James E. Leggett, MD ... active against E. coli and Serratia organisms, whereas tobramycin has ..... Levy J, Smith AL, Kenny MA, Ramsey B, Schoenknecht FD.
Update on Antimicrobial
Aminoglycoside Therapy
Agents
Current and Prospective Uses
James E. Leggett, MD
T he aminoglycoside antibiotics are a group of structurally-related compounds containing 2 or more amino sugars that are connected by glycosidic links to a hexose core. Since their introduction more than 45 years ago, these antibiotics have been major agents for treating severe gram-negative infections. In the United States, the most commonly used aminoglycosides are gentamicin, tobramycin, amikacin, and netilmicin. Three other aminoglycosides-streptomycin, kanamycin, and neomycin-have more limited applications. The primary problems associated with the use of these compounds have been toxicity and the emergence of resistant organisms when these antimicrobial agents are used singly. Because the aminoglycosides are all quite similar with respect to antimicrobial efficacy, drug selection often depends on relative toxicity and cost.
Mode of Action The aminoglycosides are highly water-soluble, polycationic drugs that do not readily diffuse across bacterial cell membranes. Their bactericidal activity utilizes at least 2 mechanisms. In the first, the drug molecules inhibit protein synthesis and cause the genetic code to be misread by binding to the 30S subunit of bacterial ribosomes. How ribosomal binding results in cell death is unclear; other more efficient, rapidly acting protein-synthesis inhibitors are only bacteriostatic, not bactericidal.1 The 2nd mechanism of bactericidal activity involves increased cell permeability brought about by the transfer of aminoglycoside molecules across the cytoplasmic membrane. This process causes a progressive, lethal efflux of sodium, potassium, and other molecules essential for cell survival.' Susceptible bacteria possess active transport systems that require oxygen as a source of energy for the cellular uptake of these drugs. Anaerobic bacteria are therefore resistant to aminoglycosides. On the other hand, an increased uptake of aminoglycosides, in combination with cellwall synthesis inhibitors such as f-lactam antibiotics or vancomycin, is believed to result in synergistic activity.2 Key words: Aminoglycosides; antibiotics; bacterial infections; drug combinations; drug resistance, microbial; amikacin; gentamicin;
kanamycin; neomycin; netilmicin; streptomycin; tobramycin From: The Department of Medical Education, Providence Medical Center, Portland, Oregon
Series editor: Layne 0. Gentry, MD Address for reprints: James E. Leggett, MD, Dept. of Medical Education, Providence Medical Center, 4805 N.E. Glisan St., Portland, OR 97213-2967 330
Aminoglycoside Therapy
Antimicrobial Activity Spectrum of Activity In general, the aminoglycosides have excellent activity against most Enterobacteriaceae (such as Escherchia coli, Klebsiella, Proteus, and Enterobacterspecies) and Pseudomonas aeruginosa. Other Pseudomonas species are usually resistant. Neisseria, Haemophilus, and Branbamella organisms are only moderately sensitive, and should not be treated with aminoglycosides alone. The differences in potency between gentamicin and tobramycin are usually minimal. Gentamicin is often more active against E. coli and Serratia organisms, whereas tobramycin has greater intrinsic activity against Acinetobacterspecies and P. aeruginosa. Amikacin is 1 to 4 times less active than gentamicin.3 The aminoglycosides are not very active against gram-positive bacteria other than staphylococci. Moreover, despite excellent in vitro potency, their clinical efficacy in serious staphylococcal infections has not been documented, so they should not be used alone in such cases. Streptococci and enterococci are usually resistant, although an aminoglycoside combined with cell-wall inhibitors will kill species other than Streptococcus pneumoniae and Streptococcus pyogenes. Some aminoglycosides are active against Brucella, Pasteurella, and Mycobacterium species. Amikacin is the only aminoglycoside with significant activity against Mycobacterium avium-intracellulare.4 Volume 1 7, Number 4, 1990
Factors that Influence Activity The aminoglycosides have rapid, concentrationdependent bactericidal activity in a wide range of concentrations.5 They also have a postantibiotic effect; that is, after exposure, they persistently suppress growth of both gram-positive cocci and gramnegative bacilli.6 All aminoglycosides have been observed to suppress bacterial regrowth for as long as 9 to 13 hours in animal models.7 In general, the duration of the postantibiotic effect increases with longer exposures and higher aminoglycoside concentrations until it reaches a maximal response. The aminoglycosides' concentration-dependent bactericidal activity and postantibiotic effect have prompted studies investigating once-daily dosing intervals (see Once-Daily Administration). Resistance Resistance to the aminoglycosides occurs through 3 mechanisms. 1) Ribosomal mutations may cause alterations at the site of aminoglycoside attachment, thereby interfering with the drug's ability to bind to the ribosome. Although this mechanism occurs with gram-negative bacilli against streptomycin, all other aminoglycosides appear to bind to multiple sites so that highlevel ribosomal resistance is rare.8 2) Decreased cell permeability may result in a diminished uptake of all aminoglycosides. Some strains of P. aeruginosa and other gram-negative bacilli exhibit a transport defect that creates low-level crossresistance to all of these drugs.9'10 In other bacterial strains, resistance is due to a change in the cell-wall structure, which presents a permeability barrier.1112 High-level resistance is due more commonly to the acquisition of R plasmids, which encode for the production of enzymes that inactivate aminoglycosides by means of acetylation, adenylylation, or phosphorylation.3 Amikacin and, to a lesser extent, netilmicin are more resistant to inactivation than gentamicin and
tobramycin.13
Absorption, Distribution, and Excretion The aminoglycosides all have very similar pharmacokinetic properties. Because of their high polarity, these drugs are poorly absorbed via the oral route, so parenteral administration is required for the treatment of systemic infections. The aminoglycosides' high water solubility accounts for their poor intracellular penetration and poor diffusion across the bloodbrain barrier. In gram-negative bacillary meningitis, they must be injected intrathecally to achieve therapeutic concentrations. Tissue penetration to other potential sites of infection is greater. Concentrations in bronchial secretions Texas Heart Itistitutejournal
and pleural effusions equal 25% to 50% of serum concentrations, but the degree of lung penetration is unpredictable. 1416 With usual doses, therapeutic concentrations are achieved in the synovial and interstitial fluids."7 Although aminoglycosides may be detected in bile, they are unable to penetrate the biliary tract if biliary obstruction is present.18 The aminoglycosides are not metabolized; they are eliminated entirely by means of renal glomerular filtration. A small amount of filtered drug is actively reabsorbed by the proximal tubules; therefore, aminoglycoside concentrations eventually accumulate with prolonged use and contribute to nephrotoxicity. Because all of the aminoglycosides have a serum elimination half-life of 2 to 3 hours in adults with normal renal function, these drugs have traditionally been given 2 or 3 times daily. Nevertheless, considerable variation exists from patient to patient.19 The rate of drug elimination is increased in patients with cystic fibrosis,20 but is decreased in neonates, severely ill patients,21'22 and patients with poor renal function. Elimination is prolonged in direct proportion to the degree of renal impairment and may be 30 to 40 times longer in uremic patients. The aminoglycosides are removed by dialysis. Hemodialysis is much more efficient at drug removal than peritoneal dialysis;23'24 hence, additional doses are required after each hemodialysis session.
Toxicity Although the aminoglycosides have a broad spectrum of activity, their use is limited because there is a narrow margin between therapeutic and toxic doses. Nephrotoxicity and ototoxicity are the major adverse effects. The risk of ototoxicity increases with renal impairment, but preexisting renal disease does not appear to be a risk factor for further, aminoglycoside-induced renal toxicity. Ototoxicity may be auditory, vestibular, or both. Auditory toxicity, which is usually irreversible, is manifested as tinnitus or any degree of hearing loss. Vestibular toxicity may cause dizziness, vertigo, or even ataxia, and a Meniere-like syndrome, which is fortunately seldom permanent. The propensities for eliciting these toxic effects differ from 1 aminoglycoside to another. Streptomycin appears to be solely vestibulotoxic, whereas amikacin is essentially cochleotoxic, and gentamicin and tobramycin are both oto- and vestibulotoxic. Netilmicin has minimal vestibulotoxicity and no cochleotoxicity. Nephrotoxicity is most often manifested by transient proteinuria and elevated serum urea and creatinine levels. Severe renal failure occurs infrequently. Neuromuscular blockade has been reported, especially when aminoglycosides are administered with neuromuscular blocking agents or calcium-channel blockers.25 Other adverse reactions include fever, Aminoglycoside Therapy
331
skin rash, circumoral paresthesias, and bacterial superinfections. Table I lists potential risk factors for aminoglycoside nephrotoxicity,6 which is determined by the specific drug's intrinsic ability to damage renal tubular cells and by the degree of renal cortical drug accumulation.27 The duration of exposure and the dosage regimen are important determinants of accumulation. Decreased dosage frequency may reduce both nephro- and ototoxicity.26'28 Although tobramycin causes less nephrotoxicity in animals than does gentamicin, its toxic potential in humans appears to he the same (probably in the 5% to 10% range, although higher values have been reported).9 Table 1. Potential Risk Factors of AminoglycosideInduced Nephrotoxicity Patient-Related Factors Increasing age Hepatic insufficiency Critical illness Intravascular volume depletion
Drug-Related Factors Dosage (duration, regimen) Previous aminoglycoside use Choice of aminoglycoside Associated drugs (diuretics, amphotericin, cisplatin, or cyclosporine)
Clinical Use Septicemia The aminoglycosides are useful in the treatment of sepsis caused by aerobic gram-negative bacilli. However, monotherapy may lead to the emergence of resistant organisms, especially in patients with persistent neutropenia or serious infections caused by organisms such as P. aeruginosa; therefore, the aminoglycosides should be combined with a broad-spectrum 3-lactam antibiotic.30-32 Although gentamicin-resistant strains of Enterobacteriaceae and P. aeruginosa have emerged over the past 2 decades, they are still relatively rare in most private community hospitals in the United States. The usual dosage of gentamicin and tobramycin is 5 mg/kg/day, divided into 2 or 3 doses. Netilmicin is less active against P. aeruginosa, so a slightly higher daily dosage (up to 6.5 mg/kg/day) is recommended. Amikacin is usually given in dosages of 15 mg/kg/day. 332
Aminoglycoside Therapy
Respiratory Tract Infections Hospital-acquired pneumonia is commonly caused by aerobic gram-negative bacilli and may be difficult to treat.33 In general, combination therapy with an appropriate ,-lactam antibiotic is superior to the use of aminoglycosides alone, since the aminoglycosides' activity is reduced in the purulent secretions of patients with cystic fibrosis or bronchiectasis.3-3' The aminoglycosides are ineffective against pneumonia due to S. pneumoniae, the most common cause of community-acquired pneumonia.
Bacterial Endocarditis The combination of penicillin G and streptomycin produces a synergistic bactericidal effect against enterococci and various oral viridans streptococci. Penicillin G by itself is ineffective in the treatment of enterococcal endocarditis. Although streptomycin is still used for this purpose in combination with penicillin G or ampicillin, gentamicin is increasingly preferred. Not only is gentamicin's toxicity profile more favorable than that of streptomycin (because gentamicin's toxicity is primarily renal and reversible rather than vestibular and irreversible), but enterococci are more likely to be sensitive to gentamicin than to streptomycin. Tobramycin is less active than gentamicin against gram-positive cocci. Enterococcusfaecalis strains have emerged with R-plasmid-mediated highlevel gentamicin resistance, thereby eliminating any synergistic effect of gentamicin and penicillin.3' For the treatment of endocarditis caused by such strains, the drug of choice is probably vancomycin alone. The aminoglycosides' role in Staphylococcus aureus endocarditis is less certain. In 1 multicenter study, a combination of nafcillin and gentamicin was only marginally more effective than nafcillin alone. More rapid defervescence and bloodstream sterility were attained with the combined drugs, but the overall outcome was unaffected.3- There is no evidence that a vancomycin and aminoglycoside combination is superior to vancomycin alone against methicillinresistant S. aureusendocarditis. Vancomycin may be combined with both gentamicin and rifampin, however, for treating prosthetic valve endocarditis due to coagulase-negative staphylococci.38'39
Urinary Tract Infections The aminoglycosides are not indicated for the treatment of uncomplicated urinary tract infections. In severely ill patients with pyelonephritis, an aminoglycoside alone or in combination with ampicillin offers effective empiric coverage until the pathogen is identified and less toxic antimicrobial agents can be substituted. Although the aminoglycosides' antibacterial activity is reduced in the presence of a low pH and hyperosmolarityv_ sufficiently high urinary concentrations are achieved to ensure drug efficacy. Vblume 17, Number 4, 1990
Once-Daily Administration In accordance with the concentration-dependent bactericidal activity of aminoglycosides in vitro, high peak serum concentrations correlate with a significantly improved clinical response (Table 11).41-45 Because peak serum concentrations may not reach high enough values when an aminoglycoside is administered 3 times daily, twice-daily administration should be considered for all patients. Although early studies suggested that high peak serum levels were associated with excessive toxicity, these studies involved a very narrow range of doses; therefore, a higher peak level was always correlated with a larger total drug dose, which is an important determinant of toxicity. In a limited number of clinical trials, once-daily aminoglycoside dosing (usually in combination with other antibiotics) has been compared with more frequent dosing (Table III).46-55 Once-daily administration appears to be as efficacious as the standard 8-hour or 12-hour regimen and no more prone to toxicity. No neuromuscular toxicity has been reported. The total number of patients enrolled in these trials is still less than 1,000, and a large number patients enrolled in the trials have had infections involving the urinary tract, so the clinical data are still insufficient to enable decisive conclusions. Nevertheless, both experimental and clinical trials have revealed a consistent trend in favor of once-daily aminoglycoside administration.
Because of the wide patient-specific variation in aminoglycoside distribution and elimination, the improved clinical outcome at higher peak levels, and the narrow margin between drug efficacy and toxicity, monitoring of serum levels is imperative in order to optimize each patient's dosage regimen. Several nomograms are available to help physicians calculate an initial dose;56-57 subsequent adjustments should be made on the basis of peak levels (measured 60 minutes after an intramuscular dose or 30 minutes after the cessation of a 30-minute intravenous infusion) and "trough" levels (measured 8 or 12 hours after infusion), especially in critically ill patients. Several computer software packages are readily available to assist in the individualization of aminoglycoside dosing.
Conclusion For more than 40 years, aminoglycoside antibiotics have been a mainstay for therapy of gram-negative bacterial infections. Due to these drugs' narrow therapeutic-to-toxic ratio, however, their principal indications have recently been limited to serious nosocomial infections or to those caused by pathogens resistant to less toxic P-lactam antibiotics. Because all aminoglycosides offer similar antimicrobial efficacy, drug selection is often made on the basis of relative toxicity. Recently, investigators have accumulated many experimental and clinical data concerning the effects of various dosages on the aminoglycosides'
Table 11. Influence of Aminoglycoside Serum Concentrations on Clinical Outcome in Gram-Negative Bacillary Infections Type of Infection
Drug
Serum Sample Time
Serum Level
(gg/mL)
Incidence of Favorable Response (%)
P Value
Urinary tract, wound, bacteremia
Gentamicin
Peak
.5 5, > 20
40/41 (98) 34/43 (79)
< 0.01
55/60 (92) 19/24 (79) 41/47 (87)
< 0.01
< 5, < 20
Mean peak
> 5, > 20
8 < 2, < 8
NS
=
Gentamicin, tobramycin, amikacin
< 0.05
28 8
16/18 (89)
Maximal peak
2 7, 2 28 < 7, < 28
14/18 (78) 6/19 (32)
< 0.01
Mean peak
> 6, > 24 < 6, < 24
14/20 (70) 6/17 (35)
< 0.04
Peak
q24h (p
