Antimicrobial Therapy



Antimicrobial Therapy





This chapter describes the intravenous antibiotics you are most likely to use in the ICU. Each is presented in the order shown below.



  • Aminoglycosides (gentamicin, tobramycin, amikacin)


  • Antifungal agents (amphotericin B, fluconazole, echin-ocandins)


  • Carbapenems (imipenem, meropenem)


  • Cephalosporins (ceftriaxone, ceftazidime, cefepime)


  • Fluoroquinolones (ciprofloxacin, levofloxacin, moxifloxacin)


  • Penicillins (piperacillin-tazobactam)


  • Vancomycin and alternatives (linezolid, tigecycline, daptomycin)


I. Aminoglycosides

The aminoglycosides (gentamicin, tobramycin, and ami-kacin) were once the darlings of critical care antibiotics, but their popularity has waned because of nephrotoxicity.


A. Activity & Clinical Uses



  • Aminoglycosides are active against staphylococci and gram-negative aerobic bacilli, including Pseudomonas aeruginosa (1). Amikacin has the greatest antibacterial activity of the aminoglycosides, and (as indicated in
    Table 44.1) it is currently the most active antibiotic against Pseudomonas aeruginosa (2).


  • Aminoglycosides can be used to treat any serious infection caused by gram-negative bacilli. However, because of the risk of nephrotoxicity, they are generally reserved for life-threatening infections involving P. aeruginosa.


  • In cases of gram-negative bacteremia associated with neutropenia or septic shock, there is evidence that empiric antibiotic therapy is more effective if an aminoglycoside is added to another drug with activity against gram-negative bacilli (3).








Table 44.1 Antibiotic Susceptibilities for the Most Frequently Isolated Gram-Negative Organisms in ICU Patients in the U.S.






















































Antibiotic E. coli Klebsiella spp P. aeruginosa
Amikacin 100% 95% 97%
Tobramycin 86% 89% 89%
Imipenem 100% 96% 72%
Meropenem 100% 95% 73%
Cefepime 91% 88% 76%
Ceftazidime 91% 88% 76%
Ciprofloxacin 65% 87% 71%
Levofloxacin 65% 89% 67%
Piperacillin/Tazobactam 91% 86% 71%
From Reference 2, which includes data from 65 hospitals collected over a 2-year period (2009–2011). The 3 organisms in the table accounted for 57% of total (3,946) gram-negative isolates.



B. Dosage

Aminoglycoside dosing is based on body weight and renal function.



  • Aminoglycoside dosing is based on ideal body weight (see Appendix 2 for tables on ideal body weight).


  • For obese patients (body weight >20% above ideal body weight), dosing is based on an adjusted body weight, which is the ideal body weight plus 45% of the difference between the actual body weight (ABW) and the ideal body weight (IBW) (1); i.e.,



  • Recommended dosing regimens for the aminoglycosides are shown in Table 44.2 (1).



    • Standard doses of aminoglycosides often produce subtherapeutic drug levels in critically ill patients (4), so higher doses are recommended (at least initially) for ICU patients.


    • Once-daily dosing is favored for aminoglycosides because outcomes are not adversely affected, and the onset of nephrotoxicity is delayed (1).


    • Dose reduction is necessary when renal function is impaired (1). This is achieved by extending the dosing interval and/or reducing the amount of drug that is administered.


C. Drug Levels

Monitoring serum drug levels is essential for optimal dosing of aminoglycosides, especially in patients with renal insufficiency.



  • Peak drug levels (drawn one hour after initiating a dose) are used as an indication of therapeutic effect. The
    target peak levels for once-daily dosing are 56–64 μg/mL for amikacin, and 16–24 μg/mL for gentamicin and tobramycin (5).


  • When a pathogen is isolated and a minimum inhibitory concentration (MIC) is available, the ratio of peak drug concentration (Cmax) to MIC is a more reliable measure of therapeutic effect. Aminoglycosides are most effective when Cmax/MIC ratio is 8–10 (4).








Table 44.2 Aminoglycoside Dose Recommendations







































Creatinine Clearance (mL/min) Gentamicin Tobramycin (mg/kg) Amikacin (mg/kg) Dosing Interval
≥80 7 20 24 hr
60–79 5 15 24 hr
40–59 4 12 24 hr
20–39 4 12 48 hr
10–19 3 10 48 hr
<10 2.5 7.5 48 hr
From Reference 1.


D. Adverse Effects


1. Nephrotoxicity



  • Aminoglycosides are known as obligate nephrotoxins because renal impairment will eventually develop in all patients. Increases in serum creatinine usually appear after one week of therapy (9).


  • The mechanism is accumulation of aminoglycosides in renal tubular cells, which culminates in lethal cell injury and acute tubular necrosis (1).



  • Nephrotoxic effects are enhanced by hypovolemia, renal disease, hypokalemia, loop diuretics, and vancomycin (1,6).


2. Less Frequent Toxicities



  • Aminoglycosides can produce irreversible hearing loss and vestibular damage (1). The incidence of ototoxicity is unclear, but low-frequency hearing loss has been reported in 13% of patients who received gentamicin (7). There is no clear relationship between aminoglycoside dose and the risk of ototoxicity.


  • Aminoglycosides can inhibit acetylcholine release from presynaptic nerve terminals (8), but clinically apparent muscle weakness has only been reported on rare occasions in patients with myasthenia gravis (9).


II. Antifungal Agents

The pathogenic fungi of concern in critically ill patients are Candida species (primarily Candida albicans), so the description of antifungal agents is limited to their role in treating Candida infections.


A. Amphotericin B


1. Activity & Clinical Uses

Amphotericin B (AmB) is active against all Candida species except C. lusitaniae (a rare pathogen) (10), but it is not favored for treating Candida infections because of the risk of adverse effects. Instead, AmB is reserved for cases of intolerance or resistance to other antifungal drugs (11).


2. Dosage



  • Central venous cannulation is preferred for AmB infusions to reduce the risk of infusion-related phlebitis (10).



  • AmB is given once daily in an intravenous dose of 0.5–1 mg/kg (10,12). The dose is usually delivered over 4 hours, but it can be delivered in one hour, if tolerated.


  • The total AmB dose is 0.5–4 grams, and is determined by the type and severity of the fungal infection.


3. Adverse Effects



  • SYSTEMIC INFLAMMATORY RESPONSE: Infusions of AmB are accompanied by fever, chills, and rigors in about 70% of instances (12). This reaction is most pronounced with the initial infusion, and diminishes in intensity with repeated infusions. The following measures help to reduce the severity of this reaction (12):



    • Thirty minutes before the infusion, give acetaminophen (10 to 15 mg/kg orally) and diphenhydramine (25 mg orally or IV).


    • If rigors are a problem, give meperidine (25 mg IV).


    • If the above measures do not provide adequate relief, add hydrocortisone to the AmB infusate (0.1 mg/mL).


  • NEPHROTOXICITY: AmB can damage the renal tubules and produce a renal tubular acidosis (distal type), with increased urinary excretion of potassium and magnesium (13). Hypokalemia and hypomagnesemia are common consequences.



    • The serum creatinine rises above 2.5 mg/dL in 30% of patients after 2–3 weeks of AmB infusions, and 15% of these patients may eventually require dialysis (14). Therefore, a rise in serum creatinine to 2.5 mg/dL during AmB therapy should prompt cessation of the drug for a few days, or a switch to a lipid AmB preparation (see next).



4. Lipid Preparations

Specialized lipid preparations of AmB have been developed to reduce the binding of AmB to mammalian cells (thereby reducing the risk of renal injury). Two lipid preparations are available: liposomal AmB, and AmB lipid complex. The dose for both preparations is 3–5 mg/kg daily (10). A comparison study showed a lower incidence of renal injury with the liposomal AmB preparation (13).


B. Fluconazole

Fluconazole is an azole antifungal agent (like itraconazole and voraconazole) that was introduced in 1990 as the first oral antifungal agent.


1. Activity & Clinical Uses



  • Fluconazole is active against Candida albicans, C. tropicalis, and C. parapsilosis, but is not active against C. krusei and C. glabrata (10).


  • According to the 2016 guidelines on treating candidiasis (11), fluconazole is a second-line drug for invasive candidiasis involving susceptible organisms, and is suitable only for patients who are not seriously ill (i.e., non-ICU patients) and have no prior exposure to azole drugs.


  • Fluconazole is the preferred agent for symptomatic urinary tract infections involving susceptible organisms, and for infections involving C. parapsilosis (11).


2. Dosage



  • Fluconazole can be given orally or IV using the same dose.


  • The dose for invasive candidiasis is 800 mg IV initially, then 400 mg IV daily (11).


  • A 50% dose reduction is recommended for a creatinine clearance <50 mL/min (10).



3. Adverse Effects



  • Fluconazole is a potent inhibitor of cytochrome P450 isoenzymes, and drugs that are metabolized by the same P450 isoenzymes will accumulate during therapy with fluconazole. Drugs in this category include drugs that prolong the QT interval (cisapride, erythromycin, quinidine), CNS drugs (carbamazepine, phenytoin, haloperidol, benzodiazepines, opiates) coumadin, and theophylline. Concurrent therapy with fluconazole and cisapride is contraindicated (10), while combined therapy with other interacting drugs can be continued, using serum drug levels to determine the need for dose reduction.


  • Fluconazole has been implicated in cases of severe and even fatal hepatic injury in HIV patients (16).


C. Echinocandins

The echinocandins are antifungal agents with a broader spectrum of activity than fluconazole. There are 3 drugs in this class: caspofungin, micafungin, and anidulafungin. Most of the early clinical experience has been with caspofungin.


1. Activity & Clinical Uses

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Nov 8, 2018 | Posted by in CRITICAL CARE | Comments Off on Antimicrobial Therapy

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