Pharm Antimicrobial DSA Flashcards
1
Q
Aminopenicillins
A
i) Ampicillin (PO, IV, IM)
ii) Amoxicillin (PO)
2
Q
Third Generation Cephalosporins
A
i) Ceftriaxone [Rocephin] (IV, IM)
ii) Ceftazidime [Fortaz] (IV, IM)
3
Q
Fourth generation cephalosporins
A
cefepime
4
Q
Carbapenems
A
b) Meropenem
c) Ertapenem
5
Q
B-lactamase Inhibitors
A
a) Ampicillin-sulbactam
b) Amoxicillin-clavulanic acid
c) Piperacillin-tazobactam
6
Q
Glycopeptides
A
Vancomycin
7
Q
Fluoroquinolones
A
Levofloxacin
8
Q
Aminoglycosides
A
Gentamicin
9
Q
Tetracyclines/Glycylcyclines
A
Doxycycline
10
Q
Macrolides/Ketolides
A
Azithromycin
11
Q
Lincosamides
A
Clindamycin
12
Q
Oxazolidinones
A
Linezolid
13
Q
to assess whether antimicrobials are warranted:
A
i) Is an antimicrobial indicated based on clinical findings?
ii) Have appropriate cultures been obtained?
iii) What is the likely causative organism?
iv) What must be done to prevent secondary exposure?
v) Is there clinical evidence or established guidelines that have determined antimicrobial therapy provides a clinical benefit?
14
Q
Once the pathogen is known, one must always continue to question whether management is appropriate and optimized:
A
i) Would a narrower spectrum antimicrobial be more appropriate compared to the empiric regimen?
ii) Is one agent or a combination of agents necessary?
iii) Has the dose, route of administration, and duration of therapy been optimized?
iv) Have the most appropriate tests been completed (e.g., susceptibility)?
v) Are adjunctive measures also applicable (e.g., surgery to remove necrotic tissue)?
15
Q
Prophylactic Therapy
A
i) Goal: prevent infection or prevent dangerous disease in those already infected.
ii) Examples: based on CD4 counts, antimicrobials are initiated in HIV infection (immunocompromised patient) to prevent opportunistic disease; post-exposure prophylaxis is provided to those who have been in contact with a patient with meningococcal meningitis.
16
Q
Preemptive Therapy
A
i) Goal: provide early, targeted antimicrobial therapy in high-risk patients who are currently asymptomatic but have become infected.
ii) Example: cytomegalovirus (CMV) treatment after stem cell and solid organ transplants.
17
Q
Empiric Therapy
A
i) Goal: provide antimicrobial therapy to a symptomatic patient without initial identification of infecting organism. Must consider knowledge of which microorganisms are most likely to cause specific infection/symptoms found in patient.
ii) Example: prescribing antimicrobials for community-acquired pneumonia (CAP) based on knowledge of most likely infecting pathogen.
18
Q
Definitive Therapy
A
i) Goal: infecting organism now known, antibiotics should be streamlined based on susceptibility and duration should be limited to appropriate length.
ii) Example: Staphylococcus aureus bacteremia treated empirically with vancomycin but susceptible to nafcillin, antimicrobials appropriately changed to most narrow spectrum antibiotic.
19
Q
Post-Treatment Suppressive Therapy
A
i) Goal: continue lower dose, antimicrobial therapy when infection has not been completely eradicated and immunological or anatomical defect still present which lead to original infection.
ii) Example: orthopedic implant that has become infected but cannot be removed.
20
Q
Most valuable, time tested method for immediate identification of bacteria
A
gram stain
21
Q
Minimum inhibitory concentration (MIC):
A
lowest concentration of drug required to inhibit growth.
22
Q
Kinds of lab interpretations
A
(a) Susceptible (S): isolates are inhibited by usually achievable concentrations of antimicrobial when dose recommended to treat site of infection is used.
(b) Intermediate (I): antimicrobial MIC approaches usually attainable blood and tissue levels, and for which response rates may be lower than for susceptible isolates.
(c) Resistant (R): isolates are not inhibited by the usually achievable concentrations of antimicrobial, and/or MICs or zone diameters fall in the range where specific resistance mechanisms are likely, and clinical efficacy of the agent has not been reliably shown.
23
Q
Dilution tests
A
(1) Antibiotics used in broth medium in serially diluted concentrations.
(2) After 18-24 hours of incubation, growth of organism is measured.
(3) MIC determined based on the lowest concentration of drug that inhibits visible growth.
(4) Can use automated system: broth dilution & measure optical density to assess bacterial growth.
24
Q
Disk diffusion
A
(1) Antibiotic containing disks on agar.
(2) Measure size of clear zone after 18-24 hours of incubation.
(3) Standardized zone sizes for bacterial species to distinguish between susceptible and resistant.
(4) Only qualitative “susceptible” or “resistant”, no MIC value measured.
25
Gradient diffusion
(1) Test strip with varying antibiotic concentrations placed on agar which shows clear elliptical zones to determine MIC.
26
Antibacterial Spectrum
a) Narrow-spectrum: act on a single or a limited group of microorganisms
b) Extended-spectrum: active against gram-positive bacteria but also significant number of gram-negative
c) Broad-spectrum: act on a wide variety of bacterial species, including both gram-positive and -negative
27
Bacteriostatic vs. Bactericidal Drugs
a) Bacteriostatic: arrests growth and replication of bacteria (limits spread of infection).
i) In general, bacterial protein synthesis inhibitors.
b) Bactericidal: kills bacteria.
i) Concentration-dependent killing: rate & extent of killing increase with increasing concentrations
(1) Examples: aminoglycosides and fluoroquinolones
ii) Time-dependent killing: activity continues as long as serum concentration is above minimum bactericidal concentration
(1) Examples: B-lactams and vancomycin
28
Antibacterial Targets:
i) Cell wall synthesis
ii) Cell membrane synthesis
iii) Protein synthesis (30S and 50S ribosomal subunits)
iv) Nucleic acid metabolism
v) Function of topoisomerases
vi) Folate synthesis
29
Bacterial Resistance
Two factors associated with development of antimicrobial resistance:
i) Evolution
ii) Clinical/environmental practices
Resistance Mechanisms
i) Reduced entry of antibiotic into pathogen
ii) Enhanced export of antibiotic by efflux pumps
iii) Release of microbial enzymes which destroy antibiotic
iv) Alteration of microbial proteins that transform prodrugs to the effective moieties
v) Alteration of target proteins
vi) Development of alternative pathways to those inhibited by antibiotics
30
Beta-Lactams
Compounds containing a four-membered lactam ring: penicillins, cephalosporins, monobactams, carbapenems, and B-lactamase inhibitors. These agents share features of chemistry, mechanism of action, pharmacology, and immunologic characteristics.
31
The penicillins: basic structure, MOA, bacterial resistance
a) Basic Structure: thiazolidine ring connected to a B-lactam ring, attached to a side-chain. Side-chains determine susceptibility to inactivating enzymes (B-lactamases), antibacterial activity, and pharmacologic properties.
b) MOA: inhibits the transpeptidation reaction, the last step in peptidoglycan synthesis. Cell wall composed of peptidoglycan which provides rigid mechanical stability. Peptidoglycan composed of two alternating sugars (N-acetylglucosamine and N-acetylmuramic acid). Five-amino-acid peptide linked to final N-acetylmuramic acid which terminates in D-alanyl-D-alanine. Penicillin binding proteins (PBPs) remove the terminal D-alanine in the process of forming the cross-link. B-lactams are structural analogs of D-Ala-D-Ala. B-lactams covalently bind the PBP active site preventing cross-linking, ultimately leading to cell autolysis.
c) Bacterial Resistance: structural difference in PBPs, decreased PBP affinity for B-lactams, inability for drug to reach site of action (i.e., gram-negative organisms), active efflux pumps, drug destruction and inactivation by B-lactamases.
32
Natural penicillins- description, use
i) Natural penicillins: highly effective against gram-positive cocci but easily hydrolyzed by penicillinase (B-lactamase).
(1) Penicillin G and penicillin V
(a) PK: penicillin G benzathine absorbed more slowly with average duration of antimicrobial activity in plasma ~26 days.
(i) Reaches cerebrospinal fluid (CSF) when meninges inflamed.
(ii) Eliminated in urine, 90% via tubular secretion, t1/2 30 minutes.
(b) Therapeutic Use: narrow-spectrum once sensitivity determined in Streptococcus pneumoniae pneumonia and meningitis. Penicillin V for Streptococcus pyogenes pharyngitis, toxic shock, viridians streptococci endocarditis if susceptible, syphilis (no alternative in pregnant women so if allergic they must be desensitized).
33
Anti-staphylococcal penicillins:
penicillinase resistant thus agents of first choice for Staphylococcus aureus and Staphylococcus epidermidis that are not methicillin-resistant.
(1) Oxacillin, dicloxacillin, nafcillin
(a) PK: oxacillin and dicloxacillin – rapid GI absorption (30-80%), more efficient on an empty stomach (give 1 hour before or 2 hours after meals).
(i) Rapidly excreted by kidney, t1/2 30-60 minutes.
(b) PK: nafcillin –90% protein bound; high concentration in bile, adequate concentration in CSF for Staphylococcus meningitis.
(c) Therapeutic Use: restricted to infections with known Staphylococcus sensitivity.
34
Aminopenicillins- description and therapeutic use
extended-spectrum, frequently administered with a B-lactamase inhibitor, extends beyond gram-positive to gram-negative (Haemophilus influenzae, Escherichia coli, Proteus mirabilis), Listeria monocytogenes, susceptible meningococci, enterococci.
(1) Ampicillin (+/- sulbactam), amoxicillin (+/- clavulanic acid)
(c) Therapeutic Use: upper respiratory tract infections (S. pyogenes, S. pneumoniae, H. influenzae), sinusitis, otitis media, enterococcal infections.
35
Antipseudomonal penicillins desc. and therapeutic use
extends spectrum to Pseudomonas aeruginosa, Enterobacter, and Proteus spp. Piperacillin superior for Pseudomonas, extends coverage to Klebsiella and anaerobes.
(1) Ticarcillin (+/- clavulanic acid), piperacillin (+/- tazobactam)
(b) Therapeutic Use: serious gram-negative infections, hospital acquired pneumonia, immunocompromised patients, bacteremia, burn infections, urinary tract infection (UTI).
36
penicillin ADRs
generally, well tolerated; most serious reactions due to hypersensitivity: allergic reactions (0.7-10%), anaphylaxis (0.004-0.04%), interstitial nephritis (rare); large, oral doses may cause nausea, vomiting, mild to severe diarrhea, pseudomembranous colitis.
37
The Cephalosporins MOA, classification and therapeutic uses
a) MOA/Resistance: see penicillins.
b) Classification (based on general features of antimicrobial activity):
i) None of the cephalosporins have activity against methicillin-resistant Staphylococcus aureus (MRSA), Listeria, or enterococci (exception ceftaroline with some enterococci activity).
ii) First-generation: good gram-positive coverage, modest gram-negative (covers Moraxella, E. coli, Klebsiella pneumoniae, P. mirabilis), orally active anaerobes.
(1) Cefazolin, cephalexin
(a) PK: cefazolin – excreted by glomerular filtration, 85% plasma protein bound, t1/2 2 hours.
(b) PK: cephalexin – 70-100% excreted in urine, not metabolized, t1/2 0.9 hours.
(c) Therapeutic Use: skin and soft tissue infections (SSTIs), surgical prophylaxis.
iii) Second-generation: somewhat increased activity against gram-negative, but less active than third-generation. Subset (cefoxitin, cefotetan) active against Bacteroides fragilis.
(1) Cefoxitin, cefuroxime
(a) PK: cefoxitin – t1/2 40 minutes.
(b) PK: cefuroxime – t1/2 1.7 hours, can be given every 8 hours.
(c) Therapeutic Use: have been displaced by third-generation for many gram-negative infections, used in facultative gram-negative mixed anaerobic (intra-abdominal infections, pelvic inflammatory disease, diabetic foot infections).
iv) Third-generation: less active against gram-positive than first-generation, much more active against Enterobacteriaceae (although resistance increasing due to B-lactamase producing strains), ceftazidime covers P. aeruginosa.
(1) Ceftriaxone, ceftazidime
(a) PK: ceftriaxone – t1/2 8 hours, may be administered once or twice daily (twice daily in meningitis), half recovered in urine and half in bile.
(b) PK: ceftazidime – t1/2 1.5 hours, not metabolized.
(c) Therapeutic Use: drug-of-choice (DOC) for serious gram-negative infections (Klebsiella, Proteus, Providencia, Serratia, Haemophilus); ceftriaxone DOC for all forms of gonorrhea and severe Lyme’s disease; meningitis; ceftazidime option for Pseudomonas.
v) Fourth-generation: spectrum beyond third-generation, useful in serious infections in hospitalized patients, good activity against P. aeruginosa, Enterobacteriaceae, S. aureus, S. pneumoniae.
(1) Cefepime
(a) PK: cefepime – stable against hydrolysis by many B-lactamases, 100% renal excretion, excellent penetration to CSF, t1/2 2 hours.
(b) Therapeutic Use: empirical treatment of nosocomial infections.
vi) Fifth-generation: ceftaroline FDA approved 2010 with activity against gram-positive and gram-negative but with unique coverage of methicillin-resistant S. aureus (MRSA).
(1) Ceftaroline
(a) Therapeutic Use: skin and soft tissue infections, community-acquired pneumonia.
38
Cephalosporin ADRs
1% risk of cross-reactivity to penicillins (patients with true anaphylaxis to penicillin should not receive first- or second-generation cephalosporins); diarrhea, intolerance to alcohol (disulfram-like reaction due to N-methylthiotetrazole (MTT) group of cefotetan).
39
Carbapenems MOA, resistance, therapeutic use, ADRs
a) MOA/Resistance: see penicillins, very resistant to hydrolysis until emergence of KPC carbapenemase.
b) Spectrum: aerobic and anaerobic microorganisms, gram-positive (Streptococcus, enterococci, Staphylococcus, Listeria), excellent activity against Enterobacteriaceae, Pseudomonas, Acinetobacter. Stenotrophomonas maltophilia is resistant. Ertapenem inferior Pseudomonas & Acinetobacter activity.
c) PK: imipenem – hydrolyzed rapidly by brush border of proximal renal tubule, active drug concentration in urine was low so combined with cilastatin which inhibits dehydropeptidase. t1/2 1 hr.
d) PK: meropenem – does not require cilastatin co-administration, not sensitive to dehydropeptidase.
e) PK: ertapenem – longer t1/2 which allows for once daily dosing.
f) Therapeutic Use: susceptible infections which are resistant to other available drugs; UTI, lower respiratory tract infection (LRTI), intra-abdominal, gynecological, SSTI, bone and joint infections.
g) ADRs: nausea/vomiting (1-20%), seizures (1.5%), hypersensitivity.
40
Monobactam MOA, resistance, spectrum, use
a) MOA/Resistance: see penicillins.
b) Spectrum: activity against aerobic gram-negatives (Enterobacteriaceae, Pseudomonas, H. influenzae, gonococci), no activity against gram-positive cocci (GPC) or anaerobes.
c) PK: t1/2 1.7 hours, most recovered in urine.
d) Therapeutic Use: patients who are allergic to penicillins and cephalosporins appear not to react to aztreonam, thus effective in treating gram-negative infections which would usually be treated with B-lactam if it were not for a history of prior allergic reaction.
41
Glycopeptides MOA, resistance, spectrum, uses
a) MOA: inhibits cell wall synthesis binding with high affinity to D-alanyl-D-alanine terminal of cell wall precursor units. Due to large size, unable to penetrate outer membrane of gram-negative bacteria.
b) Bacterial Resistance: alteration of D-alanyl-D-alanine target to D-alanyl-D-lactate or D-alanyl-D-serine which binds glycopeptides poorly. Intermediate resistance may occur if small proportion of cells growing with vancomycin present or if they have abnormally thick cell wall.
c) Spectrum: broad gram-positive coverage: S. aureus (including MRSA), S. epidermidis (including MRSE), Streptococci, Bacillus, Corynebacterium spp, Actinomyces, Clostridium; all gram-negative and mycobacterium resistant.
e) Therapeutic Use: osteomyelitis, endocarditis, MRSA, Streptococcus, enterococci, CNS infections, bacteremia, ORALLY for Clostridium difficile.
i) When given IV – monitor serum drug concentrations (within 30 minutes prior to next scheduled dose) at steady state (typically before 4th dose). Target trough 15-20 mcg/mL for endocarditis, osteomyelitis, meningitis, MRSA pneumonia. Target trough 10-15 mcg/mL for SSTIs.
f) ADRs: macular skin rash, chills, fever, rash. Red-man syndrome due to rapid infusion: extreme flushing, tachycardia, hypotension; not an allergic reaction, direct toxic effect of vancomycin on mast cells causing them to release histamine. Ototoxicity, nephrotoxicity (33% with initial trough > 20 mcg/mL).
42
Fluoroquinolones MOA, resistance, spectrum, use, ADRs
a) MOA: concentration-dependent killing, targets bacterial DNA gyrase and topoisomerase IV. DNA must be separated to permit DNA replication or transcription, anything that separates strands leads to over-winding or excessive positive supercoiling. DNA gyrase is responsible for continuous introduction of negative supercoils.
b) Bacterial Resistance: mutation in bacterial chromosome genes encoding DNA gyrase or topoisomerase IV or by active transport out of cell. No FQ modifying or inactivating activities have been found.
c) Spectrum: E. coli, Salmonella, Shigella, Enterobacter, Campylobacter, Neisseria, P. aeruginosa (ciprofloxacin most active agent in this class against gram-negatives and particularly P. aeruginosa), S. aureus (not MRSA), atypicals (e.g., mycoplasmas and chlamydiae), intracellular pathogens (e.g. Legionella, mycobacteria), limited coverage of Streptococcus spp. Levofloxacin, moxifloxacin “respiratory fluoroquinolones” cover Streptococcus spp.
d) PK: well absorbed, divalent/trivalent cations impair absorption, distributed widely.
i) Distribute to urine, kidney, prostate, lung, stool, bile, macrophages and neutrophils.
ii) Cleared by the kidney, needs dose adjustments in renal impairment with the exception of moxifloxacin (metabolized in liver).
e) Therapeutic Use: UTI (FQ more effective than trimethoprim/sulfamethoxazole), prostatitis; STI (chlamydia, Neisseria gonorrhoeae) but ceftriaxone DOC for gonorrhea; traveler’s diarrhea, shigellosis; bone, joint, SSTI infections; diabetic foot infections; prophylaxis in neutropenic patients.
i) Respiratory FQs: S. pneumoniae, H. influenzae, Moraxella, S. aureus, M. pneumoniae, C. pneumoniae, Legionella.
ii) Ciprofloxacin: Pseudomonas.
f) ADRs: generally well tolerated; GI 3-17% most common (mild nausea, vomiting, abdominal discomfort); CNS 0.9-11% (mild headache, dizziness, delirium, rare hallucinations); rash, photosensitivity, Achilles tendon rupture (CI in children).
43
Aminoglycosides
a) MOA: concentration-dependent, binds 30S ribosomal subunit and disrupts normal cycle of ribosomal function by interfering with initiation of protein synthesis. Abnormal initiation complexes and aberrant proteins (due to misreading of mRNA template) accumulate. Aberrant proteins inserted into cell membrane lead to altered permeability.
i) AGs reach site of action via diffusion through porin proteins in outer cell membrane of gram-negative bacteria and electron transport/oxygen dependent movement across cytoplasmic membrane. (Cell wall active drugs may enhance AG transport = synergism).
ii) AGs also exhibit a post-antibiotic effect (PAE) – residual bactericidal activity persists after serum concentration is lower than MIC.
b) Bacterial Resistance: AG metabolizing enzymes, impaired transport of drug into cell, altered ribosome.
c) Spectrum: aerobic gram-negative bacteria, limited action against gram-positive, produces synergistic bactericidal effects in gram-positive when combined with a cell wall active agent (B-lactam or vancomycin).
i) Kanamycin more limited – do not use for Serratia or P. aeruginosa.
ii) Tobramycin – more active against P. aeruginosa and some Proteus.
iii) Gentamicin – more active against Serratia.
e) Therapeutic Use: UTI (not uncomplicated), used when there is resistance to other agents or in seriously ill patients, pneumonia (ineffective against S. pneumoniae and anaerobes), hospital-acquired pneumonia, peritonitis associated with peritoneal dialysis, synergy in bacterial endocarditis, tobramycin inhalation in CF, amikacin used when resistance to gentamicin and tobramycin high.
f) ADRs: ototoxicity (as high as 25%), nephrotoxicity (8-26%), neuromuscular block and apnea.
44
Tetracyclines & Glycylcyclines MOA, resistance, spectrum
a) MOA: bacteriostatic, inhibits bacterial protein synthesis by binding 30S bacterial ribosome and preventing access of aminoacyl tRNA to acceptor (A) site on mRNA ribosome complex (prevents addition of amino acids to growing peptide).
i) Enters outer membrane via passive diffusion through porin proteins and cytoplasmic membrane via active/energy-dependent transport.
b) Bacterial Resistance: decreased influx, acquisition of energy dependent efflux, ribosomal protection proteins, enzymatic inactivation.
c) Spectrum: wide range of aerobic and anaerobic gram-positive and gram-negative activity as well as effective for: Rickettsia, Coxiella burnetii, Mycoplasma pneumoniae, Chlamydia spp, Legionella, atypical mycobacterium, Plasmodium, Borrelia burgdorferi (Lyme’s disease), Treponema pallidum (syphilis).
i) Others: Bacillus anthracis, L. monocytogenes, MRSA, H. influenzae, Helicobacter pylori.
ii) All strains of Pseudomonas resistant.
iii) Tigecycline: equally or more active in vitro against bacteria than tetracyclines but does not cover Pseudomonas, Proteus, and Providencia.
e) Therapeutic Use: CAP, atypical CAP coverage, community-acquired SSTIs, community-acquired MRSA, acne, Rickettsial infections (Rocky Mountain Spotted Fever), Q fever, anthrax, used in combination with other antimicrobials for H. pylori, plague, tularemia, and brucellosis.
i) Tigecycline – very broad spectrum with activity against coagulase-negative staphylococci, S. aureus (including MRSA, vancomycin-intermediate, and vancomycin-resistant strains), streptococci (penicillin-sensitive and resistant), enterococci (including vancomycin-resistant), gram-positive rods, Enterobacteriaceae, Acinetobacter spp., anaerobes. P. aeruginosa and Proteus resistant.
f) ADRs: GI (epigastric burning, abdominal discomfort, nausea, vomiting, diarrhea), superinfections of C. difficile, photosensitivity, teeth (discoloration), thrombophlebitis.
45
Macrolides & Ketolides MOA, resistance, specturm, use, ADRs, DDIs
a) MOA: bacteriostatic, binds reversibly to 50S ribosomal subunit, inhibits translocation where a newly synthesized peptidyl tRNA molecule moves from acceptor site on ribosome to peptidyl donor site.
b) Bacterial Resistance: drug efflux, ribosomal protection proteins, hydrolysis, ribosomal mutations.
c) Spectrum: aerobic gram-positive cocci (GPCs) and bacilli; Staphylococcus not reliably susceptible.
i) Clostridium perfringens, Corynebacterium diphtheria, L. monocytogenes.
ii) Inactive against most gram-negative bacteria, modest activity against H. influenzae, N. meningitides, N. gonorrhoeae, Pasteurella multocida, Borrelia spp, Bordetella pertussis, M. pneumoniae, Legionella pneumophilia, C. trachomatis, some atypical mycobacterium.
d) PK: clarithromycin – rapid absorption from GI tract, first-pass metabolism reduces bioavailability to 50-55%, liver metabolism to active metabolite 14-hydroxyclarithromycin, eliminated renally, t1/2 of parent 3-7 hours, t1/2 of metabolite 5-9 hours, dose adjust if CrCl < 30 mL/min.
e) PK: azithromycin – absorbed rapidly, wide distribution (except CNS), administration of aluminum and magnesium hydroxide antacids reduces absorption, high intracellular concentration, hepatic metabolism to inactive metabolites, biliary excretion major route of elimination, t1/2 40-68 hours.
f) Therapeutic Use: respiratory tract infections (due to coverage of S. pneumoniae, H. influenzae, and atypicals: Mycoplasma, Chalmydophilia, Legionella), alternative for otitis media, sinusitis, bronchitis, and SSTIs. Pertussis, gastroenteritis, H. pylori, Mycobacterial infections.
g) ADRs: GI (epigastric distress), hepatotoxicity, arrhythmia, QT prolongation.
h) DDIs: CYP3A4 inhibition – prolongs effects of digoxin, valproate, warfarin, others.
i) Azithromycin structure differs making it less likely to produce DDIs but should use caution.
46
Lincosamides MOA, resistance, spectrum, therapeutic use, ADRs
a) MOA: binds exclusively to 50S subunit of bacterial ribosome and suppresses protein synthesis.
b) Bacterial Resistance: ribosomal methylation.
c) Spectrum: pneumococci, S. pyogenes, viridans Streptococci, MSSA, anaerobes (B. fragilis).
i) All aerobic gram-negative bacilli are resistant.
d) PK: clindamycin – t1/2 2.9 hours, nearly completely absorbed, 90% protein bound, accumulates in polymorphonuclear leukocytes, alveolar macrophages, abscesses, 10% excreted unchanged in the urine, inactivated by hepatic metabolism (must dose adjust in hepatic failure).
e) Therapeutic Use: SSTIs, necrotizing SSTIs, penetrating wounds, lung abscesses, anaerobic lung and pleural space infections, topically for acne vulgaris.
f) ADRs: GI diarrhea (2-20%), pseudomembranous colitis (0.01-10%) due to C. difficile, skin rashes (10%), reversible increase in aminotransferase activity, may potentiate neuromuscular blockade.
47
Streptogramins MOA etc.
a) MOA: bactericidal, protein synthesis inhibitors, bind 50S ribosomal subunit. Quinpristin (streptogramin B) binds same site as macrolides which inhibits polypeptide elongation and causes early termination of
protein synthesis. Dalfopristin (streptogramin A) binds site nearby resulting in conformational change in 50S ribosome, synergistically enhancing binding of quinipristin.
b) Bacterial Resistance: ribosomal methylase, acetyltransferase inactivation of dalfopristin.
c) Spectrum: GPCs including S. pneumoniae, B and α hemolytic Streptococcus, E. faecium (not E. faecalis), and coagulase-positive and negative Staphylococcus.
i) Largely inactive against gram-negatives, but Moraxella catarrhalis and Neisseria susceptible.
ii) Active against atypical organisms (M. pneumoniae, Legionella spp, C. pneumoniae).
iii) Bactericidal against Streptococcus and many strains of Staphylococcus, static against E. faecium.
d) PK: only given IV in a combination quinipristin:dalfopristin in 30:70 ratio, incompatible in saline and heparin must be dissolved in dextrose 5% in water.
i) t1/2 0.85 hours for quinispristin, 0.7 hours dalfopristin, hepatic metabolism, 80% biliary excretion.
e) Therapeutic Use: vancomycin resistant E. faecium (VRE) and complicated SSTI by MSSA or S. pyogenes.
f) ADRs: infusion related pain and phlebitis, arthralgia and myalgia.
g) DDIs: inhibits CYP3A4 – anticonvulsants, macrolides, some FQs (moxifloxacin), antidepressants, warfarin, non-nucleoside reverse transcriptase inhibitors affected.
48
Oxazolidinones MOA etc.
a) MOA: inhibits protein synthesis binding P site of 50S ribosomal subunit, prevents formation of larger ribosomal fmet-tRNA complex which initiates protein synthesis.
b) Bacterial Resistance: ribosomal mutation.
c) Spectrum: gram-positive Staphylococcus (MSSA, MRSA, VRSA), Streptococcus (penicillin resistant S. pneumoniae), enterococci (vancomycin-resistant E. faecium, VRE), gram-positive anaerobic cocci, gram-positive rods (Corynebacterium, L. monocytogenes).
i) Poor activity against gram-negative aerobic and anaerobic bacteria
ii) Bacteriostatic against enterococci and Staphylococcus and bactericidal against Streptococcus.
d) PK: linezolid – well absorbed orally, bioavailability 100%, t1/2 4-6 hours, 30% protein bound, distributes widely to well perfused tissues.
e) Therapeutic Use: VRE faecium (SSTI, UTI, bacteremia); nosocomial pneumonia caused by MSSA and MRSA; CAP; complicated SSTI infections, uncomplicated SSTIs.
i) Because linezolid is bacteriostatic against enterococci and Staphylococcus should not be used as first-line for suspected endocarditis.
ii) DO NOT use when other agents are likely to be effective, should be reserved for multiple-drug resistant organisms.
f) ADRs: myelosuppression [thrombocytopenia (2.4%), anemia, leukopenia, pancytopenia], minor GI complaints, headache, rash.
g) DDIs: weak, nonspecific inhibitor of monoamine oxidase, concomitant adrenergic or serotonergic (selective-serotonin reuptake inhibitors, SSRI’s) may lead to serotonin syndrome (palpitations, headache, hypertensive crisis). Avoid interaction if possible; however, short-term use (10-14 days) with careful monitoring is reasonable.
14) P
49
Polymyxins MOA etc.
a) MOA: interacts with phospholipids, disrupts the structure of cell membranes, alters permeability.
b) Spectrum: restricted to gram-negative bacteria – Enterobacter, E. coli, Klebsiella, Salmonella, Pasteurella, Bordetella, and Shigella, P. aeruginosa, Acinetobacter (Proteus and Serratia resistant).
c) PK: colistin (polymyxin E) and polymyxin B (topical), not absorbed orally, poorly absorbed from mucous membranes and surfaces of large burns, cleared renally, dose modification necessary in renal impairment.
d) Therapeutic Use: topical, skin, mucous membranes, eye, ear, urinary bladder irrigation, inhalation.
e) ADRs: no systemic effects for polymyxin B, polymyxin E is nephrotoxic avoid with AGs, can cause muscle weakness and apnea due to interference with neurotransmission.
50
Lipopeptides MOA etc.
a) MOA: binds bacterial membranes resulting in depolarization, loss of membrane potential, cell death.
b) Bacterial Resistance: not fully described, may be due to changes in cell membrane charge.
c) Spectrum: bactericidal, concentration-dependent, active against aerobic, facultative and anaerobic gram-positive bacteria (Staphylococcus, MRSA, Streptococcus, enterococci, Corynebacterium, Peptostreptococcus, Clostridium perfringens).
i) Penetrates lung adequately but inactivated by pulmonary surfactant.
e) Therapeutic Use: complicated SSTIs, complicated bacteremia, right sided endocarditis.
f) ADRs: musculoskeletal damage, elevations in creatine kinase, rare rhabdomyolysis.
g) DDIs: no CYP interactions, no other important DDIs but caution with AGs (additive nephrotoxicity) and statins (additive myopathy).
51
Metronidazole MOA etc.
a) MOA: prodrug, requires reductive activation of nitro groups by susceptible organisms. Single electron transfer in anaerobic bacteria forms highly reactive nitro radical anions, kills organisms by radically mediated mechanisms that target DNA. Catalytically recycled. Increasing 02 inhibits metronidazole toxicity as 02 competes for electrons.
b) Bacterial Resistance: not well described, but due to decreased formation of nitro radicals.
c) Spectrum: All anaerobic cocci and both anaerobic gram-negative bacilli (including Bacteroides) and anaerobic spore forming gram-positive bacilli (Clostridium), trichomoniasis, amebiasis, giardiasis. Helicobacter and Campylobacter.
i) 75% eliminated in urine largely as metabolites, liver main site of metabolism accounts for > 50% of systemic clearance.
e) Therapeutic Use: bacterial vaginosis, amebic liver abscess, treatment of anaerobic bacterial infections due to Bacteroides, Clostridium, Fusobacterium, Peptococcus, Peptostreptococcus, and Helicobacter. Clinically effective levels in bone, joints, and CNS. Part of regimen for prophylaxis of colorectal surgery. Clostridium difficile, Crohn’s disease.
f) ADRs: headache, nausea, dry mouth, metallic taste. Vomiting, diarrhea, abdominal distress occasionally. Neurotoxic: dizziness, vertigo, very rarely encephalopathy. Well-reported disulfiram effect abdominal distress, vomiting, flushing, headache, if alcohol consumed during/within 3 days of drug.
g) DDIs: induced metabolism of phenobarbital, prednisone, rifampin. Prolongs prothrombin time in those receiving warfarin. Metabolism inhibited by cimetidine.
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Sulfonamides & Trimethoprim MOA etc.
a) MOA: sulfonamides are bacteriostatic, competitive inhibitors of dihyropteroate synthase. This enzyme is responsible for incorporation of para-aminobenzoic acid (PABA) into dihydropteroic acid, the immediate precursor to folic acid. Prevents bacterial use of PABA for synthesis of folic acid. Synergistic trimethoprim, inhibits microbial dihydrofolate reductase, the enzyme which reduces dihydrofolate to
tetrahydrofolate. This reduced form of folic acid is required for one-carbon transfer reactions. Simultaneous administration of a sulfonamide + trimethoprim introduces sequential blocks in pathway.
b) Bacterial Resistance: lower affinity of enzymes to drug binding, decreased bacterial permeability or active efflux, alternative pathway for essential metabolite synthesis, increased production of essential metabolite.
c) Spectrum: Chlamydia diphtheriae, N. menigitidis, S. aureus, S. epidermidis, S. pyogenes, viridans group Streptococcus, E. coli, Proteus mirabilis, Proteus morgannii, Enterobacter, Salmonella, Shigella, Serratia, Klebsiella, Brucella abortus, Pasteurella haemolytica, Yersinia pseudotuberculosis, T. enterocolitical, Norcardia asteroids.
e) Therapeutic Use: UTI, bacterial prostatitis, bronchitis, Shigellosis, Traveler’s diarrhea, Salmonella, Pneumocystis jiroveci (fungus) prophylaxis in neutropenia, Nocardia, Stenotrophomonas maltophilia, do NOT use in Streptococcus pharyngitis.
f) ADRs: allergic skin rashes, nausea, vomiting, CNS (headache, depression), photosensitivity, renal dysfunction, Stevens-Johnson syndrome.
g) DDIs: potentiates the effects of warfarin!
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Methenamine MOA, etc.
a) MOA: decomposes in water to formaldehyde, acidification of urine promotes formaldehyde formation, slow process (requires 3 hours to complete).
b) Bacterial Resistance: no resistance.
c) Spectrum: nearly all bacteria are susceptible to formaldehyde.
e) Therapeutic Use: not primary drug for acute UTI, but has value in chronic suppressive therapy.
f) ADRs: GI distress, painful and frequent micturition, albuminuria, hematuria, rashes, low systemic toxicity at usual doses.
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Nitrofurantoin MOA, etc.
a) MOA: drug reduced forming highly reactive intermediates which damage DNA, bacteria reduce drug more rapidly than mammalian cells, thought to account for selective activity.
c) Therapeutic Use: UTI, not recommended for pyelonephritis or prostatitis.
d) ADRs: nausea, vomiting, diarrhea, macro-crystalline prep better tolerated. Course of therapy should not exceed 14 days and repeated course should be separated by rest periods.
i) CI: pregnant women, impaired renal function (40 mL/min), children < 1 month.
