Week 13 Flashcards
Fungi have a cell wall composed of ___ and a cell membrane composed of ___
Chitin
Ergosterol (acts like cholesterol in human membranes, note that bacterial membranes do not have sterols)
True or false… antibacterial agents can also be used to target some fungal infections
False
____ is the leading cause of death in immunocompromised patients, patients with asthma, patients with cystic fibrosis, mainly due to hypersensitivity reactions to antigens to _____
Pulmonary aspergillosis
Aspergillus fumigatus
What are four different targets of antifungals?
Components of fungal cell membrane
Cell wall synthesis
Nucleic acid synthesis
Microtuble function
What three types of antifungal drugs interact with or inhibit ergosterol synthesis?
Amphotericin B
Azoles
Echinocandins
What two drugs bind to ergosterol in fungal membranes to disrupt membrane function and permeability? Describe their mechanism in more detail.
Amphotericin B
Nystatin
Bind to plasma membrane ergosterol and damages the membrane by forming pores which cause leakage of potassium ions.
What two drugs inhibit 14-alpha-sterol dymethylase, to prevent ergosterol synthesis, and lead to the accumulation of 14-alpha-methylsterols?
Itraconazole
Fluconazole
What two drugs inhibit squalene epoxidase to prevent ergosterol synthesis?
Naftifine
Terbinafine
What drug inhibits fungal cell wall synthesis by inhibitin glucan synthesis?
Echinocandins (caspofungin)
Is amphotericin B broad spectrum or narrow spectrum? What are its clinical uses?
Broad
However, due to its extensive side effects, it is only reserved for severe infections.
First line therapy for invasive, life threatening, systemic and localized candidemia
Effective for aspergillus infections
True or false… amphotericin is absorbed well orally
False. It is only administered parenteral (in hospital setting)
What are the adverse effects of amphotericin b?
Highly toxic chronic reactions.
Immediate reactions include fever, chills, muscle spasms, etc. but can be avoided by slow infusion, decrease daily dose, premedication
Slower reactions are most detrimental for renal toxicity and may also cause neurotoxicity, as well as other side effects
Nystatin’s mechanism is similar to amphotericin b. How is it administered? What are its clinical uses? What are some adverse effects?
Topical administration only
Treatment for oral thrush (candida albicans) and vaginal candidiasis
Adverse effects: higher systemic toxicity than amphotericin B (why its only administered topically). Disulfuram-like reactions
What is the spectrum of azoles?
Antibacterial
Antiprotozoal
Antihelminthic
Antifungal
Describe the classification system of azoles.
Based on the number of nitrogen atoms attached to the ring
Imidazoles (2)
Triazoles (3)
What is the mechanism of azoles?
Inhibit ergosterol synthesis
It does this by blocking ianosine 14a-demethylase, a fungal CYP-450-dependent enzyme that converts ianosterol to ergosterol
This will ultimately increase membrane fluidity, increase permeability, and inhibit fungal cell growth/replication
How are azoles administer? What is their clinical use? What are its contraindications?
Administered topically or systemically
Used for superficial fungal infections or systemic infections
Contraindicated in pregnancy, during lactation, or in patients with hepatic dysfunction
-it will also inhibit human gonadal steroid synthesis causing decreased testosterone
What is the most commonly prescribed systemic antifungal? It is the drug of choice for ____ but does not treat _____. It is contraindicated in ___ patients
Flucanazole
Candidiasis albicans (also used to treat fungal cryptococcal meningitis in AIDs patients
Aspergillus
Pregnant
What azole was the first azole and is used for systemic and topical therapy?
Ketoconazole
What azole requires low pH for absorption and is more toxic than fluconazole?
Itraconazole
What azole is administer topically only? It is used to treat Vulcan-vaginal candidiasis, oral candidiasis, and athletes foot.
Clotrimazole and miconazole
What drug is the first line treatment for aspergillus infections?
Vorconizole (an azole)
Ketoconozale and ____ should never be given together. Why?
Amphotericin B
Kentonazole decreases ergosterol in the fungal membrane and thus reduces the fungicidal action of amphotericin B
Amphotericin B is syndergistic with ____
Flucytosine
What is the mechanism of flucytosine? What is the spectrum of flucytosine? What is its clinical use? What are some adverse effects?
Inhibits thymidylate synthetase which inhibits DNA and RNA synthesis in fungi
Specturm: narrow, used for systemic fungal infections
Clinical use: synergistic with amphotericin B for cryptococcal meningitis
Adverse effects: bone marrow suppression
What drugs are considered the penicillins of antifungal drugs? Name one drug of this class.
Echinocandins
Caspofungin
What is the mechanism of echinocandins (caspofungin). What are some clinical uses and side effects?
Blocks cell wall synthesis and maintenance by inhibition of the enzyme 1,3-b glucan synthase.
Clinical uses: fungicidal against some candida species. Fungistatic against aspergillus. Used in azole resistant candida or as a second line agent for refractory aspergillus
Side effects: avoid in pregnancy (embryotoxic).
Note that this is administered via IV
True or false… caspofungin is involved in blocking B-glucan synthase to inhibit fungi cell wall synthesis.
It is generally safe except for in pregnancy
True
What is the mechanism of griseofulvin? What are its clinical uses? True or false… it is effective topically. What are some adverse effects?
Disrupts microtubule function, inhibiting fungal mitosis.
Inhibits growth of dermatophytes (infections of hair, skin, nails)
False. But it has entirely local effects as it accumulates in the hair and nails.
Adverse effects: teratogenic, carcinogenic, severe headaches
Note that this drug has multiple drug interactions (increases metabolism of Warfin)
The use of griseofulvin to treat onychomycosis has mostly been replace by ____. Describe its mechanism and clinical use and adverse effects
Terbinafine
Mechanism: inhibits squalene epoxidase to inhibit ergosterol synthesis, which disrupts cell membrane permeability
Clinical use: concentrated in keratin. Treats dermatophytes
Adverse effects: hepatotoxicity
What two drugs are topical antifungals used for localized candidiasis in patients with normal immune function?
Nystatin
Clotrimazole
What are two systemic antifungals that are used for disseminated disease and in immunocompromised patients?
Fluconazole tablets
Itraconazole tablets
True or false… azoles inhibit CYP-450 function
True
What is bacteriuria?
Bacteria in urine
Often colonization, not infection
What is acute cystitis?
Bacterial infection of the bladder
Infection (and symptoms) confined to lower urinary tract
What is acute pyelonephritis?
Bacterial infection of the upper urinary tract (ureters, renal pelvis, kidney parenchyma)
In order for a patient to have an uncomplicated UTI, what criteria should be met?
Not pregnant
Normal urinary anatomy
No co-morbidities (healthy, outpatient)
If a patient has any of these criteria, they are considered to have a complicated UTI. What are the criteria? (6 things)
Pregnant
Male gender
Abnormal urinary anatomy
Diabetes mellitus
Immune compromise
Indwelling bladder catheter
True or false.. UTI is one of the most common bacterial infection seen in outpatient setting
True
True or false… by age 18, half of women have had at least one UTI. (Cystitis more common than pyelonephritis)
False. By age 32
UTIs develop in ___% of patients with indwelling urinary catheters
10
In healthy individuals, in the absence of infection, which bacteria typically colonize the lower urinary tract?
None. The urinary tract is normally sterile in young, healthy patients
85% of bacteria that cause UTIs are _____
Gram negative colonizers of GI tract
E. Coli (predominant pathogen of UTIs)
May also be proteus mirabilis, klebsiella pneumoniae, staphylococcus saprophyticus
Describe the pathogenesis of UTIs
GI pathogens colonize the peri-urethral mucosa
The bacteria ascend through urethra to bladder (more common in women because the urethra is much shorter, also male prostatic fluid has anti-bacterial properties)
Infection may continue to ascend to the ureters and kidney
True or false.. most untreated lower UTIs will progress to pyelonephritis
False
What are some virulence factors of uropathogenic E.coli?
Pili Flagella Adhesins Siderophores Toxins Polysaccharide coating
What are the symptoms of cystitis?
Increased frequency of urination
Increased urgency of urination
Pain or burning with urination
Suprapubic pain
What are some symptoms pyelonephritis?
*fever or chills
Flank or Costco-vertebral angle pain
Nausea/vomiting
May also have symptoms of cystitis
What is the gold standard for diagnosis of a UTI?
SYMPTOMS + urine culture demonstrating >10^5 colony-forming units of uropathogenic bacteria per ml
True or false… a positive urine culture alone is indicative of a UTI
False. A positive urine culture without symptoms is indicative of an asymptomatic bacteruria
-note that this is an important distinction to be made because it will determine if antibiotics are prescribed or not
What are some indications of a normal urinalysis?
Specific gravity (urine density/water density) = ~1.01
Negative urine nitrite (metabolic product of bacteria)
RBC/WBC count should be less than 5
What are some indications of an abnormal urinalysis?
Cloudy urine with an increased specific gravity
Positive nitrite (indicates nitrogen-metabolising bacteria)
Hematuria and pyuria present (increased WBCs and RBCs
What are the four roles of urinalysis?
Utility for UTI diagnosis is to RULE OUT UTI based on absence of pyuria (<10 WBC or negative leukocyte esterase)
*UA is not necessary when symptoms are present or absent
Pyuria alone is not an indication for antibiotics. Doesn’t indicate if UTI or asymptomatic bacteruria (same for nitrite positive)
True or false… pyuria is common in patients with asymptomatic bacteruria. Thus, pyuria in patients with asymptomatic bacteriuria is NOT an indication for antibiotic therapy. It may be caused by STDs, catheter in place, or interstitial nephritis
True
True or false… antibiotics are generally needed in order to resolve uncomplicated cystitis, otherwise they will continue to persist.
False. Cystitis generally resolved without antibiotics; they are used to provide symptom relief
Name three drugs that can be used to treat uncomplicated cystitis.
Nitrofurantoin
Trimethoprim-sulfa methoxazole
Fosfomycin
-note that all of these drugs can be taken orally
Name three drugs that are used to treat uncomplicated pyelonephritis
Fluoroquinolones
Trimethoprim-sulfa methoxazole
B-lactams
- note that if the patient is unstable, they should be admitted to the hospital for IV antibiotics
Broad spectrum antibiotics have side effects of killing normal GI flora, thus the newer trend is to prescribe narrower antibiotics for UTIs. Name two bacteria that are growing restitant to antibiotics in UTIs
E.coli resistance to amoxicillin
Most UTI bacteira resistant to fluoroquinolone
Asymptomatic bacteriuria is a positive urine culture without symptoms. Usually you do not prescribe antibiotics, unless…. (4 things)
Pregnant
Pre-urology procedure
Renal transplant
Neutropenia
True or false… antibiotics do not decrease ASB or prevent subsequent development of UTI
True
What are the main consequences of over-testing and treatment of UTIs?
Its hard to ignore a positive test, leading to unnecessary prescriptions and missing the true diagnosis
Also will increase risk of developing resistant organisms
A patient is admitted with an indwelling catheter. Urine culture reveals >10^5 cfu e.coli. There are no urinary symptoms and the patient feels well. What is the best management?
Remove catheter if possible, no further treatment
What are some symptoms of a catheter-associated UTI?
Usually lack typical UTI symptoms
New fever with no other source
CVA tenderness, flank pain, pelvic discomfort
Explain the diagnosis of a catheter associated UTI
Presence of inflammation on urinalysis doesn’t correlate with infection, however absence of pyuria rules out CA-UTI
Urine culture with >10^5 cfu bacteria
UA/culture must be interpreted based on clinical scenario
What is the treatment for a catheter-associated UTI?
Remove catheter whenever possible
Replace catheters that have been in for more than 2 weeks if still indicated
Antibiotic duration is 7 days if prompt response. Or 3 days if catheter removed in female patient with no evidence of associate pyelonephritis
What are anaerobes?
Do not require oxygen for life and reproduction and oxygen direct toxic effect may prohibit their growth
Name three toxic byproducts of oxygen
Superoxide
Hydrogen peroxide
Hydroxyl radical
Explain why anaerobes are party animals
They tend to grow in mixtures of organisms. This is because other bacteria tend to lower the redox potential of oxygen and provide favorable conditions for the growth of anaerobes.
Volatile and foul-smelling metabolic byproducts of other anaerobes contribute to his balanced environ,ent
What genus of anaerobes are typically exogenous?
Clostridium
True or false…. most anaerobic infections are seeded from normal endogenous flora.
True
What parts of the body have anaerobes as part of the normal flora?
Mouth
Vagina
Bowels
Skin (deep in pores)
Some anaerobic species are characteristic of the site they are from, without much crossover. Name the anaerobes of the mouth, skin, vagina, and colon
Mouth Fusobacterium Veilonella Actinomyces Porphyromonas Prevotella
Skin
Proprionibacterium
Vagina
Lactobacillus
Prevotella bivia
Colon
Bacteriodes fragilis
What are predisposing factors for an anaerobic infection?
Trauma to mucous membranes or skin
Vascular stasis
Tissue necrosis
Decrease of redox potential (cutting off blood supply)
True or false… anaerobes typically require longer incubation periods in the laboratory
True
Name three anaerobic non-spore forming gram positive rods
Actinomyces
Proprionibacterium
Mobiluncus
Describe actinomyces species
Chronic, granulomatous, infectious disease with sinus tracts and fistulae, which erupt to the surface and drain pus containing sulfur granules.
Describe proionibacterium species
Normal skin and and respiratory flora. Scope of infection similar to coagulase negative staphylococcus species
P. Acnes is often found in acne pustules
Describe mobiluncus species
Act synergistically with organisms including gardenella vaginosis to cause bacterial vaginosis
Name two gram positive cocci anaerobic groups. Describe them
Peptostreptococcus species. - usually found in abscess that arise from misplaced oral flora. Brain or deep lung abscess
Anaerobic and microaerophillic streptococcus species. - habitat and appearance similar to peptostreptococcus species. Note that these species do not respond to the classic anaerobe drug metronidazole.
Name one anaerobic gram negative cocci group and describe it
Veillonella - th only anaerobic genus of gram negative cocci usually implicated as pathogenic. Found in mixed infections of oral origin
Name three gram negative anaerobic rods and describe them.
Bacteriodes- the bacteriodes fragilis group account for about 70% of clinically significant anaerobic bactermias. Bacteriodes fragalis out number E. coli 1000:
Prevotella and porphyromonas - former pigmented bacteriodes species. Common in mouth flora and dental abscesses
Fusobacterium - also mouth associated. Can be mixed with actinomyces. So if you find fusobacterium, you want to do screening to look for actinomyces as well
What is the treatment for anaerobes?
Create an environment in which anaerobes cannot proliferate. Useful measures include removing dead tissue (debridement), draining pus, eliminating obstructions, etc.
Arrest the spread of anaerobes into healthy tissue
Neutralize toxins
What are the five stages of biofilm formation?
Attachment
Irreversible binding
Layering/maturation
Ultimate thickness/maturation
Dispersion
Describe the attachment phase of biofilm formation
Occurs in seconds
Reversible binding
Logarithmic growth
Pili and bacterial adhesion molecules
Changes in gene expression (decrease flagella, increase adhesion molecules)
Describe the irreversible binding phase of biofilm formation
Occurs in minutes
Exopolysaccharides trap nutrients and planktonic bacteria
Cells are sessile
Describe the difference between the layering and ultimate thickness phases in biofilm formation
Layering - greater than 10 um thickness
Ultimate thickness - greater than 100 um thickness. Some cells released from substrate, but trapped in the EPS
Describe the dispersion phase of biofilm formation
Occurs in several days
Cells leaving
As nutrition become scarce, there are changes in gene expression
Cells again become planktonic
What are three purposes of fluid-filled channels in biofilms?
Exchange nutrients
Dispose of wastes
Some motile organisms
What are the three layers of mature biofilm? Describe them.
Outer - most exposure to nutrients. Most active organisms. Some become planktonic.
Intermediate - metabolism is down-regulated, but still using nutrients and exchanging genes
Innermost - attached, earliest and least active, includes the persister cells
What are planktonic cells?
Free living.
The can begin biofilm formation and leave the biofilm at any time
What are sessile cells?
Attached/ participating in the biofilm community
What are persister cells?
Located bottom of the heap
Metabolically inert
Present in all biofilms
Potential for maintenance of gene pool
Resist environmental stress, including antibiotics
Possibly able to disable apoptosis
What are some advantages to living in a biofilm?
Protection from host defenses
Physical barrier to PMNs
Potential to out-compete normal biota
Gene transfer (ability to spread resistance in community)
Provide protective enzymes
Perform as organic polymers
True or false… as a biofilm forms, streamers of cells extend from the surface and break away to form new biofilms elsewhere. Disaggregation can transmit already up-regulated resistant aggregates of organisms to other body sites
True
What are the primary colonizers of dental plaque?
Streptococcus mutans and actinomyces
Pili and adhesion molecules
Glucan polymer glycocalyx (EPS)
What are the bridge bacteria in dental plaque?
Glucan-binding proteins
Fusobacterium
Cant bind to pellicle, but can bind to primary colonizers
What are the late colonizers of dental plaque?
Streptococcus salivarius, proprionibacterium, prevotella, veillonella, selenomonas
Generally considered non-pathogenic
True or false… dental plaque is mostly comprised of gram-negative organisms
False.. mostly gram positive
Name four dental pathogens associated with plaque
Porphyromonas gingivalis
Bacteroides forsythia
Aggregatibacter actinomycetemcomitans
Treponema denticola (spirochete)
