Exam 2: Conceptual Flashcards
For abx to work it must do the following 4 things
- enter bacterial cells
- reach site of action
- bind to target involved in bacterial function
- significantly impair function
GP or GN?: Thick peptidoglycan layer
Gram positive
GP or GN?: Thin peptidogylacan
Gram negative
___ are enzymes in the cell wall that are vital for cell wall synthesis, cell shape, and structural integrity
Penicillin binding proteins (PBPs)
___ is the location of beta-lactamases in gram negative bacteria
Periplasmic space
Outer membrane of gram negative bacteria contain ___ and ___
Lipopolysaccharide (LPS, endotoxin) and porins
The periplasmic space of gram negative bacteria is located between __ and ___
Cytoplasmic membrane and outer membrane
GP Aerobic: Cocci: Clusters: Coagulase +
Staphylococcus aureus
GP Aerobic: Cocci: Clusters: Coagulase -
Other staphylococcus
- epidermis
- Hominis
- Haemolyticus
- Capitus
- Saprophyticus
GP Aerobic: Rods
Listeria
Nocardia
GP Anaerobic: Cocci
Peptostreptococcus
GP Anaerobic: Rods
Clostrium spp (Spore forming) – C. diff
Propionibacterium
Actinomyces
GN Aerobic: Cocci
Neisseria meningitidis
Neisseria gonorrhoeae
Moraxella catarrhalis
GN Aerobic: Rods: Lactose forming
SKEEP
Salmonella spp. Klebisella pneumoniae Escherichia coli Enterobacter spp. Proteus mirabilis
GN Aerobic: Rods: Non-lactose forming
PAS
Pseudomonas aeruginosa
Acinetobacter baumanni
Stenotrophomonas maltophilia
GN Anaerobic: Rods
Bacteroides spp
Prevotella
Fusobacterium
Atypical
Chlamydia spp (C. pneumoniae, trachomatis)
Mycoplasma spp (M. pneumoniae, genitalium)
Legionella spp (L. pneumophilia)
Two distinct systems of immunity
Innate (nonspecific)
Adaptive (specific)
Systems of immunity: Innate (non-specific)
Physical barriers, phagocytes (neutrophils, macrophages), proteins
Strategically predeployed and prepositioned to prevent and/or quickly neutralize infection
Systems of immunity: Adaptive (specific)
Evolves and adapts against invading pathogens
Divided into humoral (B lymphocytes) and cellular (T lymphocytes) mediated arms
Systems of immunity: Innate: Exterior defences
Skin, mucus, cilia, normal flora, saliva, low pH of stomach, skin, and GU tract
Systems of immunity: Adaptive: Exterior defenses
none
Systems of immunity: Innate: Specificity
Limited and fixed
Systems of immunity: Innate: Memory
None
Systems of immunity: Innate: Time to response
Hours
Systems of immunity: Innate: Soluble factors
Lysozymes, complement, C-reactive protein, interferons
Systems of immunity: Innate: Cells
Neutrophils, monocytes, macrophages, natural killer cells, eosinophils
Systems of immunity: Adaptive: Specificity
Extenisve
Systems of immunity: Adaptive: Memory
Yes
Systems of immunity: Adaptive: Time to response
Days
Systems of immunity: Adaptive: Soluble factors
Antibodies, cytokines
Systems of immunity: Adaptive: Cells
B lymphocytes
T lymphocytes
Barriers: Skin
Physical and immunologic barrier to invasion by microbes
Dryness, salinity, and mild acidity, combined with normal skin flora, help make it an inhospitable environment for invading pathogens
Sebum, a lipid-rich coating that protects and lubricates hair and skin, has antimicrobial properties
Barriers: Mucous Membranes
Most pathogens enter through mucosal surfaces of the respiratory, GI, and urogenital tracts
Mucus, formed by highly glycosylated proteins called mucins, which are often specific to the mucosal site, carries immune cells, antimicrobial factors, bacteria, nutrients, and waste
Barriers: Respiratory tract
Inhaled microorganisms can cause respiratory disease if they are not eliminated quickly
Trachea, bronchi, and bronchioles are lined with a ciliated epithelial surface that propels mucus upward, leading to the mechanical clearance of any trapped pathogens
This, with the addition of coughing, leads to 90% of deposited material being cleared in less than 1 hour
Barriers: GI Tract
Acidic pH of the stomach and the antibacterial effect of the pancreatic enzymes, bile, and intestinal secretions are effective, non-specific, antimicrobial defense factors
GI tract is also coated in mucus that has different properties
Small intestine - mucus limits the number of bacteria that can reach the epithelium and Peyer patches
Large intestine - inner mucus layer relatively free of bacteria, but the outer mucus layer supports a subset of commensal flora
Paneth cells of the small intestine, located in the crypts of Lieberkühn, secrete AMPs such as β-defensins, lysozyme, REGIIIγ, and type II phospholipase A
Most of these AMPs are localized in the mucus layer; thus, in addition to functioning as a physical barrier, mucus limits bacterial penetration by concentrating AMPs near the epithelial surface
Mucus is continuously secreted from goblet cells and Paneth cells and moves distally with peristaltic waves, expelling potential pathogens and requiring bacteria to travel against mucus flow to reach the tissue surface
Barriers: GI Tract: Small intestine
Mucus limits the number of bacteria that can reach the epithelium and Peyer patches
Barriers: GI Tract: Large intestine
inner mucus layer relatively free of bacteria, but the outer mucus layer supports a subset of commensal flora
Mucus is continuously secreted from __ and ___
goblet cells
Paneth cells
Barriers: GU tract
Lactobacillus spp. metabolize sugars into lactic acid, lowering the pH of the vagina (restricts growth of invading organisms)
The vaginal flora prevents urogenital diseases, including bacterial vaginosis, yeast infections, UTIs, and HIV
The lower urinary tract is rinsed with urine 4-8 times each day, eliminating potential pathogens– Unless they are capable of firmly attaching to epithelial cells of the urinary tract (e.g., Neisseria gonorrhoeae, certain strains of Escherichia coli )
Urine is bactericidal for some strains of bacteria, mostly because of its pH, although factors such as hypertonicity, urea, and the presence of AMPs play a role
Uromodulin is a glycoprotein produced by the kidneys that protects against kidney stones and binds to E. coli, preventing them from attaching to the cellular lining of the urinary tract
Barriers: GU Tract:____ is a glycoprotein produced by the kidneys that protects against kidney stones and binds to E. coli, preventing them from attaching to the cellular lining of the urinary tract
Uromodulin
Barriers: Eye
Constant bathing of the eye by tears is an effective means of protection
Foreign substances are diluted and washed away via the tear ducts into the nasal cavity
Cells of Innate Immunity: WBC
Major role is defense against invading organisms
Normal range 4500-10,000 cells/mm3
Usually elevated in response to infection
Cells of Innate Immunity: Neutrophils
70% of WBCs
Enter tissues to phagocytize pathogens
Segs (segmented nucleus) mature neutrophils
Bands (lack segments) immature neutrophils
Left shift (historical term) = bands increased (~5%) during acute infection and shift to the left
Cells of innate immunity differential: WBC splits to
Granulocytes
Agranulocytes
Cells of innate immunity differential: Agranulocytes splits to
Lymphocytes
Monocytes
Cells of innate immunity differential: Granulocytes splits to
Polymorphonuclear granulcytes (PMNs)
Cells of innate immunity differential: Polymorphonuclear granulocytes (PMNs) splits to
Neutrophils
Basophils
Eosinophils
Cellular function of macrophage/monocytes
Antigen presenting cell
Surveillance of antigens
Cellular function of neutrophils
Defense against bacteria and fungus
Cellular function of eosinophils
Defense against parasites
Response against allergic reactions
Cellular function of basophils
Allergic response
Cellular function of B lymphocyte
Antibody production
Antigen presenting cell
Cellular function of T lymphocyte
Cellular immunity against virus and tumors
Regulation of the immune system
Bacterial resistance: Intrinsic
some organisms are notorious for intrinsic ability to express multiple types of resistance
Acinetobacter baumanni
Pseuodomonas aeruginosa
Bacterial resistance: Acquired
some organisms acquire genes, which enable a mechanism of resistance, from another species of bacteria that already had it through transfer of mobile genetic elements
Bacterial Resistance : Intrinsic Resistance: Mechanisms
Absence of abx target
Bacterial cell impermeability
Bacterial resistance: Intrinsic resistance: Examples
Vancomycin vs. Gram-negative bacteria
Large molecule – too big to get through porin channel
Cephalosporins vs. enterococci
Beta-lactams vs. mycoplasma
Mycoplasma have no cell wall (no active site)
Aminoglycosides vs. anaerobic bacteria
Actively transported across cytoplasmic membrane into interior of cell
Process is dependent on energy, oxygen, and pH
Bacterial resistance: Acquired: Mutation
May occur spontaneously in every 106 to 107 bacterial cells
May alter the target site of the antibiotic leading to reduced affinity and decreased activity
Bacterial Resistance: Acquired: Genetic exchange
Conjugation – direct contact or mating via sex pili (most common)
Transduction – genes are transferred between bacteria by viruses
Transformation – The transfer or uptake of “free floating” DNA from the environment; then DNA is integrated into the host DNA
Plasmids (KNOW THIS)
Self replicating extrachromosomal DNA
Genes encoding for resistance to many antibiotics can exist on one
Conjugative plasmids contain additional genes that can initiate transfer from one bacterium to another
Mechanisms of resistance: Streptococcus pneumoniae: Beta-lactams
Target site changes PBPs
Mechanisms of resistance: Streptococcus pneumoniae: Macrolides
Target site changes (methylation of adenine residue in domain V of 23S rRNA)
Efflux (mefE)
Mechanisms of resistance: Streptococcus pneumoniae: Fluoroquinolones
Target site changes (DNA gyrase (gyrA mutations) and topoisomerase IV (parC mutations)
Mechanisms of resistance: Staphylococcus aureus: Penicillin
Enzymatic modification (penicillinases)
Mechanisms of resistance: Staphylococcus aureus: Methicillin, oxacillin, nafcilin, and cefazolin
Target site changes (PBP2a-mecA)
Mechanisms of resistance: Staphylococcus aureus: vancomycin (intermediate)
Alteration of cell wall precursor targets (thickened cell wall)
Mechanisms of resistance: Staphylococcus aureus: Vancomycin (resistant)
Alteration of cell wall precursor targets (plasmid-mediated transfer of vanA from VRE)
Mechanisms of resistance: Pseudomonas aeruginosa: Beta-lactams
Enzymatic modification (AmpC cephalosporinases, extended-spectrum beta-lactamases, etc.)
Active Efflux (MexAB)
Reduced outer membrane permeability (loss of OprD channel)
Mechanisms of resistance: Pseudomonas aeruginosa: Aminoglycosides
Enzymatic modification (aminoglycoside modifying enzymes)
Efflux (MexXY)
Alteration of ribosomal targets
Mechanisms of resistance: Pseudomonas aeruginosa: fluoroquinolones
Efflux
Alteration of target enzymes (DNA gyrase mutations)
Mechanisms of resistance: Klebsiella pneumoniae: Beta-lactams
Enzymatic modification (penicillinases, ESBLs, KPC, NDM-1)
Reduced outer membrane permeability
Mechanisms of resistance: Klebsiella pneumoniae: Aminoglycosides
Enzymatic modification (aminoglycoside modifying enzymes)
Alteration of ribosomal targets
Mechanisms of resistance: Klebsiella pneumoniae: Fluoroquinolones
Alteration of target enzymes (DNA gyrase mutations)
Efflux
Protection of target site (plasmid-mediated qnr genes)
What do beta-lactamases do
Enzymes that hydrolyze beta-lactam ring, inactivating it
What are 3 examples of beta-lactamases
Extended-spectrum beta-lactamases (ESBLs)
AmpC beta-lactamases
Carbapenemases (ex. KPC)
Beta-lactamase inhibitors
Beta-lactamase inhibitors structurally similar to beta-lactam antibiotics but generally lack antibacterial activity (exception: sulbactam)
When combined with beta-lactams, they bind beta-lactamases and protect active antibiotic from inactivation
Beta-lactamase inhibitors structurally similar to beta-lactam antibiotics but generally lack antibacterial activity (exception:____)
sulbactam
Term ‘ESBL’ refers to group of beta-lactamases that are able to hydrolyze penicillins and cephalosporins up through the____ generation
third
(resistance thru 3rd gen like ceftriaxone)
*Resistance thru ceftriaxone and aztreonam= ESBL
Treatment of ESBL
Getting more complex
Carbapenems – long-standing drugs of choice
ESBL: Comparable outcomes data for older beta-lactam/beta-lactamase inhibitors (piperacillin/tazobactam)
Data fairly new; role for ESBL yet to be firmly established
New data for bloodstream infections showed worse outcomes with BLBLI compared to carbapenems
ESBL: worse outcomes for ___
Cefepime
ESBL: Newer inhibitor combinations are newer paradigm as broader spectrum, however mostly being reserved for carbapenem-resistant organisms
Ceftazidime/avibactam
Ceftolozane/tazobactam
ESBL confers resistance to (3 abx classes)
penicillins, cephalosporins, and monobactams
Not carbapenems (still active, TOC) ; cefepime activity is variable
AmpC
Class C cephalosporinases (AmpC enzymes)
(“SPICE”):
Serratia
Pseudomonas aeruginosa
Indole positive Protea (Proteus vulgaris, Providencia spp.)
Citrobacter freundii
Enterobacter cloacae, Klebsiella aerogenes (previously E. aerogenes)
(“SPACE”): Acinetobacter spp. are capable of similar beta-lactamase production by a similar mechanism and should be treated as above
AmpC: Treatment options and what to avoid
Treatment options: Carbapenems Fluoroquinolones TMP/SMX Cefepime Aminoglycosides
Avoid:
Ceftriaxone
Piperacillin-tazobactam
ESBL or AmpC?: Ceftriaxone is susceptible
AmpC (if ceftrixone is susceptible, def not ESBL)
Carbapenemases: 2 types
Serine carbapenemases (KPC)
Metallo-beta lactamases (NDM, VIM, IMP)
Carbapenemases: 2 types: Serine carbapenemases (KPC)
Found worldwide in many Gram-negatives including E. coli, Citrobacter, Enterobacter, Salmonella, Serratia, and Pseudomonas
Transmitted via a plasmid
Carbapenemases: 2 types: Metallo-beta lactamases (NDM, VIM, IMP)
Confer resistance to all beta lactams except monobactams (aztreonam); however often other mechanisms combined
Found in many Gram-negatives
Carbapenemases Potential treatment options
Tigecycline BL/BLI with activity against KPC Ceftazidime-avibactam Meropenem-vaborbactam Imipenem-relebactam \+/- aminoglycosides Polymyxins (colistin, polymyxin B) Some interesting data for double carbapenem therapy (high-dose, prolonged therapy)
Altered target site 4 types
PBPs
Altered cell wall precursor targets
Altered DNA gyrase and/or topoisomerase IV
Ribosomal alterations
Altered target site is more common in ___ bacterial
GP
Altered target site: PBPs
Alteration in PBP decreased binding affinity of beta-lactam to target
Organisms may exhibit increased MICs but remain susceptible (alteration generally confers full resistance)
Examples
Penicillin and cephalosporin resistance in S. pneumoniae
Methicillin (Oxacillin) resistance in Staphylococci (PBP2a – mecA gene **won’t be asked specifically but know that GP staph strep have alterations of PBPs for beta lactams)
Altered target site: Altered cell wall precursor targets
Vancomycin inhibits cell wall synthesis by binding to D-alanyl-D-alanine terminus of the peptidoglycan precursor
Glycopeptide resistance in enterococci (vancomycin resistant enterococci; VRE)
Acquired resistance by the VanA/B genes leading to a change in the target site to D-alanyl-D-lactate
Genes can be transferred to other organisms like S. aureus because it is on a plasmid
Altered target site: Altered DNA gyrase and/or topoisomerase IV
Responsible for resistance to the fluoroquinolones
Altered target site: Ribosomal alterations
Responsible for resistance to macrolides, azalides, aminoglycosides, tetracyclines, clindamycin
Reduced outer membrane permeability
In Gram-negatives, passage of hydrophilic antibiotics is dependent on porin channels
Mutations result in loss of specific porins Resistance
Most commonly seen in Enterobacteriaceae and P. aeruginosa
Beta-lactams, including carbapenems (OprD)
Fluoroquinolones
Efflux pumps
Antibiotic efflux – multidrug resistance efflux pumps
Resistance-nodulation-cell division (RND) family of transporters responsible for significant portion of clinically relevant resistance
Majority of RND efflux systems chromosomally encoded and overexpressed due to mutations in regulator genes
Huge problem among Pseudomonas aeruginosa: at least 7 RND systems identified
Responsible for broad resistance to tetracyclines, fluoroquinolones, aminoglycosides, chloramphenicol, macrolides, azalides, beta-lactams
