Part 2: Non-b-lactam Antibiotics

• general purpose "second line" drugs if b -lactams cannot be used
• Spetrum of Activity – best against group A b -hemolytic strep, pneumococcus, community staphylococcus, atypical organisms (legionella, mycoplasma, chlamydia twar, campylobacter, atypical mycobacteria (MAC), pertussus)
• most common agent used in respiratory tract infections; also good for uncomplicated urethritis or cervicitis
• static, but act cidal in appropriate context
• Newer Macrolides – erythromycin is phlebogenic (venous clots) and causes GI upset (homolog for gut hormone motilin)
• 2 new macrolides (with identical spectrum of activity) don’t have these toxicities: azithromycin, clarithromycin
• Pharmacokinetics – penetrates 15-30 times better into tissues than b -lactams – also accumulate in tissues, so antibiotic coverage may last twice as long as dosing
• Resistance – becoming more common – most have altered ribosomes, also inactivating enzymes
• Side Effects
• interactions (especially Warfarin and theophylline)
• mild ototoxicity (temporary deafness with high dose)
• Future Developments – ketolides! – derivatives of macrolides that are effective against resistant organisms

• almost exclusively inpatient antibiotics (unlike macrolides)
• three in widespread use: gentimycin, tobramycin, and amikacin (wider spectrum with each generation)
• Spectrum of Activity: ONLY aerobic gram negative organisms (does not work against anaerobes or gram positive)
• does have synergistic effects with cell wall toxins, even in gram + (staph aureus, enterococcus, listeria)
• Route of Administration – parenteral (very little absorption from GI, but can be used to treat GI infections)
• BUT enough does get absorbed to produce toxicity with long-term oral use
• among the more "comfortable" to use IM – very good absorption this way, but peak plasma conc not as high
• v.water soluble, highly charged, don’t penetrate tissues well – so don’t enter bronchopulmonary tree or CNS; some have recommended giving the drug locally (e.g., aerosol for bronchopulmonary)
• activity is very pH dependent – at pH that is too acidic, activity will be diminished (important for many sites)
• Toxicity – three primary toxicities:
• (1) nephrotoxic – 10-20% of adults will have evidence of altered renal function; acute renal failure with prolonged use
• enhanced if already have chronic renal problems or using other nephrotoxic drugs
• (2) ototoxic – irreversable effects on hearing and balance – cochlear toxicity: can’t stand up
• (3) neuromuscular blockade–inhibit presynaptic ACh release–effect is enhanced with other drugs (NM blockade, steroids)
• these are worse with earlier drugs (gentamycin); toxicity is manageable if you watch serum concentration, but the cost of monitoring serum frequently outweighs the savings by using older drugs
• Dosing – model drug for conc dependent, significant post-antibiotic effects

• antedated b -lactams – "bactrim" in this country, "co-trim" elsewhere
• Spectrum of Activity – UTI, URI (bronchitis), otitis media, GI infections, pneumocystis carinii
• Administration – optimal serum concentration is 20:1 (SMX:TMP); oral concentration of 5:1 produces this
• works on microbial folate metabolism (PABA to folate)
• Toxicity – hard to anticipate
• cutaneous – Stevens-Johnson (dramatic ideosynchratic exfoliative dermatitis)
• hematologic – can affect human folate metabolism – aplastic anemia, leukopenia, neutropenia, thrombocytopenia
• worse in alcoholics or other folate-deficient patients
• renal – components of drug interfere with serum creatinine, and sulfa crystallizes in tubules leading to insufficiency
• also glossitis, stomatitis, displace bilirubin (kernicteris in neonate)

• only two: vancomycin, teicoplanin
• Spectrum of Activity – only against gram positive – outer membrane of gram negative excludes it
• some gram+ are naturally resistant–lactobacillus (yogurt) and leukonostoc (wine) – leads to disease in immunocompromised
• ONLY vancomycin works against MRSA – methicillin resistant staph aureus
• enterococci (2^nd or 3^rd most common hospital infection) – most are resistant to vanco (VRE=vancomycin resistant enterococcus), so withhold unless condition mandates its use
• Route of Administration – exclusively parenteral drug – cannot be used IM (produces painful sterile absesses)
• does not penetrate many tissues (CNS, bone) – but MRSA requires vanco, so use doses as high as possible
• Toxicity – two primary toxicities:
• (1) "red man" syndrome – non-IgE mediated mast cell histamine release – hypotension – NOT an allergic reaction
• prevent by giving it over a longer period of time
• (2) nephrotoxicity – worse with other nephrotoxic agents or underlying renal failure
• Resistance – on a transposon, so can be transferred to MRSA in laboratory (will be a disaster if it happens clinically)

• first broad-spectrum antibiotic (introduced in 1950s)
• Spectrum of Activity – broad, so used for infections from "great outdoors"–rickettsia, chlamydia, brusella, mycoplasma
• Available Varieties – tetracycline (500 mg), doxycycline (100 mg), minocycline (effective against VRE!)
• Pharmacokinetics – enters body compartments better than most – 100% absorbed
• Resistance – tetM – resistance pump (increased efflux); MAR locus (multiple antibiotic resistance)
• Future Developments – "glycocyclines" – resurrection of tetracyclines

• norfloxacin, ciprofloxacin –prevents DNA replication (topoisomerase, SOS response, RNA production)
• Spectrum of Activity – aerobic gram negative rods (pseudomonas, E. coli, citrobacter, serratius)
• new quinolones work against gram positive strep too (levofloxicin and gadifloxacin), even anaerobic (moxifloxacin)
• levofloxacin works against pennicillin-resistant pneumococci, but resistance develops very fast
• Pharmacokinetics – penetration – goes everywhere except CNS – urine, respiratory, bone, prostate
• Toxicity
• arthropathy, tendonitis (can cause achilles tendon rupture)
• CNS (interferes with GABA) – sleep disturbances/agitated/nightmares
• increased QTc interval – do not use with other anti-arrhythmics or congenital increased QTc or antihistamines
• phototoxicity – adverse reaction to sun exposure
• Future Developents – millions of these compounds available – there will soon be more of them than of beta lactams

• very frequently used in developing world (3^rd generation cephalosporins have replaced)
• Spectrum of Activity – cidal against CNS pathogens – pneumococcus, meningococcus, H.flu where no vaccine
• very lipophilic – virtually 100% bioavailable (oral = parenteral) and gets everywhere
• Toxicity
• grey baby syndrome – infant liver cannot conjugate the drug – causes shock, circulatory collapse
• aplastic anemia – bone marrow suppression in everyone, in 0.004% of patients, it doesn’t get better

• pneumococcal meningitis – must get the antibiotic into the CNS to treat this infections
• must be cidal; b -lactams are 1^st line, maybe quinilones in future; chloramphenicol in developing countries; historically tetracycline/sulfa drugs
• can also administer "intrathecally" – directly into CSF