A. Sulfa Compounds

1. Most common agent: Trimethoprim / Sulfamethoxazole (TMP/SMX; Bactrim®, Septra®)
2. Inhibits production of tetrahydrofolate by bacteria, not mammals
3. Agents are bacterostatic
4. Spectrum includes:
   1. Gram positive: good Streptococcal coverage (except enterococci)
   2. Pneumococci may be resistant
   3. Some activity against Staphylococcus, especially S. aureus
   4. Gram negative: E. coli, Proteus ssp, H. influenza, M. catarrhalis
   5. Atypicals: Pneumocystis carinii
   6. Also active against certain parasites
5. Agents not effective in vivo against enterococci (may be sensitive in vitro)
6. Recommended first line: sinusitis, bronchitis, urinary tract infections
7. Toxicities [1]
   1. Rash (common)
   2. Renal dysfunction - interstitial nephritis
   3. Hyperkalemia (high doses)
   4. HIV+ patients are particularly susceptible to severe rashes
   5. Slow increase in dose can lead to tolerance to higher doses (desensitization)
   6. Predisposition to general hypersensitivity in patients with sulfonamide reactions [11]
8. Contraindicated in pregnancy
9. Drug Interactions [4]
   1. Azathioprine, Methotrexate - enhanced activity causing leukopenia
   2. Cyclosporine - reduced levels and increased renal toxicity
   3. Dapsone - methemoglobinemia
   4. Digoxin - increased levels
   5. Metronidazole - avoid with intravenous sulfonamides
   6. Phenytoin - increased levels
   7. Potassium and Potassium Sparing Diuretics - hyperkalemia
   8. Procainamide - increased levels
   9. Rifampin - increased rifampin levels
   10. Sulfonylurea hypoglycemics - increased hypoglycemic effects
   11. Thiazide Diuretics - hyponatremia
   12. Warfarin - enhanced anticoagulation
   13. Zidovudine - cytopenias may occur in patients with liver problems

B. Metronidazole (Flagyl®)

1. First generation nitroimidazole
2. Excellent gram negative anaerobic coverage, especially Bacteroides fragilis
3. Not active against anaerobic streptococci (peptococcus, peptostreptococcus)
4. First line therapy for intra-abdominal infections with other agents
5. First line therapy for Clostridium difficile diarrhea (preferably oral)
6. Active against Giardia, Amoeba, Trichomoniasis
7. Approved for therapy of bacterial vaginosis and Trichomonas vaginalis
8. Dose is usually 500mg BID either PO or IV
9. Side Effects
   1. Metallic taste
   2. Nausea, anorexia, epigastric discomfort
   3. Antabuse-like reaction with alcohol
   4. Hepatitis (rare)
10. Contraindicated in pregnancy

C. Tinidazole (Tindamax®) [15,21]

1. Oral antiprotozoal nitroimidazole drug similar to metronidazole
2. Activity
   1. Protozoans: giardia, amoeba
   2. Anaerobes including Bacteroides ssp.
   3. Gardnerella vaginalis
   4. Prevotella
3. Approved for:
   1. Trichomoniasis in adults
   2. Giardiasis - adults and children
   3. Intestinal amebiasis and amebic liver abscess - adults and children
   4. Bacterial vaginosis
4. Adult dose is 1gm or 2gm per day, duration depends on disease
5. Simplest treatment for bacterial vaginosis: 2gm po QD x 2 days
6. Similar side effects to metronidazole

D. Vancomycin (Vancocin®)

1. Potent cell wall inhibitor active only against gram positive organisms
2. Bactericidal agent, though not as quickly as penicillins
3. Active against methicillin-resistant S. aureus (MRSA) and Staphylococcus epidermidus
4. Dosing: 1gm iv q12 hours with normal renal function
5. Minimal nephrotoxicity; increases in presence of aminoglycosides
6. Main side effect is "red man syndrome" [1]
   1. Due to cutaneous vasodilation ± mild hypotension
   2. Diffuse hot, red rash, mild anaphylactoid reaction
   3. Stop drug infusion until resolves, then infuse at 50% of original rate
   4. Vancomycin stimulates release of mast cell histamine and other vasoactive compounds
7. Occasionally associated with immune thrombocytopenia (IgM/G anti-platelet antibodies) [20]
8. Vancomycin Levels
   1. Only for therapeutic reasons to insure adequate levels
   2. May also be used to monitor for dose interval in patients with renal failure
   3. Renally excreted and not dialyzed, so usually given weekly to patients on dialysis
9. Acceptable in pregnancy

E. Fosfomycin (Monurol®) [2]

1. Broad spectrum organic phosphonate
2. Interferes with formation of bacterial cell wall
3. Inhibits bacterial phosphoenolpyruvate transferase
4. Avaiable only as oral agent in USA, as parenteral in Europe
5. Activity against E. coli, Staph saprophyticus, most enterococci
6. May have activity against some aminoglycoside and/or vancomycin resistant enterococci
7. Multiple doses can lead to resistance, but little cross-resistance to other drugs
8. Single 3gm oral dose FDA approved for UTI
9. Generally well tolerated
10. Cost is about $25 for single dose (compare with TMP/SMX at <$1 for 3 days)

F. Quinupristin/Dalfopristin (Synercid®) [3,5,6]

1. Both agents are derivatives of pristinamycin, a streptogramin
2. Inhibits a large variety of gram positive organisms
3. Block bacterial ribosomal synthesis
4. Quinupristin
   1. Bactericidal against streptococci
   2. Little or no bactericidal activity against enterococci
5. Dalfopristin
   1. Active against streptococci
   2. Synergistic with quinupristin with combination bacteriostatic against enterococci
6. Enterococcal (E.) Activity Restricted to E. faecium
   1. Nearly 70% of vancomycin resistant E. faecium (VREF) had clinical responses
   2. Not effective against E. faecalis
7. Active against methicillin (and vancomycin) resistant Staph aureus (MRSA, VRSA)
8. Mechanisms of Resistance
   1. Resistance has been reported, though it is very uncommon
   2. Acetylation or efflux of dalfopristin
   3. Hydrolysis of quinupristin
9. Dosing
   1. Dose is typically 7.5mg/kg iv q8-12 hours
   2. More frequent dosing for bacteremia / sepsis
   3. Metabolized mainly be liver and excreted mainly in bile
   4. Dose reduction may be required in patients with cirrhosis or hepatic insufficiency
   5. Half life is 1 hour for both agents
   6. Blocks CYP3A4 function and can increase drug levels of concommitent agents
10. Adverse Effects
    1. Pain, inflammation, edema, thrombophlebitis at infusion site occur in ~75% of patients
    2. Infusion site reactions are minimized by use of central venous catheter
    3. Athralgias and myalgias are very common
    4. Increases in conjugated bilirubin have been reported

G. Daptomycin (Cubicin®) [12,13]

1. Cyclic lipopeptide, a novel class of bactericidal membrane integrating agent
2. Exclusively kills gram positive bacteria
3. Good killing of MRSA [17], VREF, penicillin-resistant Strep pneumoniae, Strep piogenes
4. Also active against vancomycin resistant (VRSA) and intermediate (VISA) Staph aureus
5. FDA approved for complicated skin and skin structure infections
   1. Abscesses
   2. Post-surgical wound infections
   3. Infected ulcers
   4. Severe cellulitis
6. Dosing
   1. Renal Function >30mL/min: 4mg/kg IV over 30 minutes once daily
   2. Administer q48 hours for creatinine clearance <30mL/min or on dialysis
   3. Daptomycin 6mg IV qd is as effective with fewer adverse effects compared with low- dose gentamicin+antistaphylococcal penicillin or vancomycin for endocarditis [19]
7. Side Effects
   1. Gastrointestinal effects most common
   2. Some injection site reactions
   3. Less common: fever, headache, dizziness, insomnia, rash
   4. Very low incidence of creatine phosphokinase (CPK) increases at standard doses

H. Linezolid (Zyvox®) [7,8,9]

1. Oxazolidinone which inhibits protein synthesis by bacterial ribosome
   1. Bind 50S ribosomal subunit near interface with 30S subunit (unique mechanism)
   2. No cross resistance with other protein synthesis inhibitors has been seen
2. Activity against all gram positive organisms
   1. Cytostatic activity against both E. faceium AND E. faecalis
   2. Cytostatic against staphylococci, including vancomycin intermediate strains
   3. Bactericidal against pneumococci, including penicillin resistant pneumococci
   4. Poor activity against gram negative organisms
   5. Moderate to good activity against common anaerobic pathogens
3. Dosing
   1. Oral and IV available
   2. Usual dose is 600mg twice daily oral or IV
   3. No alteration for impaired renal or hepatic function
4. Clinical Efficacy
   1. Cure rates at 600mg IV q12 hours for vancomycin resistant enterococcus 67%
   2. Cure rates for other infections 50-85%
   3. Resistance can develop after very prolonged (months) use in very ill patients [10]
   4. However, resistance is very uncommon
5. Clinical Utility
   1. Susceptible organisms as described above
   2. Skin and soft tissue infections
   3. Lower respiratory infections
   4. Vancomycin resistant E. faecium (VREF)
   5. Methicillin resistant staphylococcus (MRSA) [17]
6. Side Effects
   1. Generally well tolerated
   2. Nausea, vomiting and diarrhea sometimes seen
   3. Main concerning side effect is duration-dependent, reversible thrombocytopenia
   4. Platelet counts should be checked if duration of use >2 weeks
   5. Suppression of neutrophils can also occur

I. Telithromycin (Ketek®) [14]

1. Ketolide antibiotic related to macrolides
2. Approved for:
   1. Community acquired pneumonia
   2. Acute exacerbations in COPD
   3. Acute sinusitis
3. Appears to have activity against some erythromycin resistant organisms
4. Generally well tolerated but severe liver toxicity reported [18]

J. Rifaximin (Xifaxan®) [16]

1. Non-absorbed orla antibiotic related to rifampin
2. Inhibits bacterial RNA synthesis
3. Activity
   1. FDA approved for treatment of non-bloody traveler's diarrhea
   2. Good against E. coli, shigella, salmonella including fluoroquinolone resistant
   3. Poor activity against campylobacter or yersinia or enteroinvasive E. coli
4. Dose is 200mg tid x 3 days effective in Traveler's Diarrhea
5. Fewer adverse events and side effects than systemically absorbed antibiotics

References

1. DeShazo RD and Kemp SF. 1997. JAMA. 278(22):1895
2. Fosfomycin. 1997. Med Let. 39(1005):66
3. Vo HK and Zervos MJ. 1998. Infect Dis Clin Pract. 7(8):416
4. Gregg CR. 1999. Am J Med. 106(2):227
5. Quinupristin / Dalfopristin. Med Let. 41(1066):109
6. Johnson A and Livermore DM. 1999. Lancet. 354(9195):2013
7. Linezolid. 2000. Med Let. 42(1079):45
8. Diekema DJ and Jones RN. 2001. Lancet. 358(9297):1975
9. Moellering RC Jr. 2003. Ann Intern Med. 138(2):134
10. Tsiodras S, Gold HS, Sakoulas G, et al. 2001. Lancet. 358(9281):207
11. Strom BL, Schinnar R, Apter AJ, et al. 2003. NEJM. 349(17):1628
12. Daptomycin. 2004. Med Let. 46(1175):11
13. Critchley IA, Draghi DC, Sahm DF, et al. 2003. J Antimicrob Chemother. 51(3):639
14. Telithromycin. 2004. Med Let. 46(1189):66
15. Tinidazole. 2004. Med Let. 46(1190):70
16. Rifaximin. 2004. Med Let. 46(1191):74
17. Community Acquired MRSA. 2006. Med Let. 48(1228):13
18. Clay KD, Hanson JS, Pope SD, et al. 2006. Ann Intern Med. 144(6):415
19. Fowler VG Jr, Boucher HW, Corey GR, et al. 2006. NEJM. 355(7):653
20. Von Drygalski A, Curtis BR, Bougie DW, et al. 2007. NEJM. 356(9):904
21. Tinidazole for Bacterial Vaginosis. 2007. Med Let. 49(1269):73