pharmacology of antimicrobial and antifungal agents pt I & II

what are the 2 ways to treat an infection?

empiric- based on most likely microbes and their probable susceptibility

documented/definitive- culture of microbes and determination of susceptibility to drugs

prophylactic therapy

to prevent an infection

what are the principles of antimicrobial therapy?

use the most narrow, least toxic, most cost- effective agent

antimicrobials aid the body’s defenses in clearing infection (eliminate the organism by physical means)

what are the 3 factors of antimicrobial selection?

pathogen factors- likely organism, susceptibility

antimicrobial factors- spectrum of activity, PK/PD, adverse effects, drug interactions, cost

host factors- age, immune status, renal and hepatic function, recent antibiotic exposure, allergy or intolerance, disease severity, pregnancy and lactation

pharmacokinetics

describes what the body does to the drug

absorption, distribution, metabolism, elimination

pharmacodynamics

describes what the drug does to the body/micro-organism

describes antimicrobial effect (bactericidal, bacteriostatic), post antibiotic effect (PAE), PD parameters (time dependent activity, concentration dependent activity)

MBC:MIC above 4, requires immune assistance to clear infection

bacteriostatic

MBC:MIC below 4, cell wall synthesis inhibitors

bacteriocidal

what are the pharmacodynamics of antimicrobials?

aminoglycosides- Cmax:MIC aka concentration dependent

vancomycin and fluoroquinolones- AUC>MIC time and concentration dependent

beta lactams- T>MIC aka time dependent

when a drug is concentration dependent, should it be given in smaller quantities more frequently or larger quantities less frequently?

larger quantities less frequently

when a drug is time dependent, should it be given in smaller quantities more frequently or larger quantities less frequently?

smaller quantities more frequently

cell wall synthesis inhibitors

penicillins

beta lactamase inhibitor combinations

cephalosporins

carbapenems

vancomycin

what is the mechanism of action of beta lactams?

inhibits pencillin binding proteins (PBPs)- involved in the cross linkage of peptide chains, prevents the development of normal peptidoglycan structure

cell lysis- osmostic pressure or activation of endogenous autolysins

what is the basic structure of beta lactams

manipulations of side chains alter spectrum, susceptibility, and pharmacokinetic properties

rapidly bactericidal, nontoxic, bioavailable, resistant to degradation, high affinity for PBPs

time dependent activity

from most narrow to broad, what is the range of penicillins?

penicillin VK, penicillinase resistant PCNs, amoxicillin, amoxicillin/clavulanic acid, carboxyPCNs, ureidoPCNs

what bacteria are susceptible to penicillin VK?

streptoccoci, h. influenzae, G+ anaerobes

what bacteria are susceptible to penicillinase resistant PCNs?

MSSA, streptococci, G+ anaerobes

what bacteria are susceptible to amoxicillin?

streptococci, h. influenzae, enteric G-, G+ anaerobes

what bacteria are susceptible to amoxicillin/clavulanic acid?

MSSA, streptococci, h. influenzae, enteric G-, anaerobes

what bacteria are susceptible to carboxyPCNs / ureidoPCNs?

IV only

MSSA, streptococci, h. influenzae, enteric G-, G+ anaerobes

what are the pharmacokinetics of penicillin and amoxicillin?

absorption- difficult to achieve high serum concentrations with oral formulatons

decent penetration into most tissues except prostate, eye, and uninflamed CNS

primarily excreted renally- adjust dosing with moderate-severe renal impairment

in general, shorter half life than most antimicrobials (amox > peni)

probenecid blocks renal excretion and causes increased serum penicillin levels

what are the adverse effects of penicillins?

hypersensitivity (~1%)- anaphylaxis (0.004-0.015%), cross reactivity with cephalosporins ~2%

phlebitis (1-10% when given IV)

GI disturbances (1-10%)

hematologic (<1%)

neurologic (<1%)

electrolyte disturbances (<1%)

renal (interstitial nephritis) (<1%)

prophylaxis is recommended for dental procedures that involve… ONLY for patients with…

manipulation of gingival tissues or periapical region of teeth or perforation of oral mucosa

underlying cardiac conditions associated with the highest risk of adverse outcome from infective endocarditis

what underlying cardiac conditions are associated with the highest risk of infective endocarditis from dental procedures?

prosthetic cardiac valves, including transcatheter implanted prostheses and homographs

prosthetic material used for cardiac valve repair (annuloplasty rins and chords)

prior history of infective endocarditis

congenital heart disease (CHD)- unrepaired cyanotic CHD, completely repaired but within 6 months of the procedure, or repaired CHD with residual defects

cardiac transplantation recipients who develop cardiac valvulopathy

according to the ADA… current evidence suggests that _____ and ______, NOT _____ are likely to be responsible for the vast majority of cases of IE that originate in the mouth

poor oral hygiene, periodontal disease

dental office procedures

when prophy-ing for IE, what bacteria are we most worried about?

viridans group streptococci

what is the recommended regimen for IE prophy?

oral is 1 hr prior to procedure, IV or IM is 30 min prior to procedure

2g amoxicillin PO

is prophy-ing recommended for patients with joint implants?

according to the ADA, no

according to AAOS, in select circumstances

intrinsic antimicrobial resistance

characteristics of the drug prevent an antimicrobial from reaching the target site, or the antimicrobial is inactivated

acquired antimicrobial resistance

resistance which develops horizontally or vertically

what are mechanisms of antimicrobial resistance?

drug cannot reach the target- efflux pumps, porin channel mutations

drug is inactivated- enzymatic inactivation

target site is altered- modification/protection of target sites

t/f drugs are inactivated by beta lactamases

true-ish? not all drugs, penicillins

clavulanic acid

compounded with amoxicillin

binds to beta lactamase, preventing it from breaking down the beta lactam

enhances the spectrum of the parent drug if decreased activity is a result of beta lactamases

t/f the lower MIC number, the better

true!

from most narrow to broad, what is the range of cephalosporins?

1st gen cephalexin, 2nd gen, 2nd gen cephamycins, 3rd gen cefpodoxime, 4th gen

what bacteria are susceptible to 1st gen cephalexin?

MSSA, streptococci, enteric G-

what bacteria are susceptible to 2nd gen cephalosporins?

MSSA, streptococci, h. influenzae, enteric G-

what bacteria are susceptible to 2nd gen cephamycins?

MSSA, streptococci, h. influenzae, enteric G-, anaerobes

what bacteria are susceptible to 3rd gen cefpodoxime?

MSSA, streptococci, h. influenzae, enteric G-

what bacteria are susceptible to 4th gen cephalosporins?

MSSA, streptococci, h. influenzae, enteric G-

has best G- coverage

what are the pharmacokinetics of cephalosporins?

absorption- IV for severe infections, PO for mild/moderate infections

distribution- similar to penicillins

excretion- primarily renal

what are the adverse effects of cephalosporins?

generally well tolerated

GI disturbances (1-10%), phlebitis (1-10% when given IV), hypersensitivity (<1%), hematologic (<1%), renal (<1%), neurotoxicity (<1%)

how is resistance to beta lactam antibiotics conferred?

drug is inactivated- beta lactamases, penicillinases, cephalosporinases, extended spectrum beta lactamases (ESBLs)

drugs cannot reach the target site- alterations in membrane permeability or efflux

target site is altered- alterations in PBP (PRSP and MRSA)

carbapenems

meropenem, ertapenem, imipenem-cilastatin

broad spectrum agents- reserved for last line treatment of resistant (primarily G-) organisms but have activity against G+, G-, and anaerobic bacteria

what are the pharmacokinetics of carbapenems?

IV only, decent distribution, renally excreted

what are the adverse effects of carbapenems?

hypersensitivity, seizures (caution in patients with seizure history or renal disease)

which of the following is true of beta-lactam antimicrobials?

a) common mechanisms of resistance include enzymatic and activation, and altered target sites

b) intravenous and oral formulas are equally bioavailable

c) responsible for many drug-drug interactions due to inhibition of CYP 450, isoenzyme 3A4

d) primarily bacteriostatic

e) anti-bacterial activity is concentration dependent (higher peaks have greater antibacterial activity)

a) common mechanisms of resistance include enzymatic and activation, and altered target sites

what is the spectrum of vancomycin?

G+ anaerobes and aerobes, including MRSA

NO G- activity because the molecule is too large to cross the outer membrane in G- bacteria

what is the mechanism of action of vancomycin?

inhibits glycopeptide cell wall synthesis, acts at a different (earlier) site than penicillin

bactericidal for s. aureus

AUC dependent activity

what are the uses of vancomycin?

G+ organisms resistant to beta lactams, G+ organisms in patients unable to tolerate beta lactams, C. difficile colitis

what are the pharmacokinetics of vancomycin?

poor oral absorption, oral only for C. difficile colitis

widely distributed (outside of uninflamed CNS)

minimal metabolism; renal excretion

monitor trough/AUC concentrations if course is planned for >3 days

what are the adverse effects of vancomycin?

infusion related effects (>10%)- slow infusion rate, nephrotoxicity (>10%), hypersensitivity (1-10%), ototoxicity (<1%), hematologic (<1%)

when did the first vancomycin resistant enterococci (VRE) appear?

1980s

we got over 30 years of clinical use without resistance

when was VISA/VRSA first reported?

1996

what is the mechanism of action of macrolides (azithromycin)?

reversibly binds 50S ribosomal subunit, suppressing RNA dependent protein synthesis

bacteriostatic

what is the spectrum of activity of macrolides (azithromycin)?

G+ organisms, a few G- organisms (h. influenzae, m. catarrhalis), atypicals (l. pneumophila, m. pneumoniae, c. pneumoniae)

what are the pharmacokinetics of azithromycin?

decent oral absorption

extensive distribution (except CNS), intracellular, concentrates in tissues, low serum levels

hepatically metabolized

elimination in the bile, minimal renal excretion, long half life

what are the drug interactions with azithromycin?

CYP3A4 substrate and inhibitor (erythro and clarithro »»» azithro)

increases levels of: amioderone, digoxin, warfarin, statins, calcium channel blockers, carbamazepine, and others

QTc prolonging agents

what are the adverse effects of azithromycin?

primarily GI disturbances (up to 30% of pts), QTc prolongation

what types of resistance to azithromycin can develop?

drug cannot reach target site- decreased penetration into the cell or pumped out of the cell through efflux pumps

drug is inactivated through hydrolysis

target site is altered- increased enzyme production, modifies ribosomal target

what is the mechanism of action of tetracyclines (doxycycline)?

reversibly binds 30S ribosomal subunit

bacteriostatic, time-dependent killing

what is the spectrum of activity of tetracyclines (doxycycline)?

G+ organisms, G- organisms, anaerobes, atypicals (l. pneumophila, m. pneumoniae, c. pneumoniae), lyme disease (b. burgdorferi)

what are the pharmacokinetics of tetracyclines (doxycycline)?

decent oral absorption- binds Ca, Mg, Al, Fe (dairy products, antacids) causing decreased absorption when administered together

widely distributed (high GI concentrations)

partial liver metabolism

elimination in bile and urine (1/2 life prolonged in renal dysfunction, but no need for dose adjustment)

what are the adverse effects of tetracyclines (doxycycline)?

GI disturbances, photosensitivity, tooth/bone discolortation, hepatotoxicity (rare), renal toxicity (rare)

how can resistance be developed to tetracyclines (doxycycline)?

drug cannot reach the target site- active efflus is most common

drug is inactivated- enzymatic inactivation

target site is altered- ribosomal protection proteins

what is the mechanism of action of clindamycin?

binds to 50S ribosomal subunit (similar to macrolides); time dependent killing

what is the spectrum of activity of clindamycin?

G+ aerobes and anaerobes but never first line

what are the uses of clindamycin?

respiratory, pelvic/abdominal, dental infections, third line alternative for pts truly allergic to penicillin

what are the pharmacokinetics of clindamycin?

great oral absorption, widely distributed (except CNS), primarily metabolized by the liver, excreted in bile and urine

what are the adverse effects of clindamycin?

GI disturbances, C. difficile colitis (which can be worse than the initial infection), metallic taste

what is the mechanism of action of aminoglycosides?

irreversibly binds to 30S ribosomal subunit, inhibiting protein synthesis

bactericidal

concentration-dependent killing

what is the spectrum of activity of aminoglycosides?

G-, synergy / limited G+

post antibiotic effect (PAE)

persistent suppression of bacterial growth following exposure to an antimicrobial OR the time it takes an organism to recover from the effects of antimicrobial exposure

what are the pharmacokinetics of aminoglycosides?

poor oral absorption (IV only)

distribution into extracellular space- not used as monotherapy for infections outside of the urine

renally eliminated

how is resistance to aminoglycosides conferred?

impaired drug uptake (usually intrinsic)

altered target site: ribosomal mutations (usually acquired)

enzymatic modification of aminoglycoside (usually acquired)

what are the adverse effects of aminoglycosides?

nephrotoxicity (variable but generally >10% reported)

ototoxicity (variable, but generally >1% reported)

neuromuscular blockade (<1%)

requires routine monitoring of serum concentrations for efficacy and toxicity

t/f cell wall synthesis inhibitor in combination with aminoglycosides…

increases bacterial killing

what are the uses of aminoglycoside combination therapy?

definitive for select endocarditis/endovascular G+ infections

empiric to improve activity against G- organisms

what are the protein synthesis inhibitor antibiotics?

macrolides (azithromycin), tetracyclines (doxycycline), clindamycin, aminoglycosides

which of the following combinations are most likely to be synergistic if used together?

a) cefazolin and ceftriaxone

b) doxycycline and clindamycin

c) penicillin and gentamicin

d) clindamycin and azithromycin

c) penicillin and gentamicin

what is the mechanism of action of quniolones (ciprofloxacin)?

inhibit topoisomerases II (DNA gyrase) and IV (both enzymes responsible for maintaining DNA supercoiling, replication, and separation)

inhibition of these enzymes subsequently arrests DNA replication

bactericidal, concentration dependent

what is the spectrum of activity of quniolones (ciprofloxacin)?

limited G+ coverage, primarily G- including pseudomonas, atypicals

what is the difference in spectrum of activity of ciprofloxacin and levofloxacin?

ciprofloxacin- nosocomial G- are susceptible, but MSSA and streptococcus pneumoniae are not

levofloxacin- nosocomial G-, MSSA, and streptococcus pneumoniae are susceptible

what are the pharmacokinetics of quniolones (ciprofloxacin)?

excellent oral absorption (decreased by Al, Mg, Fe, Ca / food delays peak concentration)

widely distributed

minimal metabolism

renal elimination

what are the drug interactions of quniolones (ciprofloxacin)?

divalent and trivalent cations

ciprofloxacin inhibits CYP1A2 (strong), CYP3A1 (weak)

increases levels of corticosteroids and warfarin

what are the adverse effects of quniolones (ciprofloxacin)?

GI disturbances (<5%), photosensitivity, QTc prolongation, C. difficile colitis, tendon rupture, dysglycemias

how can resistance to quniolones (ciprofloxacin) develop?

drug cannot reach target site- efflux pumps

target site is altered

increasing resistance with widespread use

what warnings did the FDA communicate about quinolones?

tendinitis and tendon rupture, worsening myasthenia gravis, peripheral neuropathy, joint pain and CNS issues, hypoglycemic risk, increased risk of ruptures or tears in aorta

what is the mechanism of action of metronidazole?

enters cell and reduced to cytotoxic produce, damages DNA, RNA, and proteins

bactericidal, concentration dependent killing

what is the spectrum of activity of metronidazole?

anaerobes

what are the uses of metronidazole?

first line for anaerobic infections

C. difficile infection- guidelines no longer recommend first line

what are the pharmacokinetics of metronidazole?

excellent oral absorption

widely distributed, including CNS

liver metabolism

excreted in bile and urine

what are the adverse effects of metronidazole?

generally well tolerated

metallic taste

GI disturbances

CNS- cumulative peripheral neuropathy

disulfiram reaction with alcohol

which antibiotics are nucleic acid structure inhibitors?

quniolones (ciprofloxacin), metronidazole

what is the mechanism of action of trimethoprim/sulfamethoxazole?

interferes wtih bacterial folic acid synthesis

sulfonamides competitively inhibit to prevent dihydrofolic acid synthesis

trimethoprim stops production of tetrahydrofolic acid

what are the uses of trimethoprim/sulfamethoxazole?

urinary tract infections, skin and soft tissue infections

drug of choice for nocardia, p. jirovecii, and s. maltophilia

what is the spectrum of activity of trimethoprim/sulfamethoxazole?

G+ aerobes including MRSA, G- aerobes, PJP, listeria, nocardia

what are the pharmacokinetics of trimethoprim/sulfamethoxazole?

good oral absorption (similar levels to IV or PO)

distributes into most tissues, including CNS

minimal metabolism

renal excretion

what are the adverse effects of trimethoprim/sulfamethoxazole?

hypersensitivity, skin disorders (25-50% of HIV patients, <10% of non-HIV patients)

GI disturbances, bone marrow suppression, photosensitivity, hyperkalemia, renal toxicity (pseudo-creatinine elevation, but also may cause true acute kidney injury)