Antimicrobial Agents

Classification of Antimicrobial Agents

Bactericidal vs. Bacteriostatic

Antimicrobial agents can be roughly divided into those which are bactericidal (they actively kill bacteria) and those which are bacteriostatic (they slow the growth of bacteria), although there is some overlap depending on the doses used and individual agents. Most antimicrobial agents in clinical use are bactericidal, including cephalosporins, aminoglycosides, fluoroquinollines, vancomycin, daptomycin, and metronidazole. Notable exceptions to this are the macrolides, tetracyclines, trimethoprim, and sulfonamides, all of which are bacteriostatic. Note that while it is rational to favor bactericidal agents over bacteriostatic agents, neither has ever been shown to be superior (probably because true recovery from infection cannot occur until the body is able to mount an appropriate immune response, thus “buying time” may be just as good as active killing)

Bactericidal vs. Bacteriostatic

  • Bactericidal: cephalosporins, aminoglycosides, fluoroquinollines, vancomycin, daptomycin, and metronidazole
  • Bacteriostatic: macrolides, tetracyclines, trimethoprim, and sulfonamides

Concentration-Dependent vs. Time-Dependent

Pharmcodynamics is a complex discipline, but the efficacy of most antimicrobial agents can be divided into those which are concentration-dependent and those which are time-dependent. The clinical efficacy of concentration-dependent agents (e.g. fluoroquinolones, aminoglycosides) is dependent on either the peak serum concentration, the area under the serum concentration curve, or both. The clinical efficacy of time-dependent agents (e.g. penicillins, cephalosporins, carbapenems, vancomycin, clindamycin, and macrolines), by contrast, is dependent only on the time above MIC exert their bactericidal (they actively kill bacteria) and those which are bacteriostatic (they slow the growth of bacteria). Application of these principles to real life would suggest that periodic high doses of fluoroquinolines and aminoglycosides would be the preferred administration strategy, as opposed to small, more frequent (or even continuous) dosing of the other agents. Real life has turned out to be more complex, as tissue concentrations do not necessarily reflect serum concentrations, and some concentration-dependence has been noted in time-dependent agents. Furthermore, the development of resistance may be affected by both concentration, area under the curve, and time above MIC, and must also be taken into account

Concentration vs. Time Dependent Killing

  • Concentration-Dependent: fluoroquinolones, aminoglycosides
  • Time-Dependent: penicillins, cephalosporins, carbapenems, vancomycin, clindamycin, and macrolides


Anti-Gram Positive Agents


Mechanism of Action

β-lactam ring inhibits cell wall synthesis by binding penicillin-binding proteins (PBPs) and inhibiting the third and final step in peptidoglycan formation. PBPs are on the outer membrane of Gram positive bacteria and on the inner membrane of Gram negatives. Efficacy of penicillins is related to the percent of time above the minimum inhibitory concentration (MIC). Of the β-lactams, penicillins kill with moderate rapidity (cephalosporins are the slowest and carbapenems are the fastest).

Risk of death is with administration is approximately 1:50,000.

Activity Against Specific Organisms

Penicillinase-resistant PCNs (nafcillin) are losing ground to MRSA. Extended-spectrum PCNs (ampicillin, ticarcillin, piperacillin) cover GNBs, with the latter two active against P.aeruginosa.


Mechanism of Action

β-lactam ring inhibits cell wall synthesis by binding penicillin-binding proteins (PBPs) and inhibiting the third and final step in peptidoglycan formation. PBPs are on the outer membrane of Gram positive bacteria and on the inner membrane of Gram negatives. Efficacy of cephalosporins is related to the percent of time above the minimum inhibitory concentration (MIC). Of all the β-lactams, cephalosporins are the slowest (carbapenems, by contrast, kill the fastest). Near-maximal effect is achieved at approximately 60-70% of time above MIC. Animal data suggests that resistance may develop when time above MIC is 50% or less. Multiple clinical trials have validated the pharmacokinetic superiority of cephalosporin infusions as compared to bolus techniques. Cephalosporins are clearly synergistic with aminoglycosides but may not be synergistic (and may actually be dyssyngergistic) with fluoroquinolones

Activity Against Specific Organisms

First generation (cefazolin) are active against GPC (but not S.epidermidis or MRSA). Second generation (cefoxitin, cefamandole) are more active against gram (-) aerobics and anaerobic bacilli. Third generations (cefoxitin, ceftriaxone, cefotaxime) have increased activity against H.influenza and sometimes of pseudomonas (ceftazidime). Fourth generations (cefipime) cover both Gram negatives (including pseudomonas) as well as Gram positives. Most are dosed 1–2g every 6-8h (except ceftriaxone, given every 12-24h). Adjust these doses in renal failure by extending the interval and not changing the weight. A 1975 study of actual allergic reactions showed that 7% of patients with a documented PCN allergy would clinically react to first-generation cephalosporins [J Antimicro Chemo 1S: 107, 1975], but these older data overestimate cross reactivity because cephalosporins from this era were contaminated with PCN [Can J Allergy Clin Immun 3: 12, 1998]. 11% of patients with a documented penicillin IgE-mediated allergy will react to cephalosporins on a skin test [Ann Intern Med 141: 16, 2004], with skin tests predicting clinical reactivity 60% of the time. The true likelihood of cross-reactivity is probably a function of the side chain (which does not correlate with generation) and must be analyzed individually [Pediatrics 115: 1048, 2005]



Mechanism of Action

Vancomycin inhibits cell wall synthesis by binding the D-alanyl-D-alanine terminus of non-PBP cell wall precursors. It has bactericidal activity against most Gram positive organisms (although it is bacteriostatic against Enterococcus and tolerant Staphylococci). Vancomycin exhibits time-dependent killing, i.e. the amount of time above the MIC for an individual organism is more important than the peak concentration. A dose of 15 mg/kg q12h (actual body weight) will provide a peak of 25-40 ucg/mL after one hour and a trough of 5 to 15 ug/mL. Because peak concentrations have no relationship with efficacy (or side effects), only trough monitoring is necessary

Activity Against Specific Organisms

Active against most aerobic Gram positive cocci as well as many anaerobic Gram positive bacteria including Corynebacterium (a Gram-positive rod [bacillus]) and C.dificile (an anaerobic, spore-forming Gram-positive rod [bacillus]) although resistance has been reported to Enterococcus (VRE) and beginning in 2002, Staphylococcus (VRA). Peaks should be < 40 mg/L and troughs above 5 mg/L. Activity is dependent on species and for many agents (e.g. MSSA) vancomycin is clearly inferior. In fact, there is some evidence from that worse mortality occurs when treating MSSA with vancomycin as opposed to nafcillin or oxacillin in both pneumonia and endocarditis [González C et al. Clin Infect Dis 29: 1171, 1999; Gentry C et al. Pharmacotherapy 17: 990, 1997].


Do not infuse faster than 10 mg/min (or ~ 1 g/hr) as rapid administration can cause vasodilation, hypotension, and flushing. Reversible renal insufficiency is found in 5% of patients [Lancet 344: 1748, 1994]. Start with 15-20 mg/kg every 12 hours and after three administrations begin to measure trough concentrations. The goal trough will be dependent on the organism you are targeting and its specific MICs


May be superior to vancomycin for pneumonia [Chest 124: 1789, 2003] because it penetrates into respiratory secretions [Inf Dis North Am 18: 651, 2004]. Prolonged use (> 1 month) may lead to thrombocytopenia, optic neuropathy, and an irreversible peripheral neuropathy [Neurology 66: 595, 2006]

Anti Gram-Negative Agents


One of the broadest spectrums available, including most Gram positives, Gram negatives, anaerobics, and missing only MRSA and P.cepacia (although some isolates of resistant P.aeruginosa have been reported). Dosed with cilastatin at 500 mg q6h except in pseudomonas where 1g is given q6h. The major side-effect of imipenem is seizures, which occur in 1 – 3% of patients, mostly in those with a history of seizures, intracranial mass, or renal failure [Mayo Clin Proc 66: 1074, 1991]. Meropenem does not have a risk of seizures

Aminoglycosides (gentamicin, amikacin, tobramycin)

Traditionally a big gun against aerobic Gram-negatives but use has decreased secondary to nephrotoxicity. Active against all enterobacteriae including Pseudomonas, and there does not seem to be much resistance emerging. Daily doses are based on ideal body weight, and loading doses are higher in critically-ill patients (who have higher volumes of distribution). Concentration-dependent killing has led to the recommendation of once-a-day dosing [Pharmacotherapy 12: 64S, 1992], which has been shown to be as effective and toxic as divided doses but less expensive [Ann Pharmacother 27: 351, 1993; Pharmacotherapy 15: 201, 1995]. Routine serum monitoring of aminoglycosides is recommended because both the peaks and troughs are important and equivalent doses lead to very different levels in individual patients. These are obligate nephrotoxins because eventually everyone will develop renal failure [Inf Dis Clin N Am 17: 503, 2003]. Early signs include urine casts, proteinuria, and inability to concentrate urine – renal toxicity is usually reversible [Surg Gynecol Obstet 171S: 24, 1986], however these drugs should still be avoided whenever possible. Their main indications are in immunocompromised or hemodynamically unstable patients. To dose, calculate true and ideal body weight and use the lower of the two. Renally cleared (reduce dose in ARF/CRI)


Has a similar spectrum to aminoglycosides but without the nephrotoxicity. Adverse reactions occur in 7% of patients, mostly nausea or diarrhea. It is an excellent choice for Gram-negatives


Active against MSSA and enterobacteriacea, including pseudomonas but with no activity against anaerobes and emerging resistance to pseudomonas. These drugs interfere with the metabolism of warfarin and theophylline. Their great advantage is that they can be given PO, but this is not particularly useful in the ICU. They are also ineffective against MRSA and are not always effective against pseudomonas

Antifungal Agents

Amphotericin is the most effective antifungal agent available but caries considerable risk of toxicity and discomfort. Infusion is accompanied by fever, chills, nausea, vomiting, and rigor in 70% of cases (premedication with acetaminophen and diphenhydramine can reduce some of these, sometimes hydrocortisone or meperidine may be necessary). The major complication of amphotericin is nephrotoxicity, leading to distal RTA, loss of potassium and magnesium, and thus hypomag/K. Cr, Mg, and K must therefore be monitored, and Mg should be supplemented daily 300 – 600 mg regardless of serum levels. D/C amphotericin temporarily if Cr > 3.0 mg/dL. Hypovolemia should be avoided during amphotericin therapy as it predisposes to renal artery vasoconstriction. There is a new lipophilic version of amphotericin which is equally as effective but has a lower incidence of side effects and renal dysfunction [NEJM 340: 764, 1999]

Fluconazole is an imidazole that some think will become a safer alternative to amphotericin for severe fungal infections [Mayo Clin Proc 67: 69, 1992]. Its major use in the ICU has been against disseminated candidiasis. Liver enzymes should probably be monitored periodically in patients with HIV or liver disease, as there are rare reports of fatal hepatic injury [Ann Pharmacother 28: 1177, 1994]

Caspofungin may be an alternative to amphotericin, as studies show that it is equally effective for treatment of invasive candidiasis [NEJM 347: 2020, 2002] and for empiric treatment of neutropenic patients [J Crit Illn 19: 3-12, 2004]

Table (left): susceptibility of gram (-) bacilli (blue) and pseudomonas (yellow) to various antibiotics [JAMA 289: 885, 2993]