In the ICU, aqueous penicillin G is appropriate in the therapy of severe, overwhelming infections caused by susceptible organisms, including pneumococcal pneumonia and bacteremia caused by penicillin-susceptible strains [1], necrotizing fasciitis due to group A Streptococcus (in combination with clindamycin), and for streptococcal bacteremia. Because of the prevalence of penicillin-resistant pneumococci, life-threatening infections (especially meningitis) due to these organisms should be treated initially with ceftriaxone, cefotaxime, or vancomycin [3]. Although aspiration pneumonia commonly involves mouth anaerobes that are susceptible to penicillin G, penicillin-resistant anaerobes can be found in putrid, cavitary pneumonia, and empyema, and clindamycin with or without a third-generation cephalosporin (or an extended-spectrum β-lactam plus metronidazole) is the preferred regimen [4,5,6]. Therapy for penicillin-susceptible Enterococcus spp causing endocarditis is penicillin G or ampicillin plus an aminoglycoside, generally gentamicin [7]. The activity of penicillin G and ampicillin against most Gram-negative bacilli is poor [2]. Staphylococcus aureus should be presumed to be resistant to penicillin, ampicillin, and piperacillin, as most strains produce a penicillinase.

Because most strains of S. aureus are resistant to penicillin G by virtue of β-lactamase production, treatment of severe infections caused by these organisms involves one of the β-lactamase–resistant penicillins (see Table 77.1). Nafcillin and oxacillin are interchangeable: Both exhibit excellent in vitro activity against most susceptible isolates of S. aureus, but are slightly less active (although generally effective) than penicillin G against streptococci, and are sufficiently metabolized by the hepatic route so that no adjustment in dose is necessary in patients with renal insufficiency. Because of high prevalence of community-acquired methicillin-resistant S. aureus (MRSA), vancomycin should be used for empiric therapy of suspected staphylococcal infections [8]. In patients with overwhelming or disseminated infection caused by β-lactam–susceptible S. aureus, therapy should be instituted with 9 to 12 g per day of intravenous (IV) oxacillin or nafcillin, in divided doses every 4 hours (see Table 77.1).

The expanded-spectrum penicillin (piperacillin) and the combination agent piperacillin/tazobactam exhibit activity against many Enterobacteriaceae that are resistant to ampicillin [9].

In the ICU patient with suspected bacteremia or overwhelming infection due to Gram-negative bacilli, therapy should be chosen with knowledge of local ICU resistance patterns and include agents that the patient has not recently received. Pharyngeal colonization with Gram-negative bacilli rapidly develops in patients in the ICU, and initial therapy of nosocomial aspiration pneumonia requires the addition of an antipseudomonal penicillin, carbapenem, or cephalosporin, usually in combination with an aminoglycoside or fluoroquinolone [10]. In patients with Pseudomonas aeruginosa infections, the intensivist should consider using higher dosages or continuous infusions of piperacillin or piperacillin/tazobactam with or without an aminoglycoside [11]. The addition of the aminoglycoside to extended-spectrum penicillins is controversial [12] but has been shown to provide broader Gram-negative coverage and synergistic killing against P. aeruginosa.

Clavulanic acid, sulbactam, and tazobactam are β-lactamase inhibitors that bind irreversibly to β-lactamases derived from S. aureus and anaerobes, as well as some β-lactamases from Gram-negative bacilli. Thus, the combination of one of these
β-lactamase inhibitors with ampicillin or piperacillin results in a drug combination that is active against β-lactamase–producing strains of S. aureus, Bacteroides sp, Haemophilus influenzae, Neisseria gonorrhoeae, and enteric Gram-negative bacilli such as Escherichia coli and Klebsiella and Proteus spp. However, chromosomally mediated β-lactamases of other Gram-negative bacilli are unaffected by these β-lactamase inhibitors, and therefore these combinations are ineffective against many isolates of P. aeruginosa, Enterobacter cloacae, Citrobacter freundii, and Serratia marcescens.

Formulations of β-lactamase combinations available parenterally include ampicillin–sulbactam and piperacillin–tazobactam. Piperacillin–tazobactam can be effective in the treatment of mixed infections, such as nosocomial pneumonia, intra-abdominal infections, and synergistic skin soft tissue infections. However, depending on local resistance patterns, the lack of efficacy against multiple-resistant Gram-negative bacilli commonly found in the ICU warrants monitoring of local resistance patterns and using a carbapenem, or adding an aminoglycoside as part of a combination regimen to ensure broad efficacy against nosocomial Gram-negative bacilli [10,13].

The usual suggested dosages of the available combinations are given in Table 77.1. For treatment of P. aeruginosa infections, the dosage of piperacillin–tazobactam should be increased to 3.375 g IV every 4 hours or 4.5 g IV every 6 hours for pneumonia. The pharmacology of the β-lactamase inhibitors is similar to that for other β-lactams: Clearance is by renal mechanisms, and dosage adjustments must be made with these combinations in the setting of renal impairment. Continuous infusion of piperacillin/tazobactam after a bolus has a pharmacodynamic advantage for organisms with relatively high minimum inhibitory concentrations (MICs) to piperacillin and in patients on continuous venovenous hemofiltration (CVVH) [11].

First-generation cephalosporins exhibit a virtually identical spectrum of antibacterial activity, and they differ only in their pharmacokinetic properties. These agents are active against staphylococci (β-lactam–susceptible staphylococci) but are not effective against enterococci, Listeria monocytogenes, MRSA, or the majority of coagulase-negative staphylococci. Community-acquired strains of E. coli, Proteus mirabilis, and Klebsiella pneumoniae often are susceptible to the first-generation cephalosporins, but in general, third-generation agents are far more potent against Gram-negative bacilli and are preferred in the treatment of such infections in ICU patients. Nosocomial isolates of Enterobacteriaceae usually are resistant to first-generation cephalosporins, as are Pseudomonas and Acinetobacter spp.

Second-generation cephalosporins (e.g., cefuroxime) have only limited activity against hospital-acquired Gram-negative bacilli and therefore are not recommended for treatment of Gram negatives in the ICU setting.

Third-generation cephalosporins exhibit an expanded spectrum and increased potency against Gram-negative organisms, especially Enterobacteriaceae [15]. A number of these agents, particularly ceftazidime, are less active than first-generation cephalosporins against Gram-positive cocci. However, ceftriaxone has significant activity against Streptococcus
pneumoniae and other oral streptococci, and has been recommended for use in severely ill patients with community-acquired pneumonia (CAP), bacterial meningitis, and bacterial endocarditis [16,17,18].

The activity of most third-generation cephalosporins against P. aeruginosa is variable and unpredictable; only ceftazidime and cefepime, a fourth-generation cephalosporin, are considered active against this organism and should be used in combination with an aminoglycoside when infection with P. aeruginosa is likely [19]. If a third-generation cephalosporin is used as a single agent, gaps in coverage may occur, including (a) enterococcal superinfection; (b) P. aeruginosa infections in neutropenic patients; (c) emergence of broad-spectrum resistance by means of chromosomally mediated inducible β-lactamases during cephalosporin monotherapy of deep-seated infections by species of Enterobacter, Providencia, Serratia, Pseudomonas, and Acinetobacter; (d) intra-abdominal or intrapelvic infections likely to involve Bacteroides fragilis; and (e) S. aureus bacteremia, endocarditis, or meningitis. Thus, in ICU patients, third-generation cephalosporins generally should be used empirically as part of combination therapy or as specific single-agent treatment of Gram-negative bacillary infections involving organisms documented to be susceptible to the agent in vitro.

Cefepime, a fourth-generation cephalosporin [20], has activity against Gram-positive organisms similar to that of cefotaxime and ceftriaxone and activity against Pseudomonas similar to that of ceftazidime. Compared with third-generation cephalosporins, cefepime has a lower affinity for β-lactamases and is not an inducer of chromosomal β-lactamases. The pharmacokinetics of cefepime are similar to those of ceftazidime: t_½ is 2.1 hours, and 80% to 90% of the dose is recovered in the urine. For treatment of infections due to P. aeruginosa, cefepime (often in conjunction with an aminoglycoside) should be dosed every 8 hours, but for moderate infections due to more susceptible species, it can be dosed every 12 hours (see Table 77.2).

All available aminoglycosides exhibit similar pharmacologic properties: (a) absorption from the gastrointestinal (GI) tract is negligible, and adequate serum levels are obtained only by the IV or intramuscular routes; (b) volume of distribution is similar to that of total volume of extracellular fluid and therefore can be somewhat unpredictable under conditions of abnormal extracellular fluid such as dehydration, third-space losses, congestive heart failure, or ascites; (c) protein binding is minimal; (d) penetration into the cerebrospinal fluid (CSF) is poor even in the presence of meningeal inflammation; (e) drug levels in bronchial secretions are only two thirds of those in serum and are poor in vitreous fluid, prostate, and bile; (f) excretion is predominantly by glomerular filtration, and t_½ of the aminoglycosides in the presence of normal renal function is approximately 2 to 3 hours (longest for amikacin) and is prolonged in patients with renal impairment, approaching 24 hours in those with end-stage renal failure; (g) all aminoglycosides are dialyzable, and greater efficacy of removal occurs with hemodialysis (approximately 60% to 75% cleared in 6 hours) than with peritoneal dialysis; and (h) aminoglycoside activity is reduced under conditions of reduced pH and oxygen tension, such as in purulent, particularly anaerobic, fluids, and tissues [25].

The primary clinical indication for aminoglycoside therapy is serious infection caused by Gram-negative bacilli. Aminoglycosides are also used in combination with a cell wall agent for therapy of enterococcal endocarditis. Another indication is treatment of mycobacterial disease. Although more toxic than penicillins and cephalosporins, aminoglycosides provide the broadest range of potent, bactericidal antibiotic activity against Gram-negative bacilli, particularly when multiple-resistant enteric Gram-negative bacilli (e.g., Enterobacter sp) or nonfermentative Gram-negative organisms such as Pseudomonas and Acinetobacter spp are considered possible pathogens.

Resistance to aminoglycosides generally emerges slowly and infrequently. However, resistance to aminoglycosides has increased dramatically among Enterococcus spp, and currently in many hospitals, up to one fourth of isolates are gentamicin
resistant [26]. Some high-level gentamicin-resistant isolates remain susceptible to high levels of streptomycin [27].

Unlike β-lactam antibiotics, aminoglycosides are characterized by a narrow therapeutic–toxic ratio, and therapy with these agents can be associated with considerable toxicity. Hypersensitivity reactions such as fever and rash are uncommon but have been reported in up to 3% of patients who receive these drugs. Anaphylaxis has been observed on rare occasions. Neuromuscular blockade has been described uncommonly and appears to be of concern only in patients with myasthenia gravis or severe hypocalcemia or those who are receiving neuromuscular blocking agents. Ototoxicity appears to occur with equal frequency (up to 10% of patients) among the modern aminoglycosides [25]. Vestibular damage has been described more commonly with gentamicin and tobramycin, whereas impairment of auditory acuity seems more common with amikacin [25]. Ototoxicity occurs unpredictably (either early or late in therapy), is related only partially to elevated serum levels, most closely correlates with duration of therapy and total dosage administered, and often is irreversible. Patients expected to receive aminoglycoside therapy for extended duration and who are conscious and communicative should be questioned periodically about symptoms of eighth cranial nerve dysfunction, such as tinnitus, diminished auditory acuity, lightheadedness, and dizziness.

Nephrotoxicity has been reported to occur in 2% to 10% of all patients receiving aminoglycoside therapy and in up to 10% to 25% of critically ill patients. However, renal damage usually is mild and reversible promptly with cessation of therapy. Aminoglycoside-induced nephrotoxicity appears to be related to dose and duration of therapy as well as to serum concentrations, especially elevated trough levels. It is seen more commonly in elderly patients, those with preexisting renal disease, those with diminished tissue perfusion caused by cardiogenic or peripheral vascular factors, and patients receiving other nephrotoxic agents. The most useful laboratory tests that are available to reduce and detect aminoglycoside nephrotoxicity are the serum creatinine levels and determinations of trough serum aminoglycoside concentrations.

Recommended dosage schedules and desired serum concentrations for the aminoglycosides are shown in Table 77.3. The use of the once-daily dosing method for aminoglycosides (see Table 77.3) may reduce nephrotoxicity and enhance efficacy against Gram-negative bacilli [30,31]. These agents induce a postantibiotic effect, and, hence, are suited for less frequent dosing. Postantibiotic effect is uncertain for Gram-positive bacteria, and the desired peak and trough levels are lower when you are using aminoglycosides for synergistic activity against Gram-positive pathogens.

In patients with impaired renal function, serum concentrations (and serum creatinine and blood urea nitrogen values) should be monitored to ensure safe and effective concentrations. Trough concentrations should be monitored frequently (and dosage/frequency adjusted accordingly) in patients with fluctuating cardiovascular function/fluid volumes or renal function and in those who are anticipated to receive prolonged therapy [25]. Trough serum concentrations should be less than 1 μg per mL (or undetectable) when large doses are given at intervals of 24 hours or greater.