INTRODUCTION

Aminoglycoside antimicrobial drugs, notably gentamicin and amikacin, constitute some of the best choices for treatment of severe gram-negative infections.^1–3 Despite the large number of antibacterial agents that have appeared over the last few years as alternatives to aminoglycosides, the latter still play an important role in clinical practice. The aminoglycosides, in comparison with other antimicrobial agents that rapidly select for resistant mutants (e.g., β-lactams and fluoroquinolones), are predictably effective for many aerobic gram-negative pathogens.^4–6

One of the primary reasons for limiting clinical use of the aminoglycosides is the nephrotoxicity observed with conventional multiple daily dosing.^1,6 Over the past several years, much has been learned about the efficacy and toxicities of the aminoglycosides, and a new dosing strategy has emerged using single daily dosing (SDD).^3,5,6 Practitioners are encouraged to reevaluate the utility of the aminoglycosides as an important component of the modern antimicrobial arsenal.

MECHANISM OF ACTION

The aminoglycosides are bactericidal agents.^1,6 They penetrate the bacterial cell wall and membrane, and impair protein synthesis by binding to components of the prokaryotic 30s ribosomal subunit.^5,6 This binding leads to bacterial misreading of messenger ribonucleic acid (mRNA), with subsequent production of nonfunctional proteins, detachment of ribosomes from mRNA, and cell death.⁵

SPECTRUM OF ACTIVITY

Aminoglycosides are effective against most community-acquired gram-negative aerobes and select gram-positive pathogens. Organisms commonly susceptible to these drugs include Klebsiella, Citrobacter, Enterobacter, Serratia, and most Acinetobacter spp.^1,5 They are frequently, although not uniformly, effective against Pseudomonas aeruginosa and Escherichia coli.^1,3

Aminoglycosides are not active against anaerobes because their uptake across bacterial cell membranes depends on energy derived from aerobic metabolism.³ This dependence on aerobic metabolism is the cause of markedly reduced activity of these agents in areas of low pH and oxygen tension, such as abscesses and other infected hypoxic tissues.^1,3

Among gram-positive organisms, the aminoglycosides, particularly gentamicin, are active against many Staphylococcus spp. Other gram-positive organisms, such as Streptococcus spp and many enterococci, are relatively resistant.

Studies of bacteria in cell culture have shown that combining an aminoglycoside with a β-lactam agent results in bacterial killing superior to the simple added activity of each of these antimicrobials, a phenomenon termed synergism.^1,3 The efficacy of the aminoglycosides appears to be enhanced by increased cell permeability induced by the β-lactam antibiotic, favoring the uptake of the aminoglycoside into certain bacteria. Classically, synergy is observed between penicillins and gentamicin toward susceptible strains of Enterococcus faecium and Enterococcus faecalis, although synergy has also been described for gram-negative pathogens, including Pseudomonas aeruginosa.^1,7 Synergism is particularly important in cases of partial resistance to gentamicin, and when low tissue pH and low oxygen tension (e.g., abscesses or tissue hypoxia) decrease aminoglycoside transport into bacteria.

The aminoglycosides are active against some mycobacteria, as well as less common pathogens such as Yersinia pestis, Brucella spp, and Francisella tularensis.^1,3 Amikacin and gentamicin are used in similar circumstances, often interchangeably.³ Amikacin, however, is not degraded by the common enzymes that degrade gentamicin and therefore has a broader spectrum of activity.³ It is the preferred agent for serious nosocomial infections caused by Klebsiella spp and Pseudomonas aeruginosa.^1,3

INDICATIONS

The aminoglycosides are used for short-term (≤7 days) treatment of infections caused by susceptible strains of gram-negative microorganisms that are resistant to less toxic antibiotics.^8,9 They are useful for severe infections of the abdomen, urinary tract, pulmonary parenchyma, endocardial valves, bloodstream, and surgical wounds.^3,10 The introduction of extended-spectrum β-lactam antibiotics and fluoroquinolones, all of which have a greater safety profile than the aminoglycosides, has necessitated a critical reappraisal of the indications for aminoglycoside therapy.^4,7

Monotherapy with an aminoglycoside is seldom appropriate in critically ill patients.⁷ Aminoglycosides traditionally have been administered in combination with another antimicrobial agent to enhance bactericidal activity and minimize resistance.^1,5,10 More specifically, in patients with life-threatening infections in which mixed organisms are suspected, aminoglycosides are appropriately administered with a β-lactam, β-lactam/β-lactamase inhibitor or a carbapenem.^3,5,10 This approach provides not only synergistic bacterial activity but also antibacterial coverage during the aminoglycoside-free interval when using SDD.¹ Although this remains a time-honored and rational strategy, the authors of a recent large-scale metaanalysis of antibiotic usage concluded that the addition of an aminoglycoside to a broad-spectrum β-lactam conferred no benefit to any subset of septic patients when compared with β-lactam monotherapy.

Metronidazole or clindamycin may be prescribed in combination with an aminoglycoside when coinfection with strict anaerobic pathogens is suspected. For partially susceptible Enterococcus spp, gentamicin must be coadministered with a β-lactam agent to facilitate penetration of the aminoglycoside into the cell.^1,3 The initial antibiotic regimen in a given patient should always be modified on the basis of response to therapy and microbiologic data. Patients receiving parenteral aminoglycosides should be well hydrated and should have stable renal function and an inactive urine sediment.^1,2,6

Aerosolized gentamicin may be administered to patients with susceptible pulmonary infections with limited risk of systemic absorption and toxicity.^1,5,11 The efficacy of inhalational therapy with aminoglycosides has not been studied critically in dogs and cats, although aerosolized gentamicin appears to decrease the clinical signs associated with Bordetella bronchiseptica infection in dogs.¹¹

Aminoglycosides are poorly absorbed following oral administration but may act within the gastrointestinal tract, largely preventing systemic toxicity. Oral neomycin is prescribed to suppress bacterial growth in the large bowel, and paromomycin is effective for enteric salmonellosis and protozoal enteritis in companion animals.^1,12 Although serum levels of neomycin and paromomycin generally are negligible in healthy animals, significant systemic absorption and toxicity are possible when the intestinal epithelial barrier is diseased or compromised.^1,9,12

PHARMACOLOGY AND DOSING

The aminoglycosides are highly water soluble and do not readily cross biologic membranes.¹ As such, they are largely confined to the extracellular fluid and have correspondingly small volumes of distribution (Vd).⁴ The aminoglycosides are mainly eliminated unchanged in the urine. They are excreted predominately by glomerular filtration, with a small fraction (<5%) undergoing tubular reabsorption.^2,3,6 Penetration into cerebrospinal fluid, prostate, and vitreous humor is minimal, and their efficacy is not reliable in these tissues.^1,3 Therapeutic concentrations are generally achieved in nonexudative pleural and peritoneal effusions, bones, and synovial fluid.¹ Following parenteral administration, adequate tissue levels are generally achieved in the pulmonary parenchyma but not in bronchial secretions. They are usually are ineffective for intracellular pathogens.

The rate and extent to which an aminoglycoside achieves bacterial killing is a function of its concentration.^4,6,10,13,14 For many years, the aminoglycosides were administered in multiple daily doses.^3,13 However, many in vitro and in vivo studies suggest that administration as an SDD is equally or more effective than conventional regimens and reduces the associated toxicities.^3,10,13 SDD implies that the total daily dosage is administered as a single dose approximately every 24 hours, rather than in multiple divided doses. With concentration-dependent antibacterial activity, the rate and extent of bacterial cell death increases with the higher drug concentrations achieved with SDD, in addition to producing more favorable outcomes and fewer resistant organisms.^1,4,10,13

Aminoglycosides provide a PAE, which means that bacterial replication is impeded even after serum drug concentrations have fallen below the minimum inhibitory concentration (MIC) of the organism in question (Figure 196-1).^1,3,4,6 This permits longer dosing intervals. The postantibiotic effect (PAE) tends to be longer in vivo than in vitro.¹ Aminoglycosides possess a PAE that is linked to (1) the species of bacteria, (2) the MIC of the bacterial strain, and (3) the concentration of drug achieved at the site of infection.⁶ The PAE demonstrated by aminoglycosides is one component of SDD that allows extended drug-free intervals without compromising patient outcome, and it may be enhanced by higher dosages and concurrent administration of a cell wall–active antibiotic such as a β-lactam.¹³

Figure 196-1 Graphic hypothetical representation of serum drug concentration versus time following bolus intravenous administration of an aminoglycoside illustrating peak serum concentrations (C_max), minimum inhibitory concentration (MIC), postantibiotic effect, and adaptive resistance. See section in this chapter entitled Pharmacology and Dosing for details.

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