Download Antibiotics

Beta Lactams: inhibit cell wall synthesis by inhibiting penicillin binding proteins
(PBPs). Generally bactericidal. Include penicillins, cephalosporins, carbapenems, and
monobactams.
Penicillins
Overall Class Properties: Poor penetrance into non-inflamed CSF, but good into
meningitic CSF. Good urine penetrance. In general, gram positive and gram negative
coverage are inversely proportional, and gram negative coverage increases w/ later
generations.
First Generation: great gram positive coverage, most anaerobes, and some gram negative
cocci (ex. some Neisseria that are not resistant)
 Penicillin G (procaine): IV form, used primarily for neurosyphilis
 Penicillin benzathine: IM form, used for non-neuro syphilis
 Penicillin V: PO form
Anti-Staphylococcal: have coverage vs. penicillinase producing staphylococci, but have
less intrinsic activity than Pen G and are ineffective vs. enterococci, Listeria, and
Neisseria
 Nafcillin: IV form
 Oxacillin, dicloxacillin, cloxacillin: PO forms
Second Generation: add coverage against gram negative bacilli
 Ampicillin: IV form, can be paired w/ sulbactam
 Amoxicillin: PO form, can be paired w/ clavulanate
o Addition of beta lactamase inhibitors provides resistance against plasmid
mediated beta lactamases. Broadens spectrum to include more GN.
Third/Fourth Generation: add coverage against Pseudomonas and against chromosomal
mediated beta lactamases (i.e. vs. more resistant gram negatives)
 Ticarcillin: IV form; paired w/ clavulanate
 Carbenicillin: IV form; not used in US
 Piperacillin: IV form; paired w/ tazobactam; in vitro has less effect on platelets,
more active vs. bacterial growth but less bactericidal than ticarcillin, but unclear if
this translates clinically
Cephalosporins
Overall Class Properties: ~10% cross reactivity with PCN allergies. Third generation
have good penetrance into inflamed CSF. All have good urine penetrance. In general,
oral forms have less activity vs. enteric gram negatives than their IV counterparts. In
general, gram positive and gram negative coverage are inversely proportional, and gram
negative coverage increases w/ later generations.
First Generation: Great gram positive coverage (including penicillinase-producing
staphylocci) except for enterococci, Listeria, MRSA, or PCN-resistant pneumococci.
Some coverage vs. gram negative rods (susceptible E. coli, Proteus mirabilis, and
Klebsiella pneumoniae) but not against the non-enteric gram negative rods or gram
negative cocci.
 Cefazolin: IV form
 Cephalexin, cefadroxil: PO forms
Second Generation: More gram negative & less gram positive coverage than first
generation
 Cefuroxime: IV form; has activity vs. H. flu but not Bacteriodes; induces
chromosomal beta-lactamases in Enterobacter & Proteus
 Cefoxitin, cefotetan: IV forms; have activity vs. Bacteriodes but not H. flu; same
inducing of chromosomal beta-lactamases in Enterobacter & Proteus
 Cefaclor, cefprozil: PO forms
Third Generation: highly active vs. enteric gram negative bacilli, lose some activity vs.
gram positives and are inactive vs. enterococci, Listeria, MRSA, and Acinetobacter.
 Ceftriaxone, cefotaxime: IV forms
 Ceftazidime: IV form; has activity vs. Pseudomonas aeruginosa
 Cefixime, cefdinir: PO forms
Fourth Generation: similar to third generation, but added coverage vs. inducible
chromosomal AmpC beta-lactamase producers and Pseudomonas aeruginosa
 Cefepime: IV form; beware seizures (especially in ESRD)
Fifth Generation: similar coverage as ceftriaxone (third generation) but has added
coverage vs. MRSA and VISA. Also vs. pneumococcus resistant to PCN or ceftriaxone.
 Ceftaroline: IV form
Carbapenems
Overall Class Properties: ~5% cross reactivity with PCN allergies. Generally resistant to
cleavage by most plasmid & chromosomal beta-lactamases. Very broad spectrum,
including gram negatives (including extended spectrum beta-lactamases [ESBL]),
anaerobes, and gram positives (including Enterococcus faecalis & Listeria). Generally
not active vs. Stenotrophomonas maltophilia, Burkholderia cepacia, Enterococcus
faecium, MRSA, or JK diphtheroids.
 Doripenem, imipenem, meropenem: IV forms; active vs. Pseudomonas
aeruginosa. Beware CNS toxicity w/ imipenem. Imipenem is given w/ cilastin to
prevent proximal tubule necrosis.
 Ertapenem: IV form; once daily, but less coverage vs. Pseudomonas aeruginosa,
Acinetobacter, and gram positives (specifically enterococci & PCN resistant
pneumococci) (Except Ertapenem)
Monobactams
Overall Class Prperties: No cross reactivity with PCN allergies. Good gram negative
coverage (including enterics and Pseudomonas aeruginosa), but virtually no activity vs.
gram positives or anaerobes. Less reliable as monotherapy vs. non-enteric gram
negatives (Pseudomonas, Acinetobacter, and Stenotrophomonas).
 Aztreonam: IV form
MRSA Coverage
Mechanism of Resistance: mecA conveys resistance by encoding PBP 2a, an inducible
protein that establishes resistance to the semisynthetic penicillinase resistant beta-lactams
as well as all cephalosporins (except ceftaroline).
Oral Agents:
 TMP/SMX: CA-MRSA only
 Doxycycline: CA-MRSA only
 Clindamycin: CA-MRSA only; if erythromycin resistance, check the D-test (to
rule out inducible resistance to clindamycin)
 Linezolid: watch out for pancytopenia & serotonin syndrome
Parenteral Agents:
 Vancomycin: bacteriostatic; good vs. invasive MRSA; beware MIC creep; want
MIC < 2 (debatable if MIC=2, but would probably use something else if MIC=2
and it is a serious infection)
 Daptomycin: bactericidal; good vs. invasive MRSA; inactivated by type II
pneumocytes, so not effective in MRSA pneumonia; beware MIC creep; want
MIC < 1; watch CPK
 Linezolid: bacteriostatic; good vs. invasive MRSA; watch out for pancytopenia &
serotonin syndrome (inhibits MAO); inhibits toxin production (good for toxic
shock)
 Ceftaroline: bactericidal; FDA approved for skin & soft tissue infections and
pneumonia, not yet for invasive infections
 Tigecycline: bacteriostatic; limited data for invasive MRSA; FDA warning for
increased mortality; remember the 4 P’s of tigecycline inactivity: Proteus,
Providencia, Pseudomonas, and Pee (doesn’t get into urine)
 Televancin: bactericidal; well established for skin & soft tissue infections, less
studied in invasive MRSA
 Synercid (Quinupristin-dalfopristin): bactericidal (each alone is static, together is
cidal); well established for skin & soft tissue infections, less so for invasive
MRSA; dosing requires central venous access
 Rifampin: bactericidal; rapid resistance develops so NEVER used alone; used in
combination w/ other agents for prosthetic device or bone infections
Fluoroquinolones: directly inhibit bacterial DNA synthesis by inhibiting DNA gyrase &
topoisomerase IV. Generally bactericidal. Resistance develops by mutations in DNA
gyrase/topoisomerase or via efflux pump, can occur rapidly. Great entrance into urine,
also good into the prostate (i.e. good for prostatitis). Great bioavailability (~100%), so
PO=IV. Great vs. gram neg bacilli (especially enterics), Pseudomonas, gram neg cocci
(Neisseria), gram pos cocci (strep, staph, pneumococcus in third/fourth generations),
intracellular/atypical (Mycoplasma, Ureaplasma, Chlamydophilia, and Chlamydia), and
TB. Generally increased gram positive coverage w/ later generations.
First Generation: No longer used (cinoxacin, nalidixic acid)
Second Generation: Not active vs. pneumococcus
 Ciprofloxacin: PO & IV; no activity vs. pneumococcus so not useful for
pneumonia (can be used as an adjunct for anti-Pseudomonal coverage in HCAP).
 Norfloxacin: PO; similar to cipro, used often as SBP prophylaxis
 Ofloxacin: PO; similar to cipro
Third/Fourth Generation: Added coverage vs. pneumococcus, somewhat less vs. gram
negatives.
 Moxifloxacin: PO & IV; only FLQ w/ clinical activity vs. anaerobes; less gram
negative coverage than cipro
 Levofloxacin: PO & IV; similar coverage as cipro for gram negatives except
slightly less active vs. Pseudomonas.
 Gemifloxacin: PO
Macrolides: bind to the 50S subunit of bacterial ribosomes to ultimately inhibit protein
synthesis. Generally bacteriostatic. Resistance develops by ermA, ermB, ermC genes
which alter ribosomal binding site, or through mef efflux pump. Active vs. gram
positives and atypicals (Mycoplasma, Ureaplasma, Chlamydophilia, and Chlamydia).
Newer agents have better activity vs. gram neg (enterics, cholera, Neisseria gonorrhea,
and H. pylori) than with erythromycin. Excellent tissue penetration. Also have antiinflammatory effects, useful for asthma/COPD.
 Erythromycin: PO & IV; original macrolide (derived from Streptomyces);
significant GI side effects, now used mainly as gastric emptying agent in
gastroparesis.
 Clarithromycin: PO; used for MAC prophylaxis when CD4<50
 Azithromycin: PO & IV; used for MAC prophylaxis when CD4<50; somewhat
better vs. H. flu than clarithro & erythro
 Telithromycin: PO; technically a Ketolide, so resistance to the macrolides does
not always confer resistance to telithromycin; beware hepatotoxicity, myasthenia
gravis, and visual disturbances (therefore not recommended as first line agent)
Tetracyclines: bind to the 30S subunit of bacterial ribosomes to ultimately inhibit
protein synthesis. Generally bacteriostatic. Resistance develops by decreased influx or
increased efflux, rarely inactivated/altered by bacteria. Active vs. rickettsial infections,
spirochetes, atypicals, chloroquine-resistant malaria (doxy, and only somewhat), gram
positives (including CA-MRSA), many enteric gram negs, actinomycosis, nocardiosis,
tularemia. Good tissue penetration. Do not give with penicillins (decreases bactericidal
activity of PCNs when co-administered). Do not give to children <8 yrs old (teeth
discoloration, hypoplasia of enamel). Beware skin toxicity.
 Doxycycline: PO & IV; best vs. tick borne disease/spirochetes, and malaria
 Minocycline: PO & IV; used often for acne
 Tigecycline: IV; technically a glycylcycline; has better MRSA and VRE
coverage but has black box warning for increased mortality (?selection bias?).
4P’s of tigecycline (holes in activity spectrum): Providencia, Proteus,
Pseudomonas, and Pee
Aminoglycosides: bind the 16S portion of the 30S ribosomal subunit, leading to
inhibition of protein synthesis. Activity is pH dependent, so low pH in lung/bronchial
secretions may reduce antimicrobial effect. Generally bactericidal. Resistance develops
by phosphorylation of the drug, efflux pump (esp. in Pseudomonas), but it is relatively
rare for resistance to develop during management of gram-neg infections. Enterococci
are intrinsically resistant to low/moderate levels, but synergy is seen w/ administration of
cell wall active agents (penicillins/vancomycin) to allow for lower aminoglycoside doses.
Active vs. many gram negs (enterics, Pseudomonas, Acinetobacter, H. flu), but usually
not vs. Burkholderia cepacia, Stenotrophomonas maltophilia, and anaerobes. Generally
active in vitro vs. gram positives, but NEVER as monotherapy (as previously stated, can
be used for synergy). Also somewhat vs. mycobacteria (streptomycin vs. MTB, amikacin
vs. M. fortuitum/abscessus/chelonae). Known to have a post antibiotic effect (persistent
suppression of bacterial growth after the drug has been cleared). Beware of
nephro/ototoxicity (dose dependent). Excellent urine concentrations (25 to 100x that of
serum), poor into CSF, bile, and bronchial secretions.
 Streptomycin: IM only; first of the class, derived from the actinobacterium
Streptomyces griseus, active vs. Mycobacterium tuberculosis
 Tobramycin: IV & nebulized; dose based off ideal body weight (IBW)
 Gentamicin: IV; dose based off IBW; used often in combination for invasive
enterococcal infections
 Amikacin: IV & IM; dose based off IBW; active vs. Mycobacterium fortuitum,
abscessus, & chelonae
Indications for Monotherapy:
 Tularemia: streptomycin & gentamicin are first line agents for severe cases
 Plague (Yersinia pestis): streptomycin & gentamicin are first line agents
 UTIs from MDR gram negs: excellent urine penetrance
 N. gonorrheae: spectinomycin is an alternate therapy for non-pharyngeal GC
infections in patients w/ severe penicillin allergies, but not available in the U.S.
Other Miscellaneous Antibiotics:
 Clindamycin: a lincosamide; binds 50S subunit of ribosome to inhibit protein
synthesis; bacteriostatic. Active vs. gram positives (check the D-test if treating
MRSA and R to erythro) & anaerobes. Also active vs. Toxoplasma gondii,
Actinomyces israelii, Nocardia asteroids, and Babesia spp. Resistance develops
by mutation of binding site or inactivation of the drug (esp. in Staph). Beware GI
side effects.
 Trimethoprim/Sulfamethoxazole: act synergistically to inhibit synthesis of
tetrahydrofolic acid (THF); TMP binds bacterial DHFR to prevent formation of
THF & SMX is a structural analog of PABA (used in synthesis of dihydrofolic
acid) and therefore competitively inhibits formation of DHF, an intermediate step
in formation of THF. Highly bactericidal given together. Active vs. aerobic gram
positives & gram negatives, Pneumocystis, and some protozoa & misc. organisms
(Nocardia, Cyclospora, Isospora, Yersinia, Vibrio cholerae, and Mycobacterium
marinum). Resistance develops by decreased permeability of membrane, efflux,
and mutations of enzymes forming THF. Beware rash, GI upset, aseptic
meningitis, hepatitis. Causes increase in creatinine without affecting true GFR
(TMP decreases urine excretion of creatinine w/out affecting true GFR).
 Colistin: a polymyxin; isolated from Bacillus polymyxa in 1949; fell out of favor
after aminoglycosides came out as they had less side effects (!). Bactericidal.
Disrupts the outer cell membrane by competitively displacing divalent cations
from the phosphate groups of membrane lipids (i.e. acts as a detergent).
Resistance is uncommon & poorly defined (disk diffusion cannot be used as
polymyxins diffuse poorly in agar), but might be related to overexpression of
outer membrane proteins (OprH) or reduction in the net negative charge of the
lipid A component of LPS. Active vs. some gram negs (primarily vs. P.
aeruginosa & A. baumannii).