always get with a sputum sample?
- always get a gram stain too! - helpful for directing empiric therapy
What will you see in a atypical pneumonia sputum culture (mycoplasma and legionella)?
The sputum will contain abundant PMNs and few or no organism will be seen on the gram stain
What will you see on a sputum culture + with pneumococcal pneumonia?
abundant inflammatory cells and gram + diplococci
What are the indications for ordering a blood culture?
- bacteremia - septicemia - unexplained post operative shock - unexplained fever of several days duration - pneumonia - chills and fever in pts with: infected burns or UTIs rapidly progressing tissue infections post-op wound sepsis indwelling venous or arterial catheters -debilitated pts receiving: abx, corticosteroids, immunosuppressives, parenteral hyperalimentation (nutrition)
When are blood cultures used to detect bacteremia (septicemia)
- should mainly be considered in pts w/ temp >101 suspected of having endocarditis or other systemic pathogens - std of care for inpatients w/ pneumonia prior to starting abx - can repeat in 1 hour or if fever (transient bacteremia) - 2 specimens obtained from 2 separate sites 15 minutes apart (aerobic or anaerobic?) - # of organisms / site is low - helps id contaminants - total: 30-40 ml of blood
Blood culture technique
- clean site first with 70% alcohol - follow with butadiene x 2 minutes - wipe bottle tops with alcohol - go to lab immediately - donβt draw blood cultures through central lines or IV (contamination)
How to collect a urine sample?
- clean catch, mid void specimen - collect 5-50 ml of urine - cath -suprapubic tap *best culture is in the morning (most concentrated)
Guideline of urine sample and transport
- midstream clean catch urine by pt - need at least 1 ml - transport a 4 degrees centigrade - straight cath specimen: same parameters - indwelling cath: disinfect port with alcohol remove 5-10 ml of urine w/ needle and syringe -> transfer to sterile container, 4 C - suprapubic aspirate: at least 1 ml, at 4 C - always send as UA and urine C & S
What does the urine dipstick test?
- pH - specific gravity - bilirubin - protein (nephritis -> elderly) - glucose -> diabetics - ketones (diabetic ketoacidosis) - blood: canβt always rely on - nitrate: certain bacteria - leukocyte esterase (pyuria)
indicators of possible pyuria
leukocyte esterase: if + on dipstick likely indicates pyuria nitrite: indicates the presence of enterobacteriaceae that converts nitrate to nitrite if neg but + symptoms of UTI still want urine culture
Microscopic analysis of urine
- eval of urine sediment from a spun sample - presence of squamous epithelial cells = contamination from genital region - normals: rbc: 0-5 HPF wbc: 0-5 HPF bacteria: absent casts: 0-4 hyaline LPF (kidney health) crystals
Indications for a lumbar puncture
- look for blood (possible subarachnoid hemorrhage) - find the organism causing the meningitis or brain abscess - can do gram stain early on while awaiting culture reports - cell and chemistry counts will aid in making the dx
CSF Culture
- suspected meningitis, high fever in infant - lumbar puncture collect 1-5 ml of CSF - transport at 25 degrees C - gram stain and bacterial culture - 4 tubes for: cell count, glucose and protein, gram stain and culture, and cell count to compare to tube 1
Pleural fluid culture
- thoracentesis - dx and/or therapeutic: therapeutic- relieves dyspnea (breathe easier) diagnostic: test the fluid for TB, CEA level (tumor marker), cytology, culture, gram stain, pH
Go under or over rib while doing a thoracentesis?
- over because nerves and vasculature along bottom of ribs
Synovial fluid eval?
- swollen joint - infection, inflammation or uric acid -meds shouldnβt be administered therapeutically at the same time because interfere with sample (corticosteroids, abx)
Body fluids collection technique
- peritoneal, pericardial, pleural, synovial - aspirate using sterile technique into sterile syringe (usually pt has fever or elevated WBCs) - remove needle and cap syringe to send to lab, sometimes put aspirate in a different container - min. of 1-10 cc, send as much fluid as possible - send at 4 degrees C
Genital tract culture for women
- swab cervix for gonorrhea, chlamydia as well as other organisms in suspected PID - swabs of urethra or urine testing for chlamydia - occasionally swabs of vagina are done
guidelines for vaginal/cervical culture
- no douching or tub bathing for 24 hours prior to collection - swab -> checking for gonorrhea, chlamydia
When is a wet mount used?
- helpful in evaluating vaginitis - saline wet mount of vaginal discharge can show epithelial cells covered with bacteria suggestive of bacterial vaginosis - trichomonads - can reveal multiple PMNβs - KOH (K+ hydroxide) wet mount can reveal candida organisms
Swabbing male urethra indications
- special smaller swabs for urethral sampling for gonorrhea and chlamydia and other less common infectious agents - urine samples for GC and chlamydia for nucleic acid amplification - nucleic acid amplification more sensitive than culture
Urethral culture techniques
- usually on men - culture for GC, chlamydia - rapid enzyme test available - Thayer martin/New York media - anaerobic transport
Stool culture indications
- routine culture (for those with prolonged diarrhea or havenβt been on abx or hospitalized) - >2 grams, 4 degrees C - C. diff toxin: test of choice for those who develop diarrhea on abx or in hospital > 3 days - >5 ml, 4 degrees C
Stool culture guidelines
- also check for ova & parasites - usually look for staph, salmonella, shigella - Donβt mix urine or TP with sample - rectal swabs: worms - βtape testβ
Difference b/t acute and chronic cough?
- acute cough: only exists for less than 3 weeks and is most commonly due to an acute respiratory tract infection. Other considerations include and acute exacerbation of underlying chronic pulmonary disease, pneumonia, and PE - Chronic: cough that has been present longer than 3 weeks is either subacute (3-8 weeks) or chronic (more than 8 weeks)
Common causes of chronic cough
- post nasal drip from allergies or chronic sinusitis - asthma - postinfectious - chronic bronchitis - GE reflux - heart failure - medication induced (ACE inhibitors) - enviro irritants -> pollution
Mycobacteria infections
- Mycobacterium TB - Mycobacterium Leprae - Atypical & nontubercular mycobacterium
Definition of TB
- an infectious disease caused by the tubercle bacillus, Mycobacterium tb, and characterized pathologically by inflammatory infiltrations, formation of tubercles, caseation, necrosis, abscesses, fibrosis and calcification - most commonly affects the respiratory system
What type of stain do you use to dx TB
- Acid fast bacilli stain mycelia acid which makes up the wall of mycobacterium take up acid fast stain (wonβt show up in gram - or + stains)
TB epidemiology
- TB is one of worldβs deadliest disease: 1/3 of worldβs pop is infected with TB - each year over 9 mill people around the world are afflicted with TB - each year, almost 2 mill TB related deaths worldwide - TB is leading killer of individuals who have HIV -Incidences of TB in the U.S> has been decreasing. Increase in 1992 (18% increase compared to 1985) associated with HIV
Is the rate of TB declining in the U.S.?
- yes, the TB rate has been going down in U.S. each year since 1992 - the average annual % decline in the TB rate slowed from 6.6% for 1993 through 2002, to an avg decline of 3.4% for 2003 - 2008 - rate from 2013: 3.2%
Who accounts for most of the increase of TB cases?
- HIV patients account for 30-50% of increase - HIV is the greatest known RF for reactivating latent TB infection
Where has TB become prevalent?
- prevalent in populations co-infected with HIV and M. tuberculosis, such as inner city minority and injection drug users - in some inner city tb clinics: 40% of all pts with TB are infected with HIV - TB in foreign born individuals accounted for 53% of cases in 2004 (mexico, philippines, Vietnam, India and China)
4 possible outcomes of TB infection
- immediate clearance of the organism 2. chronic or latent infection (gets past initial immunity barriers into lungs) 3. Rapidly progressive disease (primary disease -> rapidly spreads throughout lungs, may spread to other organs) 4. Active disease many years after the infection (reactivation disease) may lay dormant for many years
Chronic (latent) infection
- person comes in with positive PPD but is asymptomatic with clear CXR - Person is infected but not infectious
Primary disease
- small bacilli carried in droplets small enough to reach alveolar space 2. If host system fails in clearing: - Bacilli proliferate inside alveolar macrophages and kill the cells - infected macrophages produce cytokines and chemokines that attract other phagocytic cells, including monocytes, other alveolar macrophages, and neutrophils, which eventually form a nodular granulomatous structure called the tubercle or Gohn focus - if the bacterial replication isnβt controlled, the tubercle enlarges and the bacilli enter the local draining lymph nodes, this leads to lymphadenopathy, a characteristic manifestation of primary TB - Caseation/fibrosis/calcification: ghon complex (caseation: necrosis of cells (look like cheese in middle of complex) - calcification is imp step in containing bacterium
steps of Primary disease infection
- bacilli reach alveolar space 2. proliferation inside macrophages 3. initial inflammatory granulomatous tubercle formation (if bacterial replication is controlled here, pt will not develop primary disease and is said to have chronic or latent infection) 4. Enlargement of tubercle and infiltration of lymph system (Gohn complex: describes an inflammatory nodule in the pulmonary parenchyma (Gohn focus) with an accompanying hilar adenopathy, in line with lymphatic drainage from the pulmonary segment
Symptomatic primary disease
- those who develop active disease w/in 2-3 years after infection - sever illness: lung necrosis, and extrapulmonary involvement
Main symptoms of pulmonary TB?
Central: appetite loss, and fatigue lungs: chest pain, coughing up blood, productive and prolonged cough Skin: night sweats, pallor (anemia from chronic disease)
steps of secondary/reactivation TB
- asymptomatic primary infection occurs 2. cell-mediated immunity: has contained the infection (neutrophils, macrophages -> gohn complex probably present) 3. dormancy 4. then, recurrence may occur
When does secondary/reactivation disease occur and what is it associated with?
- results when the persistent bacteria in a host suddenly proliferate (no longer contained b/c decreased immunity) - clearly assoc. with immunosuppression and can be seen in the following circumstances: HIV infection and AIDs end stage renal disease diabetes mellitus malignant lymphoma corticosteroid use * in contrast to primary disease: the disease process in reactivation TB tends to be localized, there is little regional lymph node involvement and the lesion typically occurs at the lung apices (where gohn lesion resided)
Signs and symptoms of secondary/reactivation of TB
cough, hemoptysis persistent fever/night sweats wt loss malaise adenopathy pleuritic chest pain
What is a Rasmussen aneurysm in TB?
- develops aneurysm and it ruptures
What is Miliary TB?
- if the bacterial growth continues to remain unchecked, the bacilli may spread hematogenously to produce disseminated TB - lung looks like it is covered with millet seeds -Miliary TB is used to denote all forms of progressive, widely disseminated hematogenous TB even if the classical pathologic or radiologic findings are absent
Acute and Chronic Miliary TB
Acute (primary infection) - high fevers, night sweats, Occ. Resp. distress, septic shock, multigrain failure - acute tend to be young Chronic: reactivation TB - fever, anorexia, wt loss, particularly in the elderly (FTT)
Extrapulmonary manifestations
- frequency is increasing - past hx is unreliable - 50% have normal chest radiographic findings - clinical features vary widely - most common type is infection of an individual organ system (bowel, bone, spleen, brain -> depends on where disease is expressed in the body) -in most cases, same regimens used for pulmonary TB are used systems that can be effected: - pleural/pericardial effusions (can lead to pericardial constriction) - lymph node infection: tuberculous lymphadenitis -> scrofula, seen in younger pts - kidney - skeletal: 35% -> potts disease - joints - CNS tuberculosis: meningitis, intracranial tuberculoma (mass lesion on the brain), spinal tuberclous arachnoiditis (similar to meningitis, arachnoid specific) intraabdominal TB: GI tract, peritoneum, renal TB, testicular granuloma - TB retinitis - muscles: (ex: psoas)
Dx of TB
dx in most cases are clinical - most persons dx w/ TB are begun on specific tx before dx is confirmed by the laboratory because it takes a long time to confirm dx - Around 15-20% of pts that are given a presumptive TB dx never have bacteriologic confirmation of disease
What can you say if person has positive PPD (mantoux)?
- has had exposure to TB infection
What kind of technique is used to examine sputum for TB?
- Ziehl neelsen test - takes a long time to culture mycobacterium
TB skin test?
- generally used as screening test, most sensitive test for dx of infection with mycobacterium TB - far more sensitive than a chest radiography - + TB skin test doesnβt by itself prove the presence of active disease but does indicate that infection has occurred - negative reactions have been doc. in 20% of pts who have TB - Primary use in detection of Latent TB infection - testing is targeted in persons at high risk for developing symptomatic TB who would benefit by tx of LTBI or those pts at increased risk for primary TB should they acquire infection - test is discouraged in those at low risk
Importance of TB skin test technique?
- must be done intradermally ( b/c confined area: protein derivative where T cells can get to) - Must form a visible wheal with injection (subcutaneous admin. will result in a false-neg. test if the pt indeed has been infected by TB)
How to read the TB skin test properly?
- must be read 48-72 hours (reaction is from delayed type hypersensitivity response mediated by T lymphocytes) - test is read by the diameter of the induration, not the diameter of the erythema - finger vs ballpoint pen method
Indicaions for TB skin testing?
- HIV infection - ongoing close contact with cases of active TB: health care workers prison guards mycobacterial lab personnel Presence of medical condition that increases risk of active TB: DM, steroid therapy, other immunosuppressive agents, certain types of malignancies, end stage renal disease, alcoholism, suppressed immune systems - medically underserved, low income population: homeless, injection drug users - residence in long term care facility: nursing homes, correctional institutions, mental institutions - single potential exposure to TB ( dx of TB of family member): repeat testing in 6-12 weeks if pt tested shortly after exposure - presence of incidentally discovered fibrotic lung lesion - immigrants and refugees from countries with high prevalence of TB
Sources of false-negative tests
- inadequate nutrition - anergy - nontubercular mycobacterium (bovus and avian) - simultaneous presence of immunosuppressive disorder - concurrent viral infection - corticosteroid therapy
Who would be considered for + TB skin test with induration > 5 mm
- HIV positive persons - recent contacts of TB case - fibrotic changes on chest radiograph consistent with old TB - pts with organ transplants and other immunosuppressed pts ( receiving >15 mg/d prednisone for > 1 month)
Who would be considered + for TB test with induration > 10 mm
- recent arrivals (10 %, gastrectomy, jejunolieal bypass - children
Who is considered + for TB with >15 mm induration?
- persons with no RFs for TB
+ TB skin test w/ BCG vaccine?
- children who received this vaccine generally demonstrate PPD reactions of 3-19 mm several months after vaccination - TB skin testing is not CI in BCG vaccinated persons: baseline testing should be done several months following vaccination - subsequent tests can be compared to baseline tests to eval. likelihood of true TB infection - responses indicative of new TB infection include: - increase in skin test reactivity > 10 mm induration in persons less than 35 yo - increases in reactivity of > 15 mm induration in persons greater than 35 yo * if baseline values unavailable: reactivity should be interpreted and tx as for unvaccinated persons
When should the sputum be evaluated?
- when active disease is suspected, there should be an exam of sputum for Acid Fast Bacilli staining and mycobacterium culturing - if pt unable to produce sputum spontaneously attempts should be made to induce sputum: hydration pulmonary physiotherapy mucolytic agents bronchoscopy or bronchoalveolar lavage * impt test: gold standard dx test: culture bacilli
Acid Fast Bacilli staining
- Mycobacterium have a cell envelope, unlike gram - bacteria, there is no true outer membrane in mycobacterium, the envelope is composed of a number of different macromolecules including mycolic acid - AFB smear: makes presumptive dx of TB in high risk pt - not specific for Mycobacterium TB (other acid-fast organisms will be positive such as mycobacterium avium and bonus) - 2 versions: fluorchrome staining: decreases exam time and increases sensitivity versus Ziehl-Neelsen method but is expensive Ziehl Neelsen method (older)
Mycobacterium culturing
- gold std of dx of TB - slow growth rate Solid media: lowenstein- Jensen or Middlebrook - takes up to 8 weeks or longer to detect growth Liquid media: expensive, broth formulations, more rapid and can detect growth of mycobacteria in clinical samples in as few as seven days
Other screening test for TB
- whole blood interferon gamma assay (Quantiferon-TB Gold test) - screening test for asymptomatic disease - T cells of individuals previously sensitized with TB AGs will produce interferon gamma when they reencounter mycobacterial AGs - 99% accurate reading - can be used in all circumstances in which PPD is used (have negative PPD and have been exposed)
Advantages of Quantiferon-TB gold test over skin test?
- subject to less testing error - subject to less reader bias and error - can be accomplished after a single pt visit - may not be as likely to be positive following BCG vaccination - The RD1 AGs used in this testing are not shared with most nontuberculous mycobacteria (bonus and avium)
Rapid nucleic acid assays?
-Can produce results within 2-7 hours after sputum processing - requires higher level labs - highly specific for Mycobacterium TB and is generally recommended on all AFB smear-positive respiratory specimens - + nucleic acid assay of AFB smear positive respiratory sample is dx of TB
Characteristics of mycobacterium
- rod shaped bacteria with lipid rich cell walls - they grow very slowly and take a long time to eradicate with antibacterials
TB management for latent infection
- 9 months of Isoniazid alt: Rifampin PO daily for 4 months
Tb management for reactivation TB disease
- requires at least 2 effective drugs b/c of increased incidence of drug resistance - Initial therapy of active TB include 4 drugs: - INH - RIF - Pyrazinamide (PZA) -Ehtambutol (EMB)
MOA of INH
- covalently binds to and inhibits enzymes essential for synthesis of mycolic acid * very specific to TB b/c of mycelia acid cell envelope - never used alone as resistant organisms will rapidly emerge AEs: hepatotoxicity: monitor liver enzymes - most common SE: peripheral neuritis which manifests as paresthesias and is assoc. with pyridoxine ( Vit B6) deficiency
MOA of Rifampin
- broader antimicrobial activity than INH - blocks transcription by interfering with the beta subunit of bacterial RNA polymerase - in add. to mycobacteria -> effective against many gram + and - bacteria (frequently used prophylactically for individuals exposed to meningitis caused by meningococci or H. influenzae - AEs: hepatotoxicity, liver enzymes inducer of cytochrome P450 enzymes and therefore the pt may need higher dosage requirements for other drugs metabolized by this system
MOA of Pyrazinamide
- unknown - only seen in anti tubercular combo packages - AE: extensively metabolized by liver, must watch for hepatotoxicity - gout
MOA of ethambutol (EMB)
- inhibits an enzyme important for the synthesis of the mycobacterial arabinogalactan cell wall - AEs: optic neuritis: results in diminished visual acuity and loss of ability to discriminate from red and green - eye exams regularly (every couple of weeks)
Alt. second line drugs for TB
- aminsalicylic acid - capreomycin - cylcoserine - ethionamide - fluoroquinolones* - macrolides* (used outside of TB tx)
Resistance to TB drugs
- multi drug resistance: Isoniazid and Rifampin Extremely drug resistance: use Isoniazid, Rifampin, a fluoroquinolone, and injectable (amino glycoside) - requires ID specialist - 18-24 months tx - surgery often required
Why are there pt compliance issues?
- b/c sxs are often gone w/in 2 months of initiating multi drug therapy yet the pt must continue therapy for 6 months - 2 years before organism is fully eradicated - TB occurs with a higher incidence in several pt populations that show higher noncompliance (injection drug users) -
What can help with compliance issues?
DOT therapy: directly observed therapy - trained health care worker or other designated individual (excluding family member) provides the prescribed TB drugs and watches pt swallow every dose - nurse or supervised outreach worker from county public health dept can provide DOT
Chemistry of bactericidal cell wall inhibitors?
Penicillins, cephalosporins, monolactams, and carbapenems all have b-lactam ring in the center. Some of these are inactivated if the ring is cleaved by B-lactamases. monolactams and carbapenems are are reisistant to B-lactamases
What is used with penicillins and cephalosporins to inhibit b-lactamases?
Clavulanic acid binds and inhibits B-lactamase. - augmentin is trade name for amoxicillin and clavulanic acid. - Timentin is trade name for ticarcillin and clavulanic acid.
What results in higher serum levels of penicillin?
probenicid, it acts by competing with penicillin for the organic anion transport system which is primary route of penicillin excretion β> results in higher levels of penicillin in the serum.
Mechanism of Penicillin G?
B-lactam binds PBPs and inhibits cross linking of bacterial cell wall components
Spectrum of Penicillin G?
Gram postive cocci -> strep and staph gram positive rods β> listeria and actinomyces gram neg cocci -> Neisseria most mouth anaerobes (clostridium) ***Not effective against gm - aerobes or B lactase producing organisms w/o conjugative therapy - penicillinase sensitive dosage forms: IM, IV, PCN VK: oral (poor bioavailability)
DOC for which pathogens?
nonresistant staph and strep, N. meningitidis, B. anthracis, C. tetani, C, perfingens, Listeria, syphillis
Pharmokinetics of Penicillin G?
IV/IM for Penicillin G PO for Pen V Eliminated by kidneys
Side Effects of Pen G and V?
Hypersensitivity reactions, rare neurologic toxicity (seizures), Neutropenia, nephrotoxicity
MOA of B-lactams?
bactericidal β> bind to PBPs and inhibit transpeptidation which stops cross linking of polysaccharides and cell wall is destroyed and bacterial cell dies.
Classes of B-lactam compounds?
Penicillins, Cephalosporins, and B-lactamase inhibitors combined with PCNβs
Penicillin classifcation
Penicillin G Antistaphlococcal PCNs: nafcillin, dicloxacillin, oxacillin, cloxacillin Broad spectrum PCNs: 2nd generation: ampicillin, amoxicillin 3rd generation: carbenicillin, ticarcillin 4th generation: piperacillin
Combos with b-lactamase inhibitors
amoxacillin/potassium clavulanate= augmentin (PO) ampicillin/sublactam=unasyn (IV) Ticarcillin/potassium clavulanate= timentin Piperacillin/tazobactam sodium= zosyn (sepsis)
General points of PCNs
All PCNβs should be given on an empty stomach except oral amoxicillin Allergic rxns to one PCN are cross reactive to others, reactions can be urticarial to anaphylaxis to serum sickness All abs can cause C. diff colitis
PCN G benzathine and PCN G procraine
IM forms: 1 injection lasts 10-12 days used for strep and sometimes syphillis, gonorrhea now is resistant IV form: meningitis and endocarditis
Usual dosage of PCN G
1-24 million units/day every 4-6 hours erysipelas: IV 1-2 million units q 4-6 hours x 7-10 days neurosyphilis: IV 18-24 million units q 4-6 hours x 10-14 days
Penicillin G safety
Preg Cat: B -> presumed safe lactation: safe Renal dosing: adj for creatine clearance adjust`
Adverse Reactions of PCN G
local: site reaction significant reactions: CNS -> coma, seizure hematologic and oncologic: neutropenia, positive direct coombs test Hypersensitivity: anaphylaxis, reaction, serum sickness Renal: acute interstitial nephritis, renal tubular disease
Drug interactions of Penicillin G
BCG: used for TB - abx may diminish therapeutic effect of vaccine methotrexate: PCNs may increase serum conc of metho Probenecid: may increase serum conc of PCN Tetracycline derivatives: may diminish effect of PCNs Vit K antagonists (warfarin) - PCNs may enhance effect of Vit K antagonists -> monitor INR OBCPs: pen may decrease OBCP efficacy
Penicillin VK
oral form -> 250-500 mg TID-QID DOC for strep pharyngitis AEβs: GI -> N/V/D acute nephritis, convulsions, hemolytic anemia, positive coombs reaction
Antistaphyloccocal PCNs activity
activity: semisynth PCNs used for infection with B-lactamase producing staph, also used against PCN susceptible strep and pneumococci **inactive against enterococci and methicillin resistant strains
Antistaphylococcal PCNs - drugs
Dicloxacillin, oxacillin and nafcillin (not affected by beta-lactamase enzyme)
Dosage forms of Antistaph PCNs
dicloxacillin: PO Oxacillin: IM, IV Nafcillin: IV
Antistaph PCNs safety
Preg Cat: B lactation: unknown No dosage adj needed for renal or hepatic disease
Adverse effects of Antistaph PCNs
GI (dicloxacillin)-> Nausea, diarrhea, abdominal pain agranulocytosis, eosinophilia, hemolytic anemia, hepatotoxicity
Antistaph drug interactions
Aripiprazole: PCN may decrease concentration Ca channel blockers: Nafcillin may increase metabolism contraceptives: Nafcillin may increase metabolism of estrogens BCG: may diminish effects of BCG Methotrexate: may increase serum concentrations Probenecid: may increase PCN serum concentration Warfarin: may diminish effect
Broad spectrum PCNS
2nd gen: ampicillin, amoxicillin 3rd gen: carbenicillin, ticarcillin 4th gen: piperacillin
2nd gen PCNs uses
cover same as PCN G also E. coli, proteus marabilis, Salmonella, Shigella and H. influenzae, Amox is better absorbed uses: otitis, sinusitis, lower RTI Amox combined with clay acid will expand coverage to gm +, gm - and anaerobic organisms
Safety of 2nd gen PCNs
Preg Cat: B, Lacation: safe Renal dosing: adjust if CrCl
Adverse effects of 2nd gen PCNs
CNS: agitation, anxiety, confusion, seizure Hematologic: agranulocytosis, anemia, eosinophilia, hemo anemia Renal: crystalluria
What will occur if 2nd gen PCN taken while infected with mono?
high % of patients have developed rash during therapy, donβt use in these patients
Drug interactions of 2nd gen PCNs
Allopurinol: may enhance risk of hypersensitivity rxn of PCN BCG: diminish effect of BCG methotrexate: may increase metho coc tetracycline: may diminish effects of PCNs Warfarin: PCNs may enhance effect OCPs: PCNs may decrease efficacy
3rd generation PCNS, activity
carbenicillin and ticarcillin activity: strep, enteric gram-neg bacilli (e. coli, klebsiella, pneumoniae, enterobacter cloacea, enterobacter aerogenes and proteus miriabilis), pseudomonas, and anaerobes - IV only: std therapy as anti-pseudomonal med in hosp.
Piperacillin spectrum
derivative of ampicillin, covers same spectrum as 3rd generation, but more active against Klebsiella, enterococci and bacteroides **piperacillin w/ tazobacatm (zosyn): broad spectrum, used for cellulitis, postpartem endometritis, peritonitis, comm-acquired pneumonia, nosocomial pneumonia
Good to know about PCNs
can cause bleeding problems can cause nephritis IN high doses can cause near complications and seizures - common to see secondary infections such as vaginal candidiasis
B-lactamase inhibitors
clavulanic acid, sublactam, tazobactam activity: inhibitors of many bacterial b-lactamases, inactivate ahminoglycosides Use: only in comb with PCN -> PCN determines spectrum: -intra-abdominal/gynecological infections -skin and soft tissue infections RTI, sinusitis, and lung abcesses -Donβt have any antimicrobial activity by themselves.
Cephalosporins
as they progress from 1st to 3rd generation they increase in gm - coverage and lose gram positive coverage. - well absorbed from GI tract, and food enhances absorption. - allergic reactions are similar to PCNs (3-10% cross-reactivity)
Cephalosporins susceptibility to B-lactamases
are susceptible to B-lactamases and they have similar SEβs as penicillin.
Most common 1st, 2nd and 3rd generation cephalosporins?
1st: cephalexin (keflex), 2nd: cefaclor (ceclor), 3rd: cefixime (suprax)
1st gen cephalosporins
cefadroxil=oldest, cephalexin= keflex cefazolin= Ancef (IV) activity: good against gram +: strep and staph (not MRSA), some gram -, good against anaerobic cocci SE: GI, allergic reactions, C. diff
Use of 1st gen cephalosporins
cephalexin: uncomplicated cellulitis cefazolin: more complicated cellulitis or IV prophylaxis prior to surgery
2nd gen cephalosporins
cefaclor PO (more susceptible b-lactamase hydrolysis, not as useful), cefuroxime; IV, cefoxitin IV, cefotetan IV activity: gram +, better gram - against klebsiellae, H. influenza, none against pseudomonas
Uses for 2nd gen cephalosporins
cefuroxime: sinusitis, otitis, RTI, comm acquired pneumonia (H. flu, K. pneumonia, and penicillin resistant pneumococci). cefoxitin: anaerobic activity- prophylactic GI surgeries, peritonitis, and diverticulitis (active against gm - rods)
3rd gen cephalosporins
cefotaxime IV, ceftazidime IV, ceftriaxone activity: expanded gram - against meningicoccus, citrobacter, b-lactamase strains of homophiles and neisseria ceftazidime- active against pseudomonas cefotaxime and ceftriaxone: cross blood/brain barrier
Use of 3rd gen cephalosporins
ceftriaxone and ceftotaxime: meningitis empirical therapy for serious infections -> effective against PCN resistant strains pnemonococci ceftriaxone: used to tx gonorrhea, lyme disease SE: rash, N/V, LFTs, eosinophilia, HA
4th gen cephalosporins
cefepime IV activity: gram + and -, including pseudomonas, staph aureus, strep pneuma, Haemphilus and Neisseria
4th gen cephalosporin use
penetrates BBB well -> meningitis, other serious infections and sepsis sometimes used with amino glycoside w/ tx pseudomonas SE: N/V/D, HA, rash
Cephalosporins points
1st gen: cephalexin and cefazolin still used a lot 2nd gen: tx otitis, sinusitis, and RTI (Ceftin) 3rd and 4th: DOC for gram - meningitis, good alt to aminogly. need to watch for resistance strains -> combo therapy good for pseudomonas, Ceftriaxone: DOC for gonorrhea Ceftazidime: effective for pseudomonas meningitis
Carbapenems
Imipenem/cilastatin - better coverage than meropenem (IV( activity: very resistant to cleavage (b-lactamase), effective against gram + (enterococcus faecalis, and listeria), gram - (H influenza, N gonorrhoaea, enterobacter, and pseudomonas), anaerobes (bactericides)
Carbapenem uses
meropenem= meningitis, intra-abdominal infections, resistant UTIs, pseudomonas, and w/ or w/o aminoglyc for neutropenic pt SE: N/V/D, rashes, imipenem: renal failure and seizures
What is the breakpoint?
The concentration of antibiotic that can be achieved in a clinical setting If the bacteria can divide at a concentration at or higher than the breakpoint, it is deemed resistant
Name some major antibiotic resistant Gram-negative bacterial pathogens.
Pseudomonas aeruginosa Klebsiella Salmonella Acinetobacter baumanii Neisseria gonorrheae
Name some major antibiotic resistant Gram-positive bacterial pathogens.
Staphylococcus aureus (MRSA) Streptococcus pneumoniae Clostridium dificile Enterococcus spp. Mycobacterium tuberculosis
Name 7 types of antibiotic.
Beta-lactams Aminoglycosides Chloramphenicol Tetracycline Quinolones Sulphonamides Macrolides
How do beta-lactams work? Give some examples.
Penicillin and Methicillin They have a beta-lactam ring that is a similar shape to a precursor of peptidoglycan in the bacterial cell wall and hence interferes with the synthesis of the cell wall
How do quinolones work?
Quinolones inhibit the functioning of DNA gyrase (Gram-negative) and topoisomerase (Gram-positive) hence hampering the unravelling of DNA during replication
How do macrolides work? Give an example.
Only Gram-positive infections Targets the 50S ribosomal subunit and prevents the peptidyl transfer step Erythromycin
How do aminoglycosides work? Give some examples.
Aminoglycosides affect RNA proofreading leading to misfolded proteins Some of these proteins get incorporated into the membrane and cause leakage Gentamycin and Streptomycin
How do sulphonamides work?
Inhibits the folate pathway
How does tetracycline work?
Prevents charged amino-acyl tRNAs from binding to the mRNA/ribosome complex
How does chloramphenicol work?
Inhibits the peptidyl transfer step Binds to the 50S subunit
What are the four main mechanisms of antibiotic resistance?
Altered target site Inactivation of antibiotic Altered metabolism Decreased drug accumulation
Gram Positive coverage
nafcillin (IV) and dicloxacillin (PO) provide excellent coverage and are not destroyed by penicillinases (beta- lactamases) 1st gen Cephalosporins (cephalexin and cefazolin) are effective against most skin infections
Gram Negative coverage
3rd generation Cephalosporins are good, and not destroyed by cephalosporinases. They also penetrate CNS Cephalosporins and penicillins may enhance the activity of aminoglycosides against Gram - neg. Combo of Amp and Gent provides good coverage of both positive and negatives. Trimethoprim-sulfamethoxazole (Bactrim/Septra) is active against most UTIβs. Amoxicillin is used for otitis media and other bact. URIβs
Pseudomonas coverage
Ticarcillin or ceftazidime cover most Gm neg including Pseudomonas but fail to tx some Gram positive Imipenem and meropenem good against pseudomonas
Anaerobic coverage
Metronidazole or clindamycin cover most mouth anaerobes are adequately coverage by penicillin
Mycoplasma coverage
Macrolides (erythro, clarithro, azithro) tx mycoplasma pneumonia along with other organisms that cause community acquired pneumonia
Systemic fungi coverage
Amphotericin is DOC for fungemia. (only for use in severe systemic infections)
Bactericidal
abx that kill bacteria
Bacteriostatic
only inhibit bacterial proliferation while hostβs immune system does the killing. (not very effective in immunocompromised patients: cancer, HIV, diabetes, or in overwhelming infections).
Gram positive cocci: the basics
Have developed resistance to basic penicillins and some specialized penicillins Have a peptidoglycan cell wall that surrounds bacteria, makes the cell impermeable (unlike gm -), Will stain blue Effective tx: penicillins, cephalosporins, bacitracin, vanco, and cycloserine inhibit the synthesis of the peptidoglycan cell wall.
Examples of Gram positive cocci
staph aureus and staph epidermidis: inhabit skin, most likely to infect wounds, surgical sites, and indwelling catheters Strep pneumo is often cause of community-acquired pneumonia and adult bact. meningitis Strep throat is caused by Group A beta-hemolytic Streptococcus (if left untx β> cause rheumatic fever)
Anaerobes basics
common anaerobes: Bacteroides fragile, C. diff, and Fusobacterium. C. botulinum and C. tetani produce toxins responsible for botulism and tetanus. Metronidazole, chloramphenicol or clindamycin are effective against anaerobic infections Appearance: mixed gm + and - compost of most anaerobic infections. Frequently are encased in abcess wall.
Common sites of anaerobic invasion
mouth, GI, and skin infections occur when anaerobes penetrate poorly oxygenated tissues (diabetic foot) or tissues that are normally sterile (peritoneum). C. diff flourishes in bowel when broad spectrum abx diminish normal flora. C. diff proliferates and releases a toxin that causes pseudomembranous colitis
4 groups of gram negative pathogens
- enterics, organism that normally inhabit GI (escherichia, shigella, salmonella, klebsiella, enterobacter, Serrate, proteus). 2. H. influenzae 3. Neisseria 4. Pseudomonas
Appearance of gm - cells
Enterics and H. influenzae are red and elongated Plasma membrane is protected by an adjacent rigid peptidoglycan cell wall which is encased by an outer membrane. This membrane is made of lipopolysaccharides interrupted by transmembrane protein pores (which prohibit entry of most penicillins and cephalosporins).
Are penicillins good tx for gm - bacteria?
Depends, penicillins must first penetrate outer membrane in order to act on inner cell wall. Broad spectrum penicillins and 3rd gen cephalosporins are more hydrophilic and able to get through pores but even so some strains are resistant to penicillins b/c they produce B-lactamases that are concentrated in space between outer membrane and cell wall. Neisseria meningitides and N. gonorrhea are the only gm - that are susceptible to penicillin G and other narrow spectrum penicillins. *ceftriaxone is DOC for N. gonorrhea due to resistant penicillin strains
Common sites of gm - infections?
Enterics responsible for UTIs and aspiration pneumonia N. gonorrhea is responsible for sexually transmitted gonorrhea N. menigitides and H. influenzae both cause meningitis H. influenza causes pneumonia more commonly in the elderly Pseudomonas aeruginosa is sometimes responsible for hospital acquired infections.
3 primary ways to classify antimicrobial drugs
-susceptible organism -MOA -drug inhibits bacterial growth (bacteriostatic), or if it is lethal to cells (bacteriocidal)
Narrow vs. broad spectrum
narrow: active only against few microorganisms broad: active against a wide variety
MOAs
Disruption of bacterial cell wall: penicillins, cephalosporins -> act to weaken cell wall and thereby promote cell lysis inhibition of enzyme: sulfonamide drugs suppress bacterial growth by inhibiting enzyme required to produce folic acid from PABA. Disruption of bacterial protein synthesis: disrupt function of bacterial ribosomes Inhibition of bacterial nucleic acid synthesis
Inhibitors of cell wall synthesis
B-lactam abx: penicilllins, cephalosporins, carbapenems, monobactams - clavulanic acid, sulbactam, taxobactam
Protein synthesis inhibitors: 30s subunit
Aminoglycosides: gentamicin, tobramycin, amikacin Tetracyclines: tetracycline, doxycycline, minocycline
Protein synthesis inhibitors: 50s subunit
macrolides: erythromycin, clarithromycin, azithromycin others: chloramphenicol, clindamycin, linezolid, streptogramins
DNA synthesis inhibitors
Fluoroquinolones: cipro, oflaxacin, norfloxacin, levofloxacin, gatiflocacin, moxifloxacin Metronidazole
RNA synthesis inhibitors
Rifampin
Mycelia acid synthesis inhibitors
isoniazid
Folic acid synthesis inhibitors
sulfonamides, trimethoprim
Function of normal flora
GI tract: aids in digestion mucous membranes: mucosal immunity in general: protects host from colonization with pathogenic microbes
What are opportunistic pathogens?
cause disease when immune defenses are altered, when they change their usual anatomic location -the blood, brain, muscle and CSF are normally free of flora
Normal flora of the oral cavity
streptococci viridans Lactobacilli Staph (aureus and epidermidis) corynebacterium sp. bacteroides sp. streptococcus sanguis streptococcus mutans actinomyces sp.
Normal flora of the nose
staphylococcus epidermidis corynebacteria staph aureus Neisseria sp.* Haemphilus sp* strep pneumoniae*
Normal flora of the nasopharynx
non-hemolytic strep alpha-hemolytic strep Neisseria sp. strep pneumoniae strep pyogenes H. influenzae Neisseria meningitidis
Normal flora of lower resp. tract
usually sterile individual becomes infected by the pathogen descending from the nasopharynx (H. influenzae, and S. pneumoniae)
Normal flora of external ear
staph epidermidis staph aureus corynebacterium sp.
Normal flora of GI tract
Enterobacteriaceae enterococci bacteroides staph lactobacilli clostridia
Normal flora of GU tract
staph epidermidis enterococcus faeccalis Alpha-hemolytic strep E coli proteus corynebaceria sp. acinetobacter sp. mycoplasma sp. candida sp mycobacterium smegmatis
Normal vaginal flora
corynebacterium sp. staph nonpyogenic strep (Group B) E coli lactobaciluus acidophilus flavobacterium sp. clostridium sp. viridans strep other enterobacteria
causative organisms of endocarditis and tx
native valve: sterp viridans -> Pen G or Amp+Nafcillin IV drug user: MSSA, MRSA -> vanco Prosthetic valve: S. epi, S. aureus, S. viridans -> vanco+rifampin+gentamicin
causative organisms of intra-abdominal infections
Diverticulitis, perirectal abscess, peritonitis-> E. coli, p. aeruginosa, enterococci tx: TMP-SMX-DS or cipro, or levofloxacin+ metronidazole (outpt)
Skin and soft tissue causative agents
gen. cellulits: staph aureus, strep-> MSSA: cephalexin, MRSA: TMP-SMX-DS or clindamycin strep: cephalexin diabetic ulcer: staph, strep or pyogenes-> Doxy or TMP-SMX-DS or clindamycin Animal bites -> cat: amox-clav (augmentin) Necrotizing fasciitis: GABS, C. perfringens -> PCN G, cefoxitin, chloramphenicol, clindamycin, metronidazole
Urinary tract causative agents
E. coli, gram - aerobic bacilli, enterococcus, staph saprophyticus -> TMP-SMX-DS if resistance is >20% to TMP -> use cipro, levo, moxi
Respiratory tract infections (pneumonias)
Aspiration pneumonia: anaerobic or aerobic -> clindamycin or ampicillin-sulbactam or A carbapenem Lower/hosp acquired: pseudomonas aeruginosa, gram - aerobic bacilli -> imipenem -cilastatin or meropenem + cipro if suspect pseudo Hx of HIV: pneuomocystis carinii, S. pneumoniae -> Trimethoprim-sulfamethoxazole (Bactrim, Septra)
Respiratory tract causative agents
sinusitis: S. pneumo, H. influenzae, M. catarrhalis, S. auerus, Grp A strep β> peds: amox or amox-clav, pcn allergy: clinda adult: amox-clav, pcn allergy: levo or doxy Community acquired pneumonia: all same as sinusitis plus klebsiella, mycoplasma, chlaymdia -> azithro, clarithro, doxycycline
meningitis in kids
child ampicillin + gentamicin child 2 months - 12 years: strep pneuma, N. meningitis, H. influenza -> vanco + cerfriaxone
Meningitis
1 mo -> 50 years: S. pneumoniae, meningococci: cefotaxime or ceftriaxone+ vanco amp+cefotaxime or gentamycin
Prophylactic antibiotics b/f surgery
should be admin. before surgery begins via IV -often used to irrigate surgical site as well - Cefazolon (Ancef) 30 minutes before incision for pcn allergies: use vanco
who is at risk at developing endocarditis?
prosthetic heart valves congenital heart disease
prophylaxis for endocarditis
30-60 minutes prior to dental procedures: amoxicillin 2 gm PO if PCN allergy: clinda, azithro, clarithro
Complications of antibiotic therapy
toxicity C. diff alt of gut flora and change of Vit K levels leading to difficulty managing warfarin therapy candida overgrowth serious side effects
C diff diarrhea
can be life threatening, sever inflammation of colon, may lead to colectomy, highly contagious
Drugs most likely to cause C. diff
Most frequent: Ampicillin/amoxicillin cephalosporins clindamycin quinolones
Fluoroquinolones
ciprofolxacin* levofloxacin* moxifloxacin* gemifloxacin norfloxacin oflaxacin
Distribution of Fluoroquinolones
-good tissue and fluids distribution except CNS -all undergo renal elimination except moxifloxacin -Half lives range from 4-12 hours (allows for 1/day dosing)
MOA of fluoroquinolones
bactericidal - inhibit DNA gyrase and topoisomerase necessary for replication of bacteria
Spectrum of fluoroquinolones
Aerobic gram neg: all fluoroquinolones Pseudomonas Aeroginosa: cipro or levofloxacin Gram + (including Strep pneumonia): levofloxacin, moxifloxacin, and gemfloxacin Anaerobic: moxifloxacin
Clinical uses of fluorquinolones
Urinary tract= DOC -> cipro -pneumonia -STIs -skin and soft tissue (not first line) -GI infections -Travelerβs diarrhea -osteomyelitis (good penetration into bone)
What FQβs are active against gram + respiratory infections (Strep)?
Levofloxacin, moxifloxacin, and gemifloxacin
Black box warning of fluorquinolones?
associated with an increased risk of tendinitis and tendon ruptures in all ages, risk is increased in older patients usually over 60 you, in patients taking corticosteroids, and pts with kidney, hearth or lung transplants
SEβs of FQβs
N/D, dizziness, confusion, tendon rupture, QT prolongation (ventricular tachycardia= death) tendonitis -> RF for rupture, peripheral neuropathy (on long term therapy)
Drug interactions of FQβs
- ciprofloxacin potent inhibitor of CYP4501A2 -> theophylline, warfarin, tizanidine, propranolol -antacids, sucrlafate, magnesium, calcium, iron all decrease the absorption of FQs -corticosteroids increase risk of tendon ruptures
When would you not have to adjust dose for renal failure pts on FQs?
if they are on moxifloxacin
Do FQβs cover pseudomonas?
Yes, contains the only oral agents against pseudomonas
CI of FQs
not for use in pregnancy or children -> in pregnancy and lactation= exposure to infant (crosses placental barrier) in peds= arthropathy and osteochondrosis - caution when using in hepatic dysfunction
Sulfonamides
sulfamethoxazole/Trimethoprim (SMX-TMP) (Bactrim DS, Septra)
Distribution of Sulfonamides
oral med with good distribution to all body tissues and fluids -> CSF, pleural fluid, synovial fluid -eliminated through liver and kidneys
MOA of sulfonamides
Folic acid synthesis inhibitors: Bacteria need to produce folic acid to survive -> SMX inhibits dihydropteroate syntheses and TMP inhibits dihydrofolate reductase
Clinical uses of sulfonamides?
UTIs PCP (pneumonia seen in immunocompromised pts) toxoplasmosis Gram + and - infections MRSA (have resistance to strep pneumo)
SEβs of sulfonamides?
**Rash (very obvious it is sulfa related), fever, N/V/D, SJS (shed skin), vasculitis, hemolytic anemia if underlying G6PD deficiency, thrombocytopenia
Stevens-Johnson syndrome?
cell death causes the dermis and epidermis to separate -hypersensitivity reaction of skin and mucous membranes
Drug interactions of sulfonamides
up to 70% protein bound -> displaced other drugs potentiates the effects of: warfarin, phenytoin, hypoglycemic agents, methotrexate(folic acid inhibitor -> together could cause folic def) B blockers: increase activity -> severe bradycardia
Metabolism of sulfonamides
metabolized in liver excreted renally -reduce dose by 50% if CrCl 15-30 not recommended if CrCl
Why are sulfonamides CI at end term of pregnancy?
due to development of kernicterus in infants (bilirubin induced brain dysfunction b/c of hemolytic anemia leads to increased bilirubin)
Sulfonamides allergy?
donβt use with a sulfa allergy
Nitrofurantoin (Macrobid)
only for treatment and prevention of uncomplicated UTIs PO
Metabolism of Macrobid
rabidly absorbed and only in serum for 30 minutes -cleared renally and concentrated in urine -inadequate drug levels in bladder if CrCl abnormal (GFR
MOA of macrobid
thought to disrupt bacterial cell wall synthesis through inhibition of bacterial enzymes
Macro bids are effective against what organisms?
E. coli Citrobacter Staph saprophyticus enterococus faecalis enterococcus faecium -some emerging resistance against enterobacter and Klebsiella
SEβs of Macrobid
Most common: N/V pulmonary reactions: pulmonary infiltrates, pneumonitis, pulmonary fibrosis Hepatic effects (rare): hepatitis, hepatic necrosis peripheral neuropathy in long term use in patients with renal failure
Pulmonary reactions in macrobid use?
-acute pulmonary reactions usually manifested by sudden, severe dyspnea, chills, chest pain, fever, and cough -pulmonary infiltration with consolidation or pleural effusion on radiographs and eosinophilia also may occur - usually evident within first week of tx and reversible when drug d/c -Resolution is often dramatic
Drug interactions of Macrobids
No significant drug interactions because it isnβt in plasma for more than 30 minutes -> urinary tract
Safety of macrobids
pregnancy: category B But CI at term due to possibility of causing hemolytic anemia in newborn -dont use in lactation -safety and efficacy not established in children
Who should avoid using macrobids?
avoid use in older adults, avoid using for long term suppression of infection
Anti-anerobic med?
Metronidazole (flagyl)
Metabolism of flagyl?
metabolized by the liver -adjust dose with hx of liver failure -absorbed well PO -good tissue penetration in most locations -Half life 6-9 hours
MOA of flagyl
inhibitor of bacterial protein synthesis -> causes DNA strand breakage therefore inhibiting bacterial protein synthesis
Spectrum of Flagyl
good against gram + and - anaerobes Helicobacter pylori Trichomonas vaginalis (STI in men and women)
flagyl is DOC for?
Anerobic infections bacterial vaginosis trichomoniasis C. diff diarrhea
formulations of flagyl?
oral, IV, topical (roseacea), intravaginal
Black box warning for flagyl
metronidazole has been shown to be carcinogenic in mice and rats. Unnecessary use of drug should be avoided.
SEβs of flagyl?
most common: N/V, abdominal pain and metallic taste -seizures (high doses), -peripheral neuropathy (prolonged courses) -pancreatitis
Drug interactions of flagyl?
enhances anticoag effects of warfarin -alcohol: flushing, palpitations, nausea, vomiting -inhibitor of CYP34A so potential for many drug interactions -phenobarbital, phenytoin, rifampin: all increase metabolism of metronidazole which decreases the serum concentration and may lead to tx failure
Signs and Sxs of Pneumocystis Carinii Pneumonia
β most common opportunistic infection assoc. with AIDS (very rarely does it occur outside of immunocompromised pts) -fever, cough, SOB (hypoxia: w/o PO2
Dx of PCP
- CXR: cornerstone of dx see diffuse or perihelia infiltrates -Wright-Giemsa stain or direct fluorescence AB (DNA) test on induced sputum - bronchoalveolar lavage - Elevated lactase dehydrogenase (LDH): occurs in 95% of cases
Risk of getting PCP?
- CD4
Prophylaxis of PCP
- continued until CD4 count is above levels used to initiate tx - hx of infection: continue until they have had a durable virologic response to HAART for at least 3-6 months and maintain CD4 count >250
Complications of PCP
- increased incidence of pneumothorax, especially with hx of PCP and tx with aerosolized pentamidine
MAC (mycobacterium Avian complex) - what it is and dx
- R/O disseminated first if symptomatic - meningeal involvement is most common form of disseminated disease dx: blood cultures will be positive if disseminated
Signs and sxs of MAC
- spiking fevers - night sweats - diarrhea - wt loss - wasting - anemia and neutropenia - meningeal signs
Risk of MAC occurs?
- when CD4 is less than 50
Prophylaxis for MAC
- should be initiated with CD4
Kaposiβs sarcoma background
- Moritz Kaposi: 1872 - 4 subtypes - classic K.S. - middle aged men of mediterranean descent - African endemic K.S. - in iatrogenically immunosupressed pts - AIDS related K.S.(most common form seen in U.S.)
What will lesions look like and where will they appear in K.S.
- may appear anywhere: most often on face and legs, palate, eyelids, conjunctiva, pinnae, toe webs - look purplish, will be NONBLANCHING, may be papular or nodular, appear more brown in dark skinned people, they are not painful
Kaposiβs sarcoma -> visceral disease
- Dermatological Kaposiβs isnβt life threatening - but may progress to visceral disease in about 40% of patients with derm. K.S., thus becoming life-threatening.
Signs and Symptoms of KS of intestinal tract
- abdominal pain - diarrhea - intestinal obstruction
Signs of KS of lymph system
-swelling of arms or legs
KS of the Lungs
- cough, chest pain, SOB, difficulty breathing, extremity swelling, pulmonary blockage (alveoli or vascular system in lungs)
Can KS be tx?
- w/ contained skin lesions, tx may not be necessary. Lesions that involve large areas of skin or internal organs, tx is recommended. Tx include: topical meds, surgical removal, freezing with liquid nitrogen, chemo drugs
What has been proven to shrink KS lesions in advanced cases where it has affected internal organs? What adverse effects does this have?
- chemotherapy has proven effective - unpleasant SEs as N/V and hair loss - drugs can have damaging affects on the heart and bone marrow, resulting in decrease in number of white blood cells, furthering the risk of acquiring opportunistic infections
What are liposomal drugs?
Daunoxome (liposomal form of Daunorubicin) -> tx KS - these are similar to chemo drugs with one exception: they are encased in microscopic fat bubbles which seem to lessen adverse SEs - studies have shown that these forms of drugs last longer and are able to move to the KS affected areas better.
What is cryptococcus neoformans? signs and sxs?
- most common life-threatening fungal infection in AIDS -> meningitis - signs and sxs: meningitis/ subtle sxs: fever,, HA, malaise
Dx and Tx of cryptococcus neoformans
- latex agglutination serum/CSF testing for AG (CRAG) Tx: amphotericin B (Fungizone, Amphocin) prophylaxis: fluconazole (Diflucan)
Cryptosporidiosis (Crypto)
- diarrheal disease caused by microscopic parasite Cryptosporidium - can live in the intestine of humans and animals and passed in the stool - Protected by an outer shell that protects it: allows it to survive outside of the body for extended periods, makes it very resistant to chlorine-based disinfectants - one of the most common causes of waterborne diseases in humans in the US - Parasite is found in every region of US and throughout the world. - ** Generally only affects immunocompromised pts
Sxs of Crypto
- most common: watery diarrhea -stomach cramps, dehydration, N/V, fever, wt loss - some pts asymptomatic - small intestine is most commonly infected - sxs begin 2-10 days following infection - non-immunocompromised sxs last 1-2 weeks - HIV pts w/ CD4 200: 2-4 weeks, however, may remain in carrier state and give to others or infect self if CD4 count drops
Pathogenesis of crypto parasites
- millions of crypto parasites are released in each BM from infected pts: transmission through fecal oral route, swimming or bathing in contaminated water, drinking contaminated water (most filtration systems donβt filter crypto spores)
Dx of crypto
- stool specimens for cryptosporidium - specifically ask for the test (not done on routine O&P on stools) - Acid fast staining, direct fluorescent Ab (DFA), or enzyme immunoassays
Tx of crypto
- no approved tx for HIV+ pts, if CD-4 count can be improved, they may have remission but no cure
CMV signs and sxs
- most common retinal infection in AIDS pts - signs: perivascular hemorrhages sxs: usually a painless loss of vision, often unilateral, blurred vision, floaters
Tx of CMV retinitis
- ganciclovir (cytovene) given in 2 phases: induction and maintenance, due to high relapse rates - alt: foscarnet (Foscavir): less likely to cause neutropenia, but has many other possible AEs
GI manifestations in AIDS
- candidal esophagitis: very common in HIV pts, suggestive sxs are tx and only non-responsive pts are give endoscopy - Hepatic disease: autopsy shows that liver is very frequent site for disease/neoplasms, many of these are subclinical, co-infection with Hep B and C is common, low level hepatic disease may be cause for persistent N/V - Biliary Disease: acalculous cholecystitis with sclerosing cholangitis
Esophageal candidiasis Signs and sxs
- is an AIDS defining illness, as opposed to oral candidiasis. occurring in individuals with CD4 counts less than 100
Dx of esophageal candidiasis
- a presumptive dx can usually be made with a recent onset of dysphagia, especially in the presence of thrush, and empiric anti fungal therapy may be started - if pt fails to improve clinically after 3-7 days of therapy, an endoscopy should be performed for a definitive dx - endoscopy reveals: classiv diffuse raised plaques that characteristically can be removed from mucosa by the endoscope. - brushing or bx of the plaques show hyphae that are characteristic of Candida species.
Tx of esophageal candidiasis
- fluconazole 200 mg as initial dose, then 100 mg by mouth once daily for 14 days, IV therapy can be given to pt if pt is unable to swallow pills. - alt (less effective) txs include itraconazole capsules 200 mg once daily or ketoconazole 200 mg once daily for 14 days
Acute (Primary HIV) period: Window phase
- its the time between infection and detectable HIV abs (before 25 days)
Acute (primary HIV) period: Eclipse phase
- time between infection and detectable HIV RNA (0-10 days)
Acute (primary HIV) period: acute illness phase
- symptomatic disease: often precedes positive AB test (b/t day 15 and day 25), when HIV RNA peaks
What are the three best-known external factors that influence cell division?
Growth factor Cell-cell adhesion ECM-cell adhesion
Describe what happens to a cell when it is placed on a culture medium
It will begin to settle and spread across the surface It will gain some sort of polarity It will become motile NOTE: this is an active process, it is not just happening because of gravity. Energy is required to modulate cell adhesion and changes inthe cytoskeleton during spreading
Describe what happens to cells placed on: a. Non-adhesive agar b. Small adhesive patch c. Large adhesive patch
a. Non-adhesive agar Very few cells enter S phase b. Small adhesive patch A small proportion of cells will proliferation c. Large adhesive patch Almost all the cells will start proliferating
What is the difference in proliferation when a cell is placed on: a. A small patch of fibronectin b. The same amount of fibronectin spread over a larger area
a. A small patch of fibronectin The cell can stick but it canβt spread so it will probably die via apoptosis b. The same amount of fibronectin spread over a larger area The cell is able to stick AND spread so it will survive and grow NOTE: this shows that adhesion AND spreading is important for cell survival and proliferation
Cells need to be attached to ECM and they need a certain degree of spreading to be able to respond to soluble growth factors. What is the term given to the requirement of ECM binding for growth?
Anchorage dependence
Describe the structure of integrins.
There are heterodimer complexes of alpha and beta subunits They associate extracellularly via their head and each of the tail regions spans the plasma membrane
How many different alpha and beta subunits are there?
10 alpha and 8 beta There are over 20 known combinations
What do the extracellular parts of integrins bind to?
Short, specific peptide sequences (e.g. arg-gly-asp (RGD sequence))
What do most integrins bind to intracellularly?
Actin cytoskeleton
What is an exception to this generalisation?
The alpha6beta4 integrin is found in hemidesmosomes in epithelia and it binds to cytokeratin instead
What do integrins form when they cluster?
Most integrins β local adhesions al[ha6beta4 integrin - hemidesmosomes
What is the other important purpose of integrins other than cell adhesion?
It is a platform for signal transduction
Describe inside-out signalling of integrins.
Growth factors can generate signals inside the cell, which can act on the integrin complex and alter its affinity (this is important in bloodclotting)
Describe outside-in signalling of integrins.
A cell can receive information about its surrounding via adhesion to the ECM The ligand binds and opens the legs of the complex, allowing cytoplasmic signalling molecules to bind
Describe how the experiment with cultures of mammary epithelium demonstrated the profound effect of ECM on the phenotype of cells.
When the mammary cells were placed on a culture medium with interstitial matrix (type 1 collagen), they formed clumps and were loosely associated When placed on a culture medium with basement membrane matrix (e.g. laminin), the cells formed a very ordered system (organoid) and even began producing milk proteins
When cells are dividing on a culture medium, they will stop dividing once they reach the edges of the medium. What was originally thought to be the reason behind this?
Contact inhibition of cell division
What is the actual reason for this?
Density-dependence β increased competition for growth factors
In summary, what two pathways work synergistically to trigger proliferation in cells?
Anchorage dependence (ECM dependent) Density dependence (growth factor dependent)
What happens to most non-epithelial cells when they make contact with each other?
They will move away from each other The motility on the side that made contact will become paralysed meaning that the cells can then move away from each other This prevents multi-layering This is CONTACT INHIBITION OF LOCOMOTION
Which types of cells form stable cell-cell junctions when they come into contact?
Epithelial cells Endothelial cells Neurones Myocardium
What are the two types of cell-cell junction?
Zonulae (belts) Maculae (spots)
What happens to epithelial cells when they come into contact with one another?
Contact-induced spreading of epithelial cells Contact between epithelial cells leads to mutual induction of spreading, so that the total spread area of the contacted cells is greater than the sum of the two separated cells. This could result in a stable monolayer.
What effect does low calcium levels have on an epithelium?
Many cell-cell junctions are calcium dependent In the absence of calcium/low calcium, the junctions will break down This leads to: ο· Increased MAPK activation ο· Decrease activity of p27KIP1 (Cdk inhibitor) ο· INCREASED PROLIFERATION When calcium returned to normal and the junctions were reformed: ο· Decreased MAPK activation ο· Increased activity of p27KIP1 (Cdk inhibitor) ο· DECREASED PROLIFERATION
What effects do antibodies blocking adherens junctions have on an epithelium?
The same results were achieved This showed that cell-adhesion affects proliferation
Describe the structure of an adherens junction.
There is a cadherin domain that is transmembrane and projects extracellularly Cadherins are homophilic and associate with similar structures on adjacent cells Intracellularly, the cadherin is bound to beta-catenin, which is bound to alpha-catenin, which, in turn, is bound to the actin cytoskeleton
Describe the action of beta-catenin when it isnβt sequestered by cadherin at the plasma membrane.
Normally, beta-catenin is rapidly degraded by APC so it doesnβt tend to achieve high concentrations in the cytoplasm Free beta-catenin in the cytoplasm (that is not broken down by APC) can bind to LEF-1 to form a complex that acts as a transcription factor This complex can then regulate gene expression and promote proliferation
Explain how the APC mutation causes adenomatous polyposis coli.
The APC mutation means that the APC protein can no longer degrade beta-catenin as efficiently So beta-catenin accumulates in the cytoplasm, associated with LEF-1 and triggers increased proliferation
What is contact inhibition of proliferation?
When bound to cadherin at the plasma membrane, beta-catenin is NOT available to bind to LEF-1 and cause nuclear effects Cytoplasmic levels of beta-catenin can rise if there is: ο· Inhibition of degradation ο· Loss of cadherin-mediated adhesion This can lead to the formation of beta-catenin/LEF-1 complexes that promote proliferation
Describe some other cadherin-associated signalling pathways that are known to influence contact-induced inhibition of proliferation.
When cadherins cluster together you can get changes in the activation of some of the small GTPases including Rac and Rho Changes in the small GTPases can induce proliferation
Describe ways in which cells can lose their social skills.
Proliferate uncontrollably (loss of density dependence) Become less adherent and multi-layer (loss of contact inhibition of locomotion and loss of anchorage dependence) Epithelia break down cell-cell contacts Not hayflick limited (express telomerase and become immortal)
What types of components of cell proliferation tend to be oncogenes?
Anything that will make the signalling pathway constitutively active e.g. Ras mutation, over-expression of growth factor receptors, signalling intermediates and signalling targets
What are the counter-part oncogenes of the proto-oncogenes c-Raf and c-Jun?
v-Raf v-Jun
What must be achieved for carcinoma cells to be able to metastasise?
Cell-cell adhesion must be down-regulated (e.g. reduced cadherin levels) Cells must be motile Degradation of ECM must take place (matrix metalloproteinases (MMP) levels increased in order to migrate through the basal lamina and interstitial ECM) NOTE: the degree of carcinoma cell-cell adhesion is an indicator of how differentiated the primary tumour is and indicates its invasiveness and prognosis
Aminoglycosides
gentamycin* tobramycin* amikacin* streptomycin neomycin * used the most
MOA of aminoglycosides
crosses outer bacterial membrane by passive diffusion via porin channels, then binds to 30s ribosomal subunit and thus inhibits protein synthesis Bactericidal: create fissures in outer cell membrane, resulting in leakage of intracellular contents and enhanced antibiotic uptake
mechanism of resistance
*transferase enzyme inactivates aminoglycoside -impaired entry of amino glycoside into the cell - receptor protein on 30s subunit may be altered or deleted Resistance depends on the amino glycoside: amikacin shows less resistance -> only one locus that may be inactivated genta and tobra: 6 loci that may be inactivated
Pharmokinetics
poorly distributed (no PO) and poorly protein bound but distribution is increased in pts with ascites, burns, pregnancy Donβt undergo any significant metabolism Nearly all administered dose is excreted unchanged in urine * dose adjustment is required in renal insufficiency Not required in hepatic disease
Spectrum of activity
most common: serious infections caused by aerobic gram-negative bacilli including pseudomonas, enterobacter, serratia, acinetobacter, and Klebsiella - also used synergistically w/ other abx in tx of gram + infections -protozoa - mycobacterial: tobra, strepto, amikacin
Synergistic with B-lactam against what?
against gram positive cocci - enterococcus faecalis endocarditis -> ampicillin or penicillin +gentamycin or strept - staph aureus endocarditis -> quicker killing (naficillin+gentamicin) -> neglible anaerobic coverage
Concentration dependent killing
dose dependent -> increasing concentrations kill an increasing proportion of bacteria at a more rapid rate -postantibiotic effect: antibacterial activity persists despite unmeasurable drug concentrations -may last for several hours
Clinical uses
-serious, life threatening gm - infection -complicated skin, bone, or soft tissue infection - complicated UTI - sepsis - osteomyelitis - peritonitis and other sever intra-abdominal infections - severe pelvic inflammatory disease -endocarditis -mycobacterium infection -neonatal sepsis -ocular infections (topical) - otitis externa (topical)
Aminoglycosides combo uses
septicemia, nosocomial RTI, endocarditis, complicated UTI, complicated intraabdominal infections, osteomyelitis caused by aerobic gram - bacilli - often d/c in favor of less toxic abx once organism identity and susceptibility has been confirmed. - enterococci in absence of high level resistance
Gentamycin
-most widely used -both gm - and +(resistance can occur) -almost always used in combo (beta-lactam) - IV, IM -topical and ophthalmic
Tobramycin (Nebcin)
similar coverage as gentamicin, better pseudomonas coverage - more expensive than gentamicin - comes in soon for inhalation for cystic fibrosis -IV, IM, ophthalmic
Amikacin (Amikin)
used for resistant bacteria IV, IM
Streptomycin
2nd line for TB in combo w/ other agents used w/ pen or ampicillin for enterococcus faceless endocarditis or viridianβs strep endocarditis (some resistance) - IM
Neomycin (mycifradin)
limited to topical and oral use (bowel prep for surgery -> colorectal).
Paromomycin
for intestinal amebiasis and hepatic coma/encephalopathy
Aminoglycosides safety
Pregnancy: D (human risk, but benefits may outweigh risks) Lactation: unknown, probably safe - enter breast milk but not well absorbed orally
CIβs
previous allergy or hypersensitivity reaction to aminoglycosides - myasthenia gravis: neuromuscular blockade risk too high
Black box warnings!!
nephrotoxicity ototoxicity neurotoxicity neuromuscular blockade *this is why serum levels are monitored
Nephrotoxicity
reversible, non-oliguric renal failure - elevated troughs RFs: old, renal dysfunction, dehydration, hypotension, liver disease, use of other nephrotoxins Monitor: renal casts, urine output, Cr, BUN - once daily dosing is less toxic - most nephrotoxic: neomycin, tobramycin, gentamicin
Ototoxicity
both vestibular and cochlear vestibular: 2/3-> vertigo, ataxia, loss of balance, tinnitus cochlear: 1/3 -> high freq hearing loss, deafness unusal - often irreversible, relationship to peak levels - neomycin, kanamycin, amikacin: most ototoxic
Neuromuscular blockade
can produce curare-like neuromuscular blockade at very high doses given too fast in resp. paralysis. -possible w/ any route of admin -usually reversible w/ Ca gluconate
Drug interactions
Chemotherapy agents- agalsidase Alfa/beta: gentamicin may diminish effect of drugs loop diuretics: may enhance adverse effect of ahminoglycosides -> nephro and ototoxicity neuromuscular blocking agents: enhance respiratory depressant effect of NM blocking agents B-lactam: synergistic effect, cephalosporins can increase risk of nephrotoxicity Warfarin: enhance anticoag effect
Use of aminoglycosides?
use limited b/c of availability of less toxic agents with comparable efficacy and w/o need for serum [drug] monitoring. - still impt as 2nd line agent in tx of serious infections due to aerobic gram - and certain gram + - also impt in multi-drug regimen for certain mycobacterial infections
Instances when mono therapy is adequate therapy
tularemia plague uncomplicated UTI caused by drug resistant negative organisms
Why is myasthenia graves a complete CI?
b/c neuromuscular blockade risk is too high -> paralyze diaphragm and die!
What is the most common cause of CAP?
gram + -> strep pneumo
Pathogenesis of pneumonia?
inflammation of parenchymal structures of the lung in the lower respiratory tract (alveoli and bronchioles)
Differentiation b/t CAP and nosocomial pneumonia?
CAP: occurred outside of hospital or w/in 48 hours of hospital admission - in a person who has not resided in a nursing home or hospital in past 2 weeks Nosocomial pneumonia: hospital acquired, ventilator associated, health care associated (more drug resistant and virulent)
Typical and atypical pneumonia?
typical: caused by bacteria that multiply in alveoli, neutrophils and pus in alveoli, congregate in alveoli sacs, multiply and produce pus atypical: caused by infectious agents that multiply in spaces b/t alveoli (septum and interstitum) - viral infections, mycoplasm (lack a cell wall around their cell membrane)
Pathogenesis of pneumonia?
- defect in usual respiratory defense mechanisms (cough, cilia, immune response) - large infectious inoculum or a virulent pathogen overwhelms the immune system
Definition of CAP?
pneumonia infection occurred outside the hospital or w/in 48 hrs of hosp. admission - patients who are residents of long term care facilities are not included her because they are living in a healthcare facility
Epidemiology of CAP
- 4-5 million cases a year in U.S. - 25% will require hospitalization - most common infectious cause of death world wide - among top 3 causes of death worldwide - incidence peaks in winter months - more common in older adults > 65 - incidence has decreased since pneumococcal vaccine
RFs for CAP?
- advanced age - alcoholism (aspiration) - tobacco use - COPD - asthma - immunosuppression - underweight - gastric acid suppressive therapy: allows pathogens to survive in gastric contents that normally would be killed by acid - regular contact with kids (daycare) - frequent visits to a health care provider
Most common causative agents of CAP?
- strep pneumo (#1 causative agent) - H. influenzae - mycoplasma pneumoniae - chlamydia pneumoniae - staph aureus - Neisseria meningitidis - M catarrhalis - klebsiella pneumonia - gram - rods - legionella
Viral causes of pneumonia?
influenza A & B rhinovirus respiratory syncytial virus (kids) adenovirus parainfluenza virus
Outpt causative agents of pneumonia?
- S. pneumoniae - M. pneumoniae - C. pneumoniae - respiratory viruses (less severe)
hosp. non-ICU causative agents of pneumonia?
- S. pneumo - M. pneumo - C. pneumo - H. influenzae - legionella - respiratory viruses (worse symptoms)
Inpatient ICU agent of pneumonia?
- S. pneumo - Legionella (bad) - H. influenza - enterobacteriaceae* - staph aureus* - pseudomonas* (*= virulent)
What other etiologies might be causing pneumonia?
- fungal: if insidious onset with a possibility of immunocompromise (on immunosuppressive meds, HIV?) consider fungal etiologies
What factors would suggest legionella as the causative agent?
Recent travel within 2 weeks, hotel stays or cruise ships - high fever >104 F - male - multilobar involvement - GI sxs (watery diarrhea) ****unique to legionella - neuro involvement - diffuse parenchymal involvement on xray
Tips to determine etiology?
- strep pneumo: most common, may have rust colored sputum - mycoplasma pneumonia:
General sxs of pneumonia
- fever - cough - +/- sputum production - dyspnea - sweats - chills - H/A - rigors - pleuritic chest pains - pleurisy - hemoptysis - fatigue - myalgias - anorexia - abdominal pain
Signs of pneumonia
- appear acutely ill - fever - may have hypothermia (elderly) 36 C - tachypnea - tachycardia - decreased SpO2 - Rales/crackles (inspiratory) - bronchial breath sounds - dullness to percussion
Elderly presentation of pneumonia?
- more likely to have subtle symptoms - weakness - decline in fxnl status - confusion or change in mental status - tachypnea is common
out pt dx tests?
CXR: +/- urinary antigen testing: +/- (strep pneumo, legionella) CBC: +/- BMP: +/- ( maybe not necessary in younger pts)
inpt dx tests?
CXR sputum gram stain urinary antigen testing: s. pneumo, legionella - rapid antigen test for influenza - prior to initiation of abx therapy: sputum culture (2 sets) -> want to start abx within 6 hours - CBC with diff - CMP (legionella messes with electrolyte balance) - arterial blood gases for hypoxic patients - consider HIV testing in all adult patients
What kind of CXR should be ordered and what will you see on the films?
- always order a PA, and lateral Xray if possible - findings: patchy opacities, lobar consolidation with air bronchograms, diffuse alveolar or interstitial opacities, pleural effusions, cavitation
Why are CXRs helpful?
- helpful to assess severity - assess response to therapy - may take 6 weeks to completely clear (f/u until CXR is clear)
What should be considered if pt presents with pleural effusion?
- consider a thoracentesis - dx eval of pleural fluid includes: glucose, LDH, total protein, leukocyte count, pH, gram stain and culture *fluid will shift if turned on side - pleural effusion occurs in cancer, cancer increases risk for pneumonia because of decrease in immunity
When should fungal dx testing be done?
- order fungal tests on sputum and test for mycobacterium if cavitary opacities are seen - likely need to obtain samples from bronchoscopy
When should CA-MRSA pneumonia be considered?
when: - influenza infection preceded present illness - necrotizing pneumonia (destroying the lung tissue) - empyema: collection of pus secondary to infection - respiratory failure or shock - if MRSA infection: tx with vanco or linezolid * CA MRSA is genetically different from HA MRSA
1st step in tx of pneumonia?
- determine if the pt warrants hospital admission or if it safe to tx as an output
What is CURB-65?
C= confusion U= BUN> 19 mg/dl R= RR> 30 min B= BP= 90/60 age = >65 * 1 pt for each yes, hospitalize if > 1, higher the points the higher the mortality * get confusion from being hypoxic, hyper carbon -> dehydration, elect. imbalance * hypotension: worried about sepsis
Is CURB-65 a good indicator of tx for pneumonia?
- low sensitivity (39%) for ID of those needing intensive respiratory support - it is good at predicting 30 day mortality: 0-1: 0.7-2.1% 2 = 9.2% 3 or more = 15-40%
How sensitive is the pneumonia severity index?
- 74% sensitivity for prediction of those needing intensive respiratory support
Empric abx tx for non-hosp and no comorbidity patients?
- azithro or clarithomycin or doxy (covers H. flu and is better for pts with hx of smoking
Empiric abx tx for non-hosp. patients with comorbidities?
- Resp FQ or azithro or clarithro + high dose amox or high dose Amox-CL or cefdinir, cefpodoxime, cefprozil
Empiric abx tx for hospitalized pts not in the ICU?
- Respiratory FQ (levo) - or macrolide + Beta lactam: cefriaxone, ampicillin, cefotaxime
Empiric abx tx for hospitalized pts in the ICU?
- respiratory FQ or Azithro - + antipseudomonal B-lactam: cefotaxime, ceftriaxone, ampicillin/sublactam - if at risk for pseudomonas add antipneumococcal + antipseudomonal b-lactams: piperacillin/tazobactam, cefepime, imipenem, miropenem + cipro or levo or antipseudomonal B-lactam + aminoglycoside + azithro or resp. FQ * If MRSA is suspected: add vanco
When is the best time to start abx?
- best outcomes if abx started within 6 hours of admission - customary to require first dose to be given in ED
Why would you change the therapy?
- based on severity of presentation - recent abx use in the last 3 months - post influenza infection -> think staph (MRSA) - suspicion of drug resistant organisms in the community - after obtaining culture and sensitivity results
Duration of abx therapy?
- min. of 5 days (tx longer then a week, no benefit) - afebrile for 48-72 hours - average for meds other than azithro 5-7 days unless severe infection or other sites infected - azithro has a very long half life so duration of therapy doesnβt equate to other drugs
Prevention of pneumonia?
- pneumococcal vaccine (against 23 strains of S. pneumonia), seasonal influenza vaccine
RFs of anaerobic pulmonary infections?
- decreased level of consciousness due to drug or ETOH use - seizures - general anesthesia - CNS disease - impaired swallowing - GERD - hiatal hernia - tracheal tubes - NG tubes - periodontal disease - poor dental hygiene
Pathogenesis of anaerobic pulmonary infections?
- inhalation of oropharyngeal secretions colonized by pathogenic bacteria: macro aspiration and chronic micro aspiration - Goes to dependent lung zones: posterior segments of upper lobes and superior and basilar segments of lower lobes
What do anaerobic lung infections cause?
- necrotizing pneumonia - lung abscess - empyema
What are the anaerobic pathogens?
- Prevotella melaninogenica - Peptostreptococcus - Fusovacterium nucleatum - Bacteroides
Symptoms of anaerobic lung infection?
onset: insidious fever, wt loss, malaise - cough productive of foul smelling sputum
Work up of anaerobic lung infection?
- CXR and most likely CT scan of chest (wonβt see extent of damage with CXR -> need CT) - canβt do sputum culture due to contamination from oropharyngeal secretions - if sputum sample is needed: do a bronchoscopy or transthoracic/transtracheal aspiration - if aspiration suspected a swallowing eval is needed -> RF: is having sleep apnea
Tx of anaerobic lung infection?
- DOC: Clindamycin or augmentin or amoxicillin or PCN G + metronidazole - longer courses of therapy are generally needed, continue abx until CXR improves which may be a month or more - lf lung abscess -> continue abx until resolution of abscess - may require surgical removal of abscess or empyema
When should you consider an anaerobic infection?
if lung abscess, empyema, necrotizing pneumonia or sig. risk factors like recent LOC due to multiple factors * not all cases of aspiration pneumonia are caused by anaerobes.
Why is it interesting and also scary that MRSA resistant?
Methicillin is an antibiotic that is stable to a beta-lactamase producing organism so if something is resistant to methicillin it can be very dangerous because it means it is resistant to something that typically works against bugs that are resistant.
Why is Mycoplasma Pneumoniae resistant to penicillins and cephalosporins?
Because it lacks a peptidoglycan cell wall, not because it produces beta-lactamase. (penicillins and cephalosporins are inhibitors of cell wall synthesis - they will have no effect on this organism).
What do protein synthesis inhibitors target?
target the bacterial ribosome within the cell, not the cell wall.
What is the bacterial ribosome?
It has a smaller (70S) than the mammalian ribosome which is 80S -> it is composed of 50s and 30s subunits as opposed to 60s and 40s in humans -> so protein synthesis inhibitors wonβt effect human ribosomes, itβs selective.
Protein Sythesis Inhibitors
tetracyclines macrolides chloramphenicol (ind. drug) clindamycin (ind. drug).
Class of Tetracyclines
tetracycline: prototype, hardly used doxycycline: Super important!!! minocycline: acne demeclocycline
MOA of Tetracyclines
Binds to 30s subunit of bacterial ribosome, believed to block access of amino acyl-tRNA to mRNA-ribosome complex at the acceptor site, thus inhibiting bacterial protein synthesis.
Spectrum of Tetracyclines
Broad spectrum: active against many gram positive and gram negative organisms including anaerobes.
Resistance to Tetracyclines
- any organism resistant to one tetracycline is resistant to all tetracyclines - cell develops efflux pumps (pumps drug out of cell) - forms ribosomal protection proteins
Absorption of Tetracyclines
all tetracyclines adequately but incompletely absorbed thru oral ingestion
What decreases absorption?
dairy foods (less of a problem with doxy)
Distribution of Tetracyclines?
concentrate in liver, kidney, spleen, and skin and bind to tissues undergoing calcification β> teeth and bones -Doesnβt penetrate CSF -All cross placental barrier and concentrate in fetal bones and dentition
Elimination of tetracyclines
concentration in liver -> metabolized and conjugatedβ> released in bile β> reabsorbed in intestine and enter urine via glomerular filtration (doxy -> bile and into feces)
What makes doxycycline an acceptable drug for renally compromised patients/
Because instead of being filtered by the kidneys it stays in bile and is excreted into the feces.
Adverse effects of Tetracyclines?
Calcified tissues: deposition in the bone and primary dentition occurs during calcification of growing children -> causes discoloration and hypoplasia of teeth and temporary stunting of bones for growth. Gastric discomfort: controlled if taken with foods other than dairy products. Phototoxicity: severe sunburn can occur when the patient taking a tetracycline is exposed to sun or UV rays Vestibular problems: dizziness, nausea, and vomiting occur with minocycline.
CIβs of Tetracyclines
pregnant women (category D) Breast feeding women Children
Tetracyclines routes of administration
Oral, IV, IM (not recommended b/c of pain and inflammation at injection site).
Tetracycline uses
STDs, atypical pneumonia, exacerbations of chronic bronchitis, acne vulgaris, and great alternative for sinusitis and acute prostatitis
Why do you never use tetracyclines for skin infections?
Because of decreased activity against staph aureus
Doxycycline uses:
DOC for mycoplasma pneumonia, chlamydiae (resp for variety of STIβs), rickettsiae (Rocky Mountain Spotted Fever), and excellent for Lyme Disease
Minocycline uses
acne vulgaris (rarely anything else)
Demeclocycline uses
Tx of SIADH because of its inhibiting action of ADH. *SIADH= syndrome of inappropriate antidiuretic hormone secretion
What are the 3 macrolides?
erythromycin: first one in drug class and prototype, not used nearly as much any more. azithromycin (Zithromax): most popular macrolide, used extensively in a variety of circumstances. Clarithromycin (Biaxin)
Macrolides MOA
bind irreversibly to a site on the 50S subunit of bacterial ribosome, thus inhibiting the translocation steps of protein synthesis - Bacteriostatic
Are macrolides stable against b-lactamase producing organisms?
yes, because they are protein inhibitors not cell wall inhibitors
Erythromycin spectrum
effective against same organisms as PCN G -> used in pts allergic to penicillins. Also effective against chlamydial species and mycoplasma pneumoniae and legionella pneumophila
Clarithromycin (Biaxin) spectrum
similar to erythro but also effective against H> influenzae (community acquired pneumonia) * Use instead of Azithro -> new trend
Azithromycin (Zithromax) spectrum
less active against strep and staph than erythro but more active against respiratory infections due to H. influenzae and Moraxella catarrhalis. Excellent for urethritis caused by Chlamydia trachomatis
Resistance to macrolides?
most strains of staph in hospital isolates are resistant to erythro clarithro and azithro show cross resistance to erythro *Not good in skin coverage -> donβt use for staph aureus (MRSA)
Resistance mechanisms to Macrolides
alteration in the binding site of the ribosome. manifestation of an efflux pump to get the drug out of the cell. Enzymatic inactivation
Absorption of Macrolides
Erythro: destroyed by gastric acid and therefore need enteric coated tablet, adequately absorbed on oral administration Clarithro and Azithro: stable to stomach acid and readily absorbed
Distribution of Macrolides
widely distributed in tissue except for CSF
Metabolism of Macrolides
Erythro: cytochrome P450 drug Clarithro: metabolized by liver and may also interfere with other drugs Azithro: not a p450 drug and tends to have few interactions with other meds
Excretion of Macrolides
Erythro and azithro primarily concentrated in the bile Clarithro and its metabolites are eliminated by kidney and liver -> recommended that dosage be adjusted in pts with compromised renal function
Common adverse effects of Macrolides
GI distress including diarrhea big problem with erythro -> leads to poor pt compliance (sometimes used for constipation even) Azithro and Clarithro are much better tolerated in GI Ototoxicity: transient deafness has been associated with erythromycin especially at high dosages. prolonged QT with erythro and clarithro (rare)
Why is Azithro preferred over erythro and clarithro?
Fewer adverse effects fewer drug interactions donβt have to worry about adjusting dose with kidney and liver disease unless severe Long half life -> easy to use and pts are more compliant (daily dosing compared to 2x daily or 4x daily)
Are Macrolides good for staph disease?
Nope, not good for staph just like doxycycline
Why are macrolides liked for tx of chlamydial cervicitis and urethritis STIβs compared to doxy?
because it works really well against chlamydial species - only have to dose single 1 gram versus a 7-10 day course of doxy
When are macrolides DOC?
Excellent for broad spectrum coverage of both typical and atypical pneumonias, used all the time for exacerbations of chronic bronchitis in the patient with COPD - used first line alt. for group A strep pharyngitis (strep throat)
Chloramphenicol -> should we use?
Active against wide range of gram + and gram - organisms but because of its HIGH toxicity, its use is restricted to life-threatening infections in which there are no alternatives!!
MOA of chloramphenicol
Binds to bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction
Spectrum of Chloramphenicol
very broad -> including anaerobes - not effective against pseudomonas or chlamydiae
Pharmacokinetics of Chloramphenicol
completely absorbed orally Readily enters CSF
Adverse effects of Chloramphenicol
-Hemolytic anemia -aplastic anemia β> idiosyncratic and usually fatal, occurs independent of dose and may occur after therapy has ceased! -Gray Baby syndrome -> because of interference with human mitochondrial ribosomes, can lead to poor feeding, depressed breathing, cardiovascular collapse, cyanosis, and death - can interfere with a number of other drugs
Clindamycin MOA
same as macrolides β> bind to 50s subunit of bacterial ribosome.
Clindamycin spectrum
great coverage against anaerobic bacteria but also active against many gram + cocci: staph and strep
Clindamycin absorption and distribution
well absorbed orally, distributes well into all body fluids except CSF
What is always resistant to clindamycin?
Clostridium difficile -> which is a bug that hangs out in gut and is usually harmless but with the administration of Clindamycin there can potentially be overgrowth of C. difficile which can lead to potentially fatal disease β> pseudomembranous colitis with side effects of diarrhea, nausea, and skin rash
What are the common meds used against anaerobes?
Clindamycin or Metronidazole (Flagyl) - Excellent in treating infections of the gut and used to treat penetrating wounds of abdomen and gut
What should you think of when you hear anaerobic infection?
gut flora or female genital tract flora
Impact of STIs?
- sterility, cancer, and death
RFs for STIs
- unmarried - residence in urban area - new sex partners - multiple sex partners (concurrent) - history of a prior STI - illicit drug use - contact with sex workers - young age (15-24) - African-American race - admission to correctional facility or juvenile detention center -meeting partners on the internet
Causes of genital ulcers (STI and noninfectious etiology)
STI: - HSV - Treponema pallidum (syphilis) - Haemophilus ducreyi (chancroid) - chlamydia trachomatis (lymphogranuloma venereum; LGV) noninfectious etiology: Behcetβs disease fixed drug reactions and trauma
HSV infection -> causative agents
- causative agents: HSV- 1 and HSV-2 - no longer separated into genital and oral - both serotypes can cause either type of infection Very common: 50 mill people in US - frequently under-recognized b/c infection is often subclinical
Types of HSV infection
Primary: infection in a pt w/o abs to HSV-1 or HSV-2 nonprimary: 1st episode infection due to acquiring HSV-1 w/ preexisting abs to HSV-2 or vice versa Recurrent: reactivation of genital herpes in which the HSV type recovered in the lesion is the same type as the abs recovered in the serum
Symptoms of HSV infection
- Primary: highly variable from very symptomatic to asymptomatic - sxs tend to be more severe in women than in men - systemic sxs, local pain/itching, dysuria, lymphadenopathy - Dysuria can be due to acute urinary retention or more rarely to lumbosacral radiculomyelitis nonprimary: less symptomatic than first episode recurrent: less severe, shorter duration - asymptomatic shedding - if women get in cervix or vagina it could go unnoticed, shedding virus without lesions
Transmission of HSV
- highly transmittable - can be transmitted by oral-genital contact - greater risk of acquiring HSV w/ male source - 70% of transmission occurred during periods of asymptomatic shedding - condom use 50% decline in transmission - HSV -2 genital ulcer disease has been linked to an increased risk for acquiring HIV-1 infection (any break in the skin increases risk of HIV)
Dx HSV
- viral culture: if active lesions present - PCR: more sensitive - Direct fluorescent ab serology: - type-specific ab testing of serum - helps to determine if the pt is at risk of acquisition - determines if pt has hard evidence of prior infection - can do screening for HSV
Tx of HSV
drugs: acyclovir Famcilovir -> more bioavailable Valacyclovir -> more bioavailable/BID primary genital HSV: should be treated (w/in 72 hours) - decreases duration of symptoms - increases healing of lesions - decreases viral shedding - analgesics may be required/ sitz baths helpful Recurrent disease: chronic suppressive therapy: expensive and may not be covered by all insurance carriers - episodic therapy: start at 1st sign of prodromal symptoms usually take for 3 days - no intervention
HSV in pregnancy
- most common mode of transmission is from direct contact of fetus w/ infected vaginal secretions during delivery - Maternal immunity is impt: if mother contracted HSV before pregnancy -> have abs that will transfer to baby - biggest risk: if mother contracted HSV while pregnant - Acyclovir can be used to tx a primary infection prophylactic C-section: do if active lesions at birth canal, not recommended if mother has no active lesions or if lesions have crusted at time of delivery (or have feeling of prodromal sxs), not recommended if have active nongenital HSV lesions
Prevention of HSV
- counseling!!! - pts need to be educated that they may not have acquired the infection recenetly and that there has not necessarily been infidelity in a monogamous partner - education on recurrences - monogamous partner testing - telling future sexual partners
Syphilis causative agent and tests available?
- Treponema palidum canβt be cultured, can be seen with dark field microscopy - serologic tests available: nontreponemal: VDRL, RPR, TRUST/ reported as titers treponemal: reported as reactive or nonreactive: - fluorescent treponemal ab absorption - microhemagglutination test for abs to T. palidum - Treponema palidum particle agglutination assay - Treponema pallidum enzyme immunoassay
Who should be screened for Syphilis?
- pt with suspected disease - screening high risk populations (pts with other STIs, persons with multiple sex partners) - routine screening of pregnant women - commercial sex workers - all sexually active HIV infected pts at least annually, more frequent screening for those w/ multiple sex partners and unprotected intercourse
What is syphilis associated with?
- reportable infection in the U.S. - number of cases increasing since 2001: primarily in MSM (HIV pop not using protection, syphilis started to spread then branched out into other populations - also in heterosexual pop. **It is associated with an increased risk for acquisition and transmission of HIV - all pts who are dx with syphilis should be offered HIV testing and counseling
Transmission of Syphilis?
- Primary and secondary syphilis produce chancres, mucous patches and condyloma lata - estimated transmission occurs in 30% exposed to someone who is infected - syphilis can be spread by kissing or touching a person who has active lesions on the lips, oral cavities, breasts or genitals - it can be acquired through passage through the placenta
Primary syphilis characteristics
- incubation period of 2-3 weeks from inoculation - a papule forms and soon ulcerates to the chancre - chancre is usually painless - usually there is bilateral lymphadenopathy - chancres heal spontaneously within 3-6 weeks even without tx - widespread dissemination of the organism occurs at the same time
Secondary syphilis characteristics
* weeks to a few months later 25% of people with untreated infections will develop systemic illness: - rash: any form BUT vesicular, includes palms and soles. - Gray/white lesions warm moist areas -> condyloma lata - systemic sxs - lymphadenopathy - alopecia (patchy) - hepatitis - GI abnormalities ( can be misdx as lymphoma) - musculoskeletal and renal abnormalities - ocular disease
Tertiary syphilis characteristics
- 1-25 years after secondary syphilis: early tertiary syphilis presents = year - late tertiary syphilis presents > 1 year from initial infection systems involved: -subcutaneous tissue (gumma) - granulomas -CV: ascending thoracic aorta becomes dilated aortic valve regurgitation occurs. CNS (most common): early: meningitis, meningiovascular disease late: general paresis, tabes dorsalis, ocular, otosyphilis
Characteristics of neurosyphilis
- when suspected need to do a lumbar puncture CSF findings: lymphocytic pleocytosis, elevated protein, + CSF-VDRL and or FTA-ABS Need to follow CSF during tx to make sure there is a response (lumbar punctures)
Tx of early syphilis
For primary, secondary syphilis and early latent: - 2.4 mill units of benzathine PCN G IM - for PCN allergies DOC: doxy 100 mg BID for 14 days - tetracycline, azithro, and ceftriaxone are other alternatives although not well documented.
Tx for late syphilis
- pts with gumbos or CV involvement need to have a LP to r/o neurosyphilis tx - if they have localized disease tx is: - 2.4 mill units of benzathine pin G IM weeks for 3 weeks - gumma will resolve - it will only halt progression of CV disease and some prefer to treat CV disease like neurosyphilis
Tx for neurosyphilis
- IV PCN G either 3-4 mill units q 4 hrs or 18-24 mill units per day by continuous infusion for 10-14 days - pts who are allergic to PCN should undergo desensitization since PCN G is doc for tx neurosyphilis and an allergist should be consulted * non-pcn regimens are not recommended for pts w/ documents neurosyphilis
Monitoring tx of syphilis
- pts need to be reexamined clinically and serologically at 6 and 12 months after tx - a fourfold reduction in titer of the nontreponemal ab test is evidence of a response to therapy - a titer should be drawn just prior to starting tx and the same test and lab should be used for f/u - Think tx failure or reinfection if not getting better
HPV who it infects
- double stranded DNA viruses Papillomavirus genus - Human HPV only infects humans - more than 100 types of HPV - 75-80% sexually active adults will acquire genital tract HPV b/f age of 50
How does HPV manifest?
- genital warts (condyloma acuminatum) - Bowenoid papule and Bowenβs disease - Giant condyloma (Buschke-Lowenstein tumors) - intraepithelial neoplasia and/or carcinoma of the vagina, vulva, cervix, anus or penis - plays a role in squamous cell carcinomas of the head and neck particularly in the oral cavity
HPV genotypes
- over 40 mucosal HPV genotypes infect lower female genital tract - carcinogenic types HPV16 & HPV18 account for 70% of all cervical cancers worldwide - HPV6 and HPV11 cause about 90% of genital warts
Natural hx of HPV
- most HPV infections usually resolve w/in 6-12 months (Including the carcinogenic HPV genotypes) - paradigm of cervical carcinogenesis: - HPV acquisition - HPV persistence - Progression of persisting infection to precancerous lesion - local invasion
Anogenital warts
- most common viral STI disease in the U.S. - 67% of pts -> women - persistent infection especially w/ other risk factors (such as infection w/ HIV) can result in development of squamous cell carcinoma - acquisition is related to sexual activity - Fomites can also spread the virus
Sxs of anogenital warts
- depends on number, size, and location - asx - pruritus, burning - bleeding - tenderness, pain - discharge (women) - large condylomata can interfere with defecation intercourse and vaginal delivery - lesions in proximal anal canal may cause strictures
Dx of anogenital warts
- usually made by visual inspection - document extent of involvement by PE, anoscopy, sigmoidosopy, colposcopy (looks at vagina and cervix), and/or vaginal speculum exam - 5% acetic acid causes lesions to turn white - biopsy can be considered: when dx is uncertain or presence of atypical features - lesions that donβt respond to tx
Tx of anogenital warts
- spontaneous regression occurs 20-30% of cases - al therapies have a 30-70% recurrence rate ablative: Podophyllin (CI in pregnancy) Imiguimod (Aldara) Trichloroacetic acid 5-fluoruracil (5-FU) - intralesional injected alpha interferon Excisional: cryotherapy (freezing) - laser therapy: reqrs anesthesia/ risk of scarring - excisional procedures w. knif or scissors: reqrs anesthesia, risks of infection and hemorrhage, need to send specimen to path
Prevention of HPV
- gardisil 9: 16, 18, 31, 33, 45, 52, 58 (cancers: cervical, vulva, penile, vaginal, throat) 6 and 11 -> anogenital warts recommendations for vaccine: - 9-26 in women -9-15 in males monitoring of women with pap smears currently recommended, needs to continue
Urethritis in Men causes?
-3 main causes: gonorrhea: common cause - usually can get discharge w/ milking the urethra, urethral swab: +WBC & +gram negative intracellular diplococci - chlamydia: common concurrent infection or may be primary - Trichomonas vaginalis: cause of nongonococcal urethritis (NGU)
Trichomonas vaginalis
- accounts for 20-35% of vaginitis dx in sx women in primary care settings - flagellated protozoan, humans only natural host - Trichomoniasis: - always sexually transmitted - assoc w/ high prevalence of coinfection w/ other STIs - organism can be ID in 30-40% of male sex partners of infected women
Trichomoniasis presentation in women
- asymptomatic carrier state - symptomatic cases: purulent, malodorous, thin discharge (70%) - burning, pruritus - dysuria, frequency -> urethral involvement - dyspareunia, postcoital bleeding
Dx of trichomoniasis
- vaginal swab: wet mount for microscopy in normal saline - can see motile trichomonads (dx) - classic: green, frothy, foul-smelling discharge (4.5) & increased PMNs - culture on diamondβs media: test not readily available, takes up to 7 days for results
Trichomoniasis tx
- Metronidazole (Flagyl): single oral dose of 2 gems 500 mg BID for 7 days (if recurrent infection) - metranidazole tx for symptomatic pregnant women (if not sx -> not tx) - male partners need to be tx for maximal cure rates in women - no intercourse until all parties are tx
Trichomoniasis in men
- usually transient q/ spontaneous resolution and asx - sxs are typical for urethritis - no definitive dx tests: low yield with swabs for motile organisms - tx is usually b/c of + female dx or empirically for NGU
Neisseria gonorrhea
- 2nd most commonly reported communicable disease in U.S. - trend toward decreasing infections, lowest 1970s highest rates among: adolescents/ young adults minorities persons living in the SE U.S - increasing abx resistance
Gonorrhea manifestations
- women: any portion of the genital tract (PID -> causes infertilitry, abscesses), most common site is the cervix, urethritis -men: urethritis, epididymitis, proctitis (anal region) - oropharyngeal infections: frequently asymptomatic
Disseminated gonococcal infection (DGI)
- occurs in 1-3% of pts infected - 3x more common in women than in men - hx of recent symptomatic genital infection is uncommon - asymptomatic mucosal infection predisposes - pt w/ decreased immunity more at risk: pregnancy, SLE, complement deficiencies
Manifestation of DGI
- triad: tenosynovitis, dermatitis, polyarthralgias: acutely systemic signs/sxs occur multiple tendons are inflamed (small joints) skin: painless lesions, few in #, transient purulent arthritis w/o skin lesions: - knees. wrist, and ankles most common joints - typically asymmetric, sometimes there is overlap with triad (joint will become septic if you donβt tap and tx)
Dx of gonorrhea
culture: can be difficult-> organism fastidious gram stain: used primarily dx of urethritis in men Nucleic acid amplification testing (NAAT): recommended as optimal method for dx amplifies N. gonorrhoeae DNA or RNA sequences using various techniques - samples: endocervix, vagina, urine, urethra in men - not approved for nongenital sites (culture those)
Tx of Gonorrhea
- ceftriaxone preferred tx: resistance emerging -> 250 mg IM single dose + (to cover tx of chlamydia) azithro 1 gram single dose or doxy 100 mg BID for 7 days except in pregnant women * give in office - if allergic to ceftriaxone can give azithro 2 g single dose alt: cefotaxime and cefoxitin w/ probenecid
Epididymitis tx
in men if intolerance to doxy then can use azithro > but f/u evals are needed
Chlamydia trachomitits
- small gram - organism, oblique intracellular parasite - immunity to infection isnβt long lived hence reinfection or persistent infection is common -4,000,000 cases in women are estimated to occur annually in U.S. -> making it the most common STI - prevalence in men more difficult to determine -> common to screen women and tx men empirically - chlamydia is on the rise in both genders
Clincial manifestations of chlamydia in women
- asymptomatic, common presentation, usually picked up on routine check or culture - cervicitis - urethritis - PID: 30% of women w/ chlamydia will develop PID if left untx pregnancy: if left untx can increase risk of premature rupture of membranes and low birth weight - newborns can develop conjunctivitis and pneumonia (when mother untx)
Chlamydia tx
- often coexists w/ gonorrhea so tx for both - 1st line agents: azithro: 1 g single dose - or doxy: 100 mg BID for 7 days (cheap) 2nd line agents: expensive and CIs: - ofloxacin for 7 days - levofloxacin for 7 days * test for cure in pregnant pts
chlamydia manifestations in men
urethritis epididymitis: men
Dx of chlamydia
- culture - NAAT: vaginal, urethral, urine specimens (gold std) - AG detection: swab from cervix/ urethra - genetic probe: swab from cervix/ urethra - chlamydia rapid testing: under development * reportable infection
Pregnancy routine early screening for what?
- chlamydia - gonorrhea - syphilis - Hep B - offered test for HIV - take hx for HSV - pap done to assess for HPV
STI prevention
- ID those at high risk and screen - HIV positive persons need to be screened for other STIs - counsel safe sex behavior and protection especially those who are most likely to engage in risky behavior
2 categories of anaerobes
- spore forming: rod, gram +: clostridium - nonspore-forming: gm +rod -> propionibacterium, bifidobacterium, lactobacillus, eubacterium, actinomyces nonspore-forming gm - rod β> bacteroides, fusobacterium, camplyobacter nonspore-forming gm + cocci -> peptococcus, peptostreptococcus nonspore forming gm - cocci -> veillonella
Clostridium species
- clostridia are opportunistic pathogens, but they are responsible for some of the deadliest diseases including gas gangrene, tetanus and botulism. Less life threatening diseases include pseudomembranous colitis (c. difficile) and food poisoning. - cause disease primarily through the production of numerous exotoxins
Subtypes of clostridium species
perfringens, tetani, botulinum, difficile
Pathogenesis of C. Tetani?
- entry through wound (rusty nail) 2. spread of toxin 3. disease: rigid paralysis ex: lockjaw, cardiac failure, respiratory failure 4. no exit
Where is C. tetani found?
worldwide, ubiquitous in the soil, it is occasionally found in intestinal flora of humans and animals
What does C. tetani cause
tetanus or lockjaw. When spores are introduced into wounds by contaminated soil or foreign objects such as nails or glass splinters (no inhibition of ACh (in constant contraction β> tetany)
Morphology of C. tetani, culture, biochem. activities, resistance, and classification
Morphology: long and slender, flagella no capsule, terminal located round spore (drum stick appearance) Culture: obligate anaerobic, gram +, swarming occurs on blood agar, faint hemolysis Biochem activities: doesnβt ferment any carbohydrate and proteins resistance: tolerate boiling for 60 min. Live for several years in the soil. classification and antigenic types: C. tetani is only species, no serotypes
Pathogenicity of C. tetani
-produces 2 exotoxins: tetanolysin, and tetanospasmin (type of neurotoxin, toxicity strong) - taken up at neuromuscular junction - Actions of tetanospasmin are complex and involve 3 components of the nervous system: central motor control, autonomic fxn, and neuromusc. junction. - retrograde transport to CNS -delitescence (latency): few days to several weeks - the 2 animal species most susceptible to toxemia are horses and humans
Tetanospasmin (exotoxin of c. tetani)
disseminates systemically -binds to ganglioside receptors, inhibitory neurons in CNS -glycine: neurotransmitter - spastic paralysis - severe muscle contractions and spasms - can be fatal
signs and sxs of tetanus
- initial sx: cramping and twitching of muscles around a wound, pt usually has no fever but sweats profusely and begins to experience pain, especially in area of the wound and around the neck and jaw muscles (trismus -> lock jaw) - portions of the body may become extremely rigid, and opisthotonos (a spasm in which the head and heels are bent backward and body bowed forward) is common - complications: fractures, bowel impaction, intramuscular hematoma, muscle ruptures, and pulmonary, renal, and cardiac problems
generalized disease of C. tetani clinical manifestations
involvement of bulbar and paraspinal muscles (truisms, rises sardonicus (creepy smile), difficulty swallowing, irritability, opisthotonos), involvement of autonomic nervous system (sweating, hyperthermia, cardiac arrhythmias, fluctuations in BP
cephalic disease of C. tetani clinical manifestations
- primary infection in head, particularly in the ear, isolated or combined involvement of CNs, particularly the 7th, very poor prognosis
Localized disease of C. tetani clinical manifestations
involvement of muscles in area of primary injury, infection may precede generalized disease, favorable prognosis
Neonatal disease of C. tetani clinical manifestations
generalized disease in neonates, infection typically originates from umbilical stump; very poor prognosis in infants whose mothers are nonimmune
Epidemiology of Tetanus
- 1 mill. cases occur annually in the world -> mortality rate ranging from 20-50%, rare in most developed countries - in developing countries, tetanus is still one of the ten leading causes of death, and neonatal tetanus accounts for 1/2 of these cases - in less developed countries -> mortality: 85% neonatal tetanus and 50% non-neonatal tetanus - in U.S. -> IV drug users victim to this - in untx tetanus, fatality rate is 90% for newborn and 40% for adults
Immunity to C. tetani
humoral immunity (antitoxin), there is little, if any, innate immunity and the disease doesnβt produce immunity in the patient - active immunity follows vaccination with tetanus toxoid
Dx of tetanus
dx is primarily by clinical sxs, the wound may not be obvious - C. tetani can be recovered from the wound in only about 1/3 of the cases - it is imp. for the clinician to be aware that toxigenic strains of C. tetani can grow actively in the wound of an immunized person - numerous syndromes, including rabies, and meningitis, have sxs similar to those of tetanus and must be considered in d. dx
vaccination for tetanus
- infant: get DTap - (diphtheria, pertussis, tetanus) - tetanus toxoid: antigenic, no exotoxic activity
Control of tetanus
- offending organism must be removed by local debridement - toxoid - TAT (tetanus antitoxin; metronidazole (for more serious wounds - AIDS patients may not respond to prophylactic injections for tetanus toxoid
C. perfringens where does it come from and what does it cause?
-found in soil, fecal contamination - causes gas gangrene: swelling of tissues, gas release from fermentation products (spores in anaerobic environment: release exotoxins) - wound contamination
Pathogenesis of C. perfringens
- tissue degrading enzymes: lecithinase (toxin), proteolytic enzymes, saccharolytic enzymes β> spongy, crackling noise made when palpated, gas is produced by enzymes and is a waste product from toxins - destruction of blood vessels - tissue necrosis - anaerobic enviro created - organism spreads
What will happen in gas gangrene without tx what is tx?
DEATH occurs within 2 days - effective abx therapy -debridement: get rid of necrotic tissue - anti-toxin - amputation & death is rare
Symptoms of gas gangrene and severity
- life threatening disease w/ poor prognosis and often fatal outcome - initial trauma to host tissue damages muscle and impairs blood supply -> lack of oxygenation - initial sxs: fever & pain in infected tissue, more local tissue necrosis and systemic toxemia. Infected muscle is discolored (purple mottling) and edematous and produces a foul-smelling exudate; gas bubbles form from the products of anaerobic fermentation
progression of gas gangrene
- as capillary permeability increases, the accumulation of fluid increases, and venous return eventually is curtailed - as more tissue becomes involved, the clostridia multiply w/in the increasing area of dead tissue, releasing more toxins into the local tissue and the systemic circulation
Biologic features of C. botulinum
- anaerobic -gram + - rod shaped - spore former - produces a protein neurotoxin - soil, sediments of lakes, ponds, decaying vegetation - intestinal tracts of birds, mammals, fish - found in honey, natural spores (donβt give to infants less than 1 -> donβt have immunity) - found in improperly canned foods
Transmission of botulism
- spores that are heat resistant, canning, anaerobic environment - botulism: eating uncooked foods, spores - GI, duodenum, blood stream, neuromuscular synapses - Binds to peripheral nerve receptors and block ACh neurotransmitter, - inhibits nerve impulses - leads to flacci paralysis - death b/c of respiratory and cardiac failure
Why would the botulinum toxin be considered for bioterrorism?
- not an infection - resembles a chemical attack - 10 ng can kill a normal adult
Clinical syndromes of botulism
- 18-36 hours - weakness, dizziness, dryness of the mouth - N/V - neuro features: blurred vision, inability to swallow, difficulty in speech, descending weakness of skeletal muscles, respiratory paralysis
How can you get botulism?
- food poisoning: rare but fatal - comes from germination of spore - inadequately sterilized canned food -> from home - not an infection
neonatal botulism (infection with C. botulinum)
- uncommon, the predominant form of botulism - colonization occurs - no normal flora to compete - unlike adult botulism - donβt give babies honey until 1 yo
Dx of botulism
- by clinical sxs alone - differentiation difficult - most direct and effective: serum or feces - most sensitive and widely used: mouse neutralization test 48 h - culturing of specimens 5-7 days
Tx of botulism
- individuals known to have ingested food w/ botulism should be tx immediately w/ antiserum - abx therapy if infection - vaccination will not protect hosts from botulism, however passive immunization w/ ab is the tx of choice for cases of botulism - need supp. care: respiratory support
Prevention of botulism
- proper food handling and preparation - spores surviving boling (100 degrees at 1 atm) 1 hr - toxin heat-labile, boiling or intense heating, inactivate the toxin - bulge, gas -> spoiled
When does C. difficile occur?
after abx use - intestinal normal flora -> greatly decreased - colonization occurs - enterotoxin secreted - pseudomembranous colitis
Pseudomembranous colitis?
results predominantly as consequence of elimination of normal intestinal flora through abx therapy - sxs include abdominal pain w/ watery diarrhea and leukocytosis - pseudomembranous consisting of fibrin, mucus, and leukocytes can be observed by colonoscopy - untx pseudomembranous colitis can be fatal in about 27-44%
Therapy for pseudomembranous colitis?
1st: discontinue initial abx (usually clindamycin) 2nd: specific abx therapy (doc: vanco , resistance to flagyl increasing)
Where will you see anaerobe infections?
throughout the body, in the muscle, cutaneous/sub-cutaneous necrosis - abscesses - deep: ex -> liver infections - wound will be foul smelling - also see dental and sinus infections
Why is it so hard to ID anaerobic infections?
- air in sampling -> no growth b/c of O2 - ID takes several days at least -> limiting usefulness - often derived from normal flora: sample contamination can confuse
Characteristics of anaerobic infections
- most pathogenic anaerobes are usually commensals -> originate from our own flora 2. predisposing conditions: breeches in mucocutaneous barrier so normal flora gets displaced, compromised vascular supply, trauma with tissue destruction - antecedent infection
Characteristics of anaerobic infections
complex flora: multiple species, less complex than normal flora, fecal flora: 400 diff species, species uniquely suited to cause infection predominate - synergistic mixture of aerobes and anaerobes: e. coli consumes O2 so anaerobes are allowed to grow and anaerobes promote the growth of other bacteria by being antiphagocytic and producing B-lactamases
Clues to anaerobic infection
- infections in continuity to mucosal surfaces 2. infections with tissue necrosis, and abscess formation 3. putrid odor 4. gas in tissues 5. polymicrobial flora 6. failure to grow in the lab
Bacteroides fragilis
Major disease causing strict anaerobic after abdominal surgery, non-spore-former -prominent capsule: anti-phagocytic, abscess formation -endotoxin: low toxicity, structure different than other lipopolysaccharide
What is meningitis?
- swelling and inflammation of the membranes covering the brain and spinal cord
What is encephalitis?
- inflammation of the brain
What is an abscess?
- confined pocket of pus that collects in tissue, organs, or spaces inside the body
Most common epidemiologies of BM by age group?
- newborn-1 month: Group B strep - 70% - age 1-23 months: S. pneumonia - 50% - age 2-18: N. meningitidis - 60% - adults to 50: S.pneumo - 60% - 50 and above S. pneumo
Nosocomial bacterial meningitis epidemiology?
- disease of neurosurgical pts, trauma - organisms: E. coli, K. pneumonia, P. auruginosa strep, S. aureus, and coag neg staph listeria
Impt changes in BM epidemiology?
- decline in Hib - increasing incidence of S. pneumo (50+% of cases in US) - shift from peds to adult disease - increase incidence of ATB resistance organisms esp S. pneumo PCN resistance: 35% Ceph resistance: 15-20%
Predisposing factors of bacterial meningitis? host risk factors?
- colonization of nasopharynx (N. menigitidis, S. pneumo, and Hib) - invasion of CNS following bacteremia due to localized source - direct entry of organisms in CNS from contiguous infection, trauma, neurosurgery, CSF leak or medical device (pacemaker) - host risk factors: asplenia chronic corticosteroid use immune comp - HIV or on immunosuppresants exposure to someone with meningitis
pathogenesis of meningitis/encephalitis?
- virulence factors of pathogen overcome host defense mechanisms and invade CSF - CSF has inadequate humoral immunity so bacteria can multiply to high concentrations - bacteria can produce an inflammatory response through inflammatory cytokines - leads to vasogenic brain edema, increased ICP resulting in brain ischemia, cytotoxic injury (from bacterial secretions) and neuronal apoptosis
Presentation of bacterial meningitis? Triad? other sxs?
- duration of sxs 2-3 days sometimes but it can also progress over hours - triad: fever (95% have over 100.4 temp) nuchal rigidity: 88% change in mental status (lethargy) - other sxs: HA photophobia charcteristic rash (N. meningitidis) N/V neuro complications: seizures, focal beuro deficits, papilledema
Exanthem of meningitis?
- due to small hemorrhages under body - all parts of body are affected - rashes donβt fade under pressure (non blanching) pathogenesis: septicemia wide spread endothelial damage activation of coag thrombosis and platelets aggreg reduction of platelets - sign of septicemia
What tests are specific to meningitis? What should be included in PE?
- thorough physical exam including complete neuro exam - 2 tests that are specific: kernig sign: supine position, flex hip and inabilty to allow full extension when hip is flexed brudzinski sign: spontaneous flexion of hips during attempted passive flexion of neck - also check for passive flexion, extension and rotation of neck
When can meningitis be essentially ruled out?
- if pt has no fever, no neck stiffness, and no alt mental status - utility of PE in detecting meningitis not great, if you suspect meningitis strongly consider LP to definitely rule it out
Labs and dx tests for meningitis work up?
- CBC with diff - CMP - UA - blood cultures x 2: 50-75% - LP: if delayed or deferred obtain blood cultures and start empiric ab therapy - possible CT to r/o mass lesion or other causes of IICP or route of infection
What pts need a head CT b/f LP?
- immunocomp. or impaired cellular immunity - hx of seizure w/in 1 wk prior to presentation - any of following neuro abnormalities: *hx of CNS disease (stroke, lesion, focal infection) *alt Level of consciousness *papilledema *focal neuro deficit * pts with these RFs should have CT done to ID possible mass lesions and other causes of IICP - over-employed dx modality leads to unnecessary delays in tx and added cost - rarely indicated in pt with suspected acute meningitis - mandatory in pt with possible focal infection - increased sensitivity with contrast enhancement (see cerebral edema)
What is CT in bacterial meningitis used for? Indicated in what pts?
- used to ID CIs to LP and complications that reqr prompt neurosurgical intervention such as sx hydrocephalus, subdural empyema, and cerebral abscess - indicated in pts who have evidence of head trauma, sinus or mastoid infection, skull fracture and congenital anomalies - may ID cerebral edema, effusion, hydrocephalus, abscess - may reveal cause of infection - may provide normal findings - dx of acute BM isnβt made on basis of imaging - made by hx, PE and labs!
Is a MRI useful in meningitis workup?
- not generally useful in acute dx - very helpful in investigating potential complications developing later in clinical course such as venous sinus thrombosis or subdural empyema
LP findings in bacterial meningitis?
- elevated opening pressure - cloudy, purulent appearance - leukocytosis (1000-5000 with greater than 80% neutrophils) - protein of 100-500 mg/dL - glucose of less than 40 mg/dl
Gram stain findings in bacterial meningitis?
- gram + diplococci suggest S. pneumo - gram - diplococci suggest N. meningitidis - small pleomorphic gram - coccobacilli suggest H flu - gram + rods and coccobacilli suggest listeria
Empiric tx for BM?
- mainly aimed at S. pneumo and N, meningitidis: cefotaxime (claforan) or ceftriaxone (rocephin) + vanco - for L monocytogenes (older than 50): ampicillin or PCN G + gentamicin alt: TMP-SMX or meropenem - nosocomiaL cover gram (-) (E.coli, K, pneumoniae and pseudomonas) and gram + use ceftazidime (Fortaz) + vanco *tx time doubled in immunocompromised pts
RFs for drug resistant S. pneumoniae (DRSP)?
- extremes of age - recent ATB rx - significant comorbid disease - HIV infection or other immunodeficiency - day care or day care pt/sib - recent hospitalization - congregate settings (correctional facilities, military, college dorms)
Neuro complications of BM? CV complications?
- IICP and cerebral edema - seizures - CN palsies (5-11%) - hemiparesis CV complications (rare): - vessel wall irregularities and focal dilatations - arterial occlusions - focal arterial bleeding - venous thrombosis - sensorineural hearing loss: greater with s. pneumo as cause
Role of steroids in tx of BM?
- early IV admin of glucocortiocoids has been eval as adjuvant therapy in an attempt to diminish the rate of hearing loss, cerebral edema, and other neuro complications as well as mortality - adding dexamethasone 0.15 mg/kg q 6 IV b/f or w/ start of abx reduces mortality and neuro disability in pts with GCS scores of 8-11 and pneumococcal dx - must be given early for best results - continued for 4 days if gram stain and/or culture consistent consistent with S. pneumoniae
Prevention of meningitis?
- avoid sharing anything personal with anyone who could potentially be sick - good hand washing/sanitizing vaccines: -Hib (routine childhood) -PCV13 (routine) -PPSV23 (older children and adults) -Meningococcal conjugate vaccine (menactra): older children and adults -serogroup B meningococcal vaccine (Bexsero) CDC recommends all 11-12 yos be vaccinated with quadrivalent vaccine with booster at 16 - adolescents and young adults may also be vaccinated with serogroup B vaccine at age 16-18 if outbreak or complement component deficiences, fxnl or anatomic asplenia
Adults should get quadravelent meningococcal conjugare vaccine (mennactra) if?
-complement deficiency -fxnl or anatomic asplenia - microbio exposed to N.meningitidis - traveling to countries where disease is common - part of pop idβd to be at risk b/c of outbreak - first year college student living in residence hall -military recruit
what is aseptic meningitis?
- clinical and lab evidence for meningeal inflammation with neg bacterial cultures, most common cause is enterovirus, but other etiologies: mycobacteria, fungi, spirochetes, parameningeal infections, meds and malignancy
Presentation of aseptic meningitis?
- fever - HA - stiff neck - photophobia - contrast to BM: aseptic meningitis is self limited course that resolves w/o specific therapy
Etiologic agents of aseptic meningitis?
- enterovirus, HSV, HIV, West Nile, varicella zoster, mumps, influenza, lymphocytic chorio-meningis virus (LCM), syphilis, lyme dz, fungal infections, TB, neoplasms of leptomeninges (breast, lung, melanoma, GI), NSAIDs, IVIG, TMP-SMZ
Approach to figuring out aseptic meningitis?
- comprehensive hx: travel, exposure, exanthems, drugs - if CSF with LP fairly clear, you can observe pt w/o abx - if uncertain, start on abx and wait 24-48 hrs for culture results: if pt improving and cultures neg then abx can be stopped if pt not improving and cultures neg may need to repeat LP and send for viral cultures and other specialized tests (PCR) depending on clinical situation - tx is supportive
What is encephalitis? Causes?
- inflammation of brain parenchyma, manifested by neuro dysfxn - true incidence of encephalitis is difficult to determine b/c the clinical syndromes and results of routine lab tests are typically nonspecific - causes: viral post infectious autoimmune paraneoplastic med induced
Clinical presentation of encephalitis?
- alt mental status (hall mark) - seizures common - focal neuro abnorm can occur - exaggerated DTRs and/or pathologic reflexes - motor or sensory deficits - altered behavior and personality changes - speech or movement disorders - hemiparesis, flaccid paralysis, and parasthesias
Imaging findings in encephalitis?
- CT can r/o space-occupying lesion or brain abscess - MRI detects demyelination and certain pattern clues to specific etiologies - EEG often abnormal
Complications of encephalitis?
- status epilepticus - cerebral edema - inapprop secretion of ADH - cardiorespiratory failure - DIC - death
Diff b/t meningitis and encephalitis?
- presence or absence of normal brain fxn is impt distinguishing feature b/t encephalitis and meningitis - pts with men. may be uncomfortable, lethargic, or distracted by HA, but their cerebral fxn remains norm. - in encephalitis: abnorm in brain fxn are expected, included alt mental status, motor or sensory deficits, alt behavior, and personality changes and speech or movement disorders - seizures and postictal states can be seen in meningitis and shouldnt be just assoc with encephalitis - sxs and signs of meningeal irritation (photophobia and nuchal rigidity) usually absent with pure encephalitis - distinction b/t 2 entities is frequently blurred since some pts may have both parenchymal and meningeal process - meningoencephalitis
Etiologies of encephalitis? viral?
- only found in 35% of cases - HSV type 1 - arbovirus (arthropod vectored) - *3 alpha viruses: Western, Easter, and Venezualan equine encephalitis *flaviviruses: west nile virus, st. louis encephalitis, japanese B encephalitis, dengue and yellow fever - buny viruses: california encephalitis
Non-viral/post infectious etiologies?
- lyme disease - RMSF - rabies encephalitis - syphilis - TB - hx depending on travel, activity, area, time of year can give clues to etiologies
Viral encephalitis findings from LP tap?
CSF: - may have increased WBCs with diff showing mostly lymphocytes - elevated protein, but less than 150 mg/dL - normal glucose
Dx of viral encephalitis?
- knowledge of pts immune status is critical - dx: after all other tests a brain bx can be done as last resort, but in majority of cases of aseptic meningitis and encephalitis the cause isnβt determined
Signs and sxs of West nile virus caused encephalitis?
- fever - malaise - stiff neck - sore throat - N/V - stupor leads to convulsions leads to coma - signs of UMNL (exaggerated DTRs, absent superficial reflexes, pathologic reflexes, spastic paralysis) - CSF protein and opening pressure increased and there will be lymphocytic leukocytosis - approx 1/150 infections will result in severe neuro disease - most sig RF is advanced age tx is supportive and RIBAVARIN - helpful
RMSF encephalitis? Sxs and signs CSF? other test?
- rickettsia rickettsii: gram - intracellular bacteria endothelial cells: small vessel vasculitis - Southeast, summer - 2nd most common tick borne illness: Fever, HA, N, rash: 80% rash: blanching maculopapular, palms and soles, spreads centrally, later petechial and purpuric - hyponatremia, thrombocytopenia - CSF: increased lymphocytes/PMNs, increased protein, and neg gram stain - mild increase in LFTs
Dx of RMSF encephalitis? Tx?
- clinical suspicion - low threshold to empirically tx - rash may be absent in 20% - RMSF serologies: initial may be negative, need convalescent titers several weeks later
Tx of RMSF?
- doxycycline 100 BID x 7 days - donβt delay! - no indication for proph. tx after uncomplicated tick bite
Big pts of RMSF? Where is it? Sxs? lab values?
- empiric tx if even suspected - in NC - any fever, HA, neuro syndrome will need tx - first serology titers not reliable - hyponatremia, low platelets, elevated LFTs, think RMSF - Donβt wait for the rash
Lyme disease? stages?
- Borrelia burgdorferi - deer tick (smaller) - NE/great lakes, but reported in almost all states - most common cause of tick borne disease - stages: 1. erythema migrans rash, viral like syndrome 2. multiple EM lesions and/or neuro and/or cardiac findings 3. late/chronic: intermittent or persistent arthritis and possibly subtle encephalopathy or polyneuropathy
Tx of early and late lyme disease?
- early: doxy 18-21 days amoxicillin 21-28 days cefuroxime 21 days -late or severe: cefotaxime (claforan) q 8 hrs PCN G q 4 hrs
Brain abscess?
- focal pyogenic infection, ringed by granulation tissue and outer fibrous capsule surrounded by edematous brain tissue
Hematogenous spread leading to brain abscess?
- chronic pulm infections, lung abscess or empyema - skin infections - pelvic infections - intraabdominal infections - esophageal dilation and endoscopic sclerosis of esophageal varices - bacterial endocarditis (brain abscess complicates 2-4% of cases) - cyanotic congenital heart disease (most common in children)
Contiguous spread - leading to brain abscess? other origins of brain abscess?
- (middle ear, sinus, teeth): otogenic (strep, bacteroides)- temporal lobe/cerebellum - sinogenic and odontogenic (anaerobic and microaerophilic streptococci) - frontol lobe - trauma: can develop years after the injury - post neurosurgical procedures: may also be delayed, more difficult to tx
Classic triad of brain abscess?
- HA, fever, focal deficit (less than 1/3 of cases) - toxic appearance rare - seizures, vomiting, confusion, obtundation possible - frontal lobe - hemiparesis - temporal lobe-homonymous superior quadrant visual field deficit or aphasia - cerebellum - lim incoordination or nystagmus
Dx of brain abscess?
- CT with contrast or MRI - LP CI!!! - needle guided bx or aspiration for confirmation or to direct tx in cases not responding - tx: -otogenic: cefotaxime -sino or odontogenic: Pen + flagyl - penetrating trauma or neurosurgery: Nafcillin + ceftazidime - hematogenous: Pen + flagyl - no obvious source: cefotaxime + flagyl
Every pt with suspected meningitis should have what done unless CI?
- LP - screening CT scan if worried about IICP but isnβt necessary in majority of pts
Usual CSF findings in pts with BM?
- elevated WBCs, elevated protein and low glucose - absence of one or more ot typical findings is of little value
Advantage of gram stain in susp. BM?
- advantage of suggesting the bacterial etiology one day or more b/f cultures are available
Pt with encephalitis will most likely deny what sxs?
- CP - sore throat - fever - abdominal pain - N/V/D - rash - can be either primary or post infectious, but typically viral - get a good hx!!
