Arhnoglycoside Antibiotics in Infectious Diseases

An Overview

WALTER E. SIEGENTHALER, ANTONIO BONETTI, M.D. RUEDI LUTHY, M.D.

Zurich, Switzerland

M.D.

This article presents an overview of the aminoglycoside antibiotics used in clinical practice. Facts concerning the discovery and properties of the aminoglycosides are followed by information about spectrums of activity and mechanisms of action and resistance. Individual compounds are compared and proposals on the possibilities for their clinical use, both as single drugs and in combination with beta-lactam antibiotics, are made. The importance placed on measuring the serum concentrations of aminoglycoside antibiotics should serve as a reminder that this procedure is important, on one hand, to increase clinical efficacy and, on the other, to reduce the side effects of these antibiotics. Finally, the aminoglycosides are compared briefly with other antibacterial compounds, some of which are very new. There is no doubt that in the future the aminoglycosides will continue to occupy an important place in the treatment of severe infections, although newly developed agents appear to be effective complements.
Since the discovery and clinical use of streptomycin by Waksman and co-workers [l] more than 40 years ago, various aminoglycosides have been developed and introduced in clinical medicine. This article provides an overview of the actual significance of aminoglycosides in infectious disease. The discovery of streptothricin in 1942 and the isolation of streptomycin from Streptomyces griseus by Waksmans research group in 1943 ushered in an exploratory era for a new chemical class of antibiotics, the aminoglycosidic aminocyclitols, i.e., the aminoglycosides (Table I). The clinical application of streptomycin began in 1944, followed in 1949 by neomycin, isolated from Streptomyces fradiae; in 1957 by kanamycin, isolated from Streptomyces kanamyceticus; in 1963 by gentamicin, isolated from Micromonospora purpurea; in 1967 by tobramycin, isolated from Streptomyces tenebrarius; and in 1970 by sisomicin, isolated from Micromonospora inyoensis. Amikacin, introduced in 1972, is a semisynthetic derivative of kanamycin A, and netilmicin, introduced in 1975, is a semisynthetic analog of sisomicin. Kanamycin is composed of three fractions, 98 percent A and 2 percent 6 and C. Gentamicin is also composed of three fractions, 40 percent gentamicin Cl, 20 percent gentamicin Cl a, and 40 percent gentamicin C2. The newer aminoglycosides, however, are single substances. As shown in Table II, all aminoglycosides are obtained from microorganisms of the genus Streptomyces (e.g., streptomycin, neomycin, kanamycin, tobramycin, and amikacin) or from the genus Micromonospora (e.g., gentamicin, sisomicin, and netilmicin). Structurally, all representatives of the kanamycin and gentamicin fami-

From the Department of Medicine, University Hospital, Zurich, Switzerland. Requests for reprints should be addressed to Dr. Walter E. Siegenthaler, Department of Medicine, University Hospital, Ramistrasse 100, CH 8091 Zurich, Switzerland.

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lies possess two amino sugars, whereas neomycin and paromomycin possess three. The amino sugars are glycosidically linked with a central hexose, aminocyclitol, a 2-deoxystreptamine. In streptomycin, this aminocyclitol is streptidine, and is not located in the center of the molecule. Various structural arrangements for these compounds are depicted in Figure 1. The aminoglycosides are strongly polar cations, stable in the pH range of 6 to 8, and basic in character. Being water soluble, they are distributed throughout the extracellular space, i.e., about 25 percent of the lean body mass. Metabolically, they are highly stable; about 95 percent is excreted via the kidneys. Aminoglycosides are poorly absorbed from the intestinal tract, and because of their polarity, they inadequately penetrate the intracellular space and cerebrospinal fluid. SPECTRUM OF ACTIVITY

TABLE Year
1944

Discovery Antibiotic

of the Aminoglycosides Species

From Streptomyces griseus From Streptomyces fradiae From Streptomyces kanamyceticus From Micromonospora purpurea From Streptomyces tenebrarius From Micromonospora inyoensis Semisynthetic derivative of kanamycin Semisynthetic derivative of sisomicin

1949 1957 1963 1967 1970 1972 1975

Streptomycin Neomycin Kanamycin Gentamicin Tobramycin Sisomicin Amikacin Netilmicin

TABLE

II

Groups

of Aminoglycosides Micromonospora Group

Gentamicin Sisomicin Netilmicin

Streptomyces Group
Streptomycin Neomycin Kanamycin Tobramycin Amikacin

The aminoglycosides have a very broad antimicrobial spectrum, extending from gram-positive cocci to gramnegative bacilli. They are ineffective against all anaerobic organisms, and their activity against the enterococci is inadequate when used as monotherapy [2]. Listeria monocytogenes and Nocardia species are generally resistant to the aminoglycosides; however, amikacin is effective against Nocardia [3]. Streptomycin and kanamycin are used successfully against Mycobacterium tuberculosis [3], but their activity against Pseudomonas aeruginosa is limited. All aminoglycosides share similar antibacterial action against gram-negative aerobic pathogens, although their intrinsic activities and sensitivity patterns differ. In addition, individual differences between agents are reported from hospital to hospital due to time- and indication-related induction of resistance. MECHANISM OF ACTION AND RESISTANCE

Although the mechanisms of aminoglycoside action are only partially understood, it is now known that the drugs bind to the surface of the bacteria and are transported through the cell wall. Once within the cell, they bind to the 30s ribosomal subunit, causing a misreading of messenger RNA during the translation process and producing nonsense proteins. The sum of the events from drug entry into the cell to interference with protein synthesis disturbs membrane function and causes potassium, sodium, amino acids, and other ,essential constituents to leak out, resulting in bacterial death. Almost all pathogens that are sensitive to aminoglycosides can develop resistance. Resistance develops most commonly in response to plasmid-mediated enzymes that can modify the aminoglycoside molecule in three different ways: by acetylation at an amino group, by phosphorylation, or by adenylation at a hydroxyl group. The molecule becomes changed in such a way that it can no longer bind to the ribosome subunits. The enzymes involved include

acetyltransferases, phosphotransferases, and adenyltransferases, all of which have numerous subtypes (Figure 1). Due to chemical differences, not all aminoglycosides are suitable substrates for all enzymes, and the binding sites for these enzymes even differ within the molecule. Amikacin, the agent most resistant to inactivation, is inactivated principally by an acetyltransferase from gram-negative organisms, whereas an adenyltransferase from certain staphylococci and a phosphotransferase from various enterococci are not important quantitatively [4-71. This also explains why cross-resistance does not necessarily exist between aminoglycosides. A second possibility for development of resistance is that the complex and energy-dependent transport system across the cytoplasmic membrane to the ribosomes becomes changed in such a way that the target cannot be reached. P. aeruginosa, Serratia species, and Streptococcus faecalis can become resistant to aminoglycosides in this way, whereas the group resistance of the anaerobes results from the absence of an oxygen-dependent transport system across the cytoplasmic membrane [8]. A third possibility appears to be of importance only for streptomycin. In contrast to the other aminoglycosides, streptomycin binds only to a subgroup of the 30s ribosomes [6]. These proteins can mutate in such a way that no binding takes place between streptomycin and the ribosomes. This phenomenon can be clinically important in combination therapy of enterococcal endocarditis, a situation in which streptomycin resistance necessitates the use of gentamicin along with penicillin for adequate treatment.

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ZGip Kanamycin A

CH,NH, j-0. Gentamlcin C,a

Tobramycin

b
0 OH

Slsomicin

Amlkacin

Netllmicln

OH

gure 1. Chemical structure of aminnoglycosides. AAC = site of action of acetylation !ion enzymes; APH = site of action of phosphoryiation enzymes.

enzymes; AAD = site of action of adeny-

CdM~ARATlVE

REVIEW

OF THE AMINOGLYCOSIDES

Streptomycin. Although streptomycin. has been replaced by newer aminoglycosides, it is still used today for special indications in tuberculosis therapy [9] and in enterococcal endocarditis. In the latter condition, it should be used only when the minimal inhibitory concentration is less than 2,000 mg/liter, and it should be combined with penicillin G or, in the case of penicillin allergy, with vancomycin [IO]. The same regimen is used under certain conditions to treat other streptococci implicated in endocardi-

tis. In Francisella tularensis infection, i.e., in tularemia, streptomycin ranks as the drug of first choice, as it does against Yersinia pestis, i.e., in bubonic plague. Streptomycin is principally vestibulotoxic, but in 4 to 15 percent of treated patients, cochleotoxic side effects also appear after one week of therapy. They begin primarily in the high-tone range and are demonstrable only on the audiogram; the entire hearing range becomes affected in later stages [ll]. Certain side effects that are virtually never observed with the other aminoglycosides can de-

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velop with streptomycin use, including neuromuscular block, peripheral neuritis, perioral paresthesia with flushing, exfoliative dermatitis, scotoma, and eosinophilia. In contrast, the nephrotoxic potency of streptomycin is very low [ll]. Neomycin. For years, neomycin has not been used parenterally because of its marked ototoxicity and nephrotoxicity. In combination with bacitracin, which is bactericidal against gram-positive organisms, neomycin is an effective and safe topical agent. Occasionally, neomycin is administered orally for preoperative sterilization of the gut and in portal encephalopathy. Despite the minimal intestinal absorption (between 1 and 6 percent of the total dose), severe side effects such as tubular necrosis and deafness have occurred [12]. Malabsorption syndrome can also develop locally [I 31. Kanamycin. Kanamycin is another aminoglycoside that is rarely used today because of its considerable ototoxicity. Against P. aeruginosa, kanamycin is almost completely inactive, and the Enterobacteriaceae become rapidly resistant due to numerous modifying enzymes, i.e., two acetyltransferases, two phosphotransferases, and two adenyltransferases [4,14]. Only in the presence of multiple mycobacterial resistance to other drugs can kanamycin still be used as a reserve tuberculostatic agent. Gentamicin. Since 1963, gentamicin has been used worldwide, and during its years of clinical application, resistance and sensitivity changes have appeared repeatedly in Staphylococcus aureus [I!%171, P. aeruginosa, and other Enterobacteriaceae [18,19]. Here, too, the most important cause of resistance lies in the bacterial production of modifying enzymes coded by plasmids, transposons, episomes, and phages. In sensitive Enterobacteriaceae, tobramycin and gentamicin are identical in efficacy, according to the findings of controlled clinical double-blind studies [20]. Against Escherichia coli and Serratia species, gentamicin appears to have greater efficacy [21]. Gentamicin can be modified primarily by four enzymes: two acetyltransferases, one adenyltransferase, and one phosphotransferase [4]. Cross-resistance with other aminoglycosides is common and, with netilmicin, almost complete [22]. In contrast, amikacin is still effective against gentamicin-resistant Enterobacteriaceae and P. aeruginosa strains, because amikacin is rarely inactivated by gentamicin-modifying enzymes. Gentamicin appears to have the most definite nephrotoxic potency compared with tobramycin, netilmicin, and amikacin [23]. With regard to cochleotoxicity and vestibulotoxicity, the findings need to be interpreted with some caution. Audiograms and vestibular investigations are harder to perform and assess in a standardized manner than are creatinine clearance measurements or an excretion analysis of tubular enzymes. In part, the discrepancies in results from various investigators reflect

these technical difficulties. In a retrospective analysis, Lance and co-workers [24] found ototoxicity with amikacin in 2 to 4 percent of cases, whereas Black and associates [25], in prospective studies, found an ototoxicity incidence of 24 to 25 percent with amikacin. The comprehensive results of investigations by Kahlmeter and Dahlager [23], who reviewed comparative aminoglycoside toxicity studies published between 1975 and 1982, showed that gentamicin, tobramycin, and amikacin were about equally vestibulotoxic, that amikacin was more cochleotoxic than gentamicin and tobramycin, and that netilmicin showed the lowest potency for cochlear and vestibular toxicity. In directly comparative studies between individual aminoglycosides, these investigators obtained somewhat divergent results, due to the technical problems already mentioned. In seven comparative trials between gentamicin and netilmicin, the incidence of cochleotoxicity for gentamicin amounted to 2.1 percent; in contrast, in 10 comparative trials between gentamicin and amikacin, cochlear toxicity with gentamicin was 11.4 percent. Tobramycin. Tobramycin closely resembles gentamicin in terms of antimicrobial and pharmacokinetic properties. One recognized difference is that tobramycin has greater activity agains P. aeruginosa [26,27]. However, it should be noted that, depending on each individual situation, gentamicin-resistant strains are not always tobramycinsensitive [28,29]. Tobramycin-resistant Pseudomonas strains are generally cross-resistant with streptomycin, kanamycin, gentamicin, and netilmicin [30]. Against gentamicin-resistant Klebsiella, Serratia, and Enterobacter species, tobramycin is also usually inactive. Sensitive Enterobacteriaceae, with the exception of Serratia and E. coli, are killed by tobramycin just as they would be by gentamicin [31]. Tobramycin is mainly modified by five enzymes: two acetyltransferases, two adenyltransferases, and one phosphotransferase. Resistance associated with a second acetyltransferase is inconsistent [4]. Tobramycin ototoxicity appears to develop as commonly as does gentamicin ototoxicity, whereas tobramytin is less nephrotoxic than gentamicin 1231. A large-scale, double-blind study in the United States showed that elevations of the serum creatinine level were recorded significantly less frequently with tobramycin than with gentamitin [32]. In the comparative assessment of ototoxicity, the investigators found no significant differences. Other studies have also established a lower nephrotoxicity rate for tobramycin when compared with gentamicin [33,34]. Sisomicin. Introduced in 1970, sisomicin is chemically related to gentamicin and is described as 4,5 dehydrogentamicin Cl a. It appears to be superior in efficacy to the other aminoglycosides, especially against Serratia and Proteus species, including some resistant strains [35-371. Sisomicin is more active than gentamicin against P. aeruginosa, and comparable in this respect to tobramycin, to

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TABLE

III

Aminoglycosides Disadvantages
Nephrotoxicity and ototoxicity Lack of activity against anaerobic organisms Low concentration in cerebrospinal fluid and bile Variable pharmacokinetics Lack of correlation between administered dose and measured serum concentration Inactivation of aminoglycosides

Advantages
Chemical stability Broad antibacterial spectrum Rapid bactericidal action Experience over many years Rare- allergic side effects Synergism with beta-lactam antibiotics

the extent that tobramycin-resistant strains of P. aeruginosa are usually also resistant to sisomicin [30,38]. This agent, which seems to penetrate bacterial cells better than other aminoglycosides, is primarily modified by five enzymes: three acetyltransferases, one adenyltransferase, and one phosphotransferase [4]. The factor limiting broad clinical application of sisomicin is its well-documented renal toxicity in animal studies. A comparison of so-called tubulotoxic threshold doses revealed that the dose of sisomicin that first leads to excretion of renal epithelial cells is one-fifth and one-tenth lower than the doses of tobramycin and gentamicin, respectively, that produce this effect [39]. Amikacin. A semisynthetic analog of kanamycin A, amikacin was introduced in 1972. The main advantage of this aminoglycoside lies in its extensive resistance to inactivating enzymes. Only an acetyltransferase from gramnegative pathogens, principally P. aeruginosa, is of quantitative relevance, whereas both an adenyltransferase from certain staphylococci and a phosphotransferase from certain enterococci and staphylococci are of minor importance [4-71. Amikacin can, therefore, be used against gentamicin-resistant pathogens, for which it offers the greatest certainty of therapeutic response. It continues to be active against organisms resistant to tobramycin and netilmicin, including such resistant strains as P. aeruginosa [40]. Cross-resistance between gentamicin and amikacin is observed less often than between gentamicin and tobramycin or sisomicin [41]. Certain non-fermenters such as Acinetobacter species, Flavobacter species, and P. aeruginosa show cross-resistance against amikacin, tobramycin, and gentamicin, caused by failure of aminoglycoside uptake into the cell [42,43]. Like the other aminoglycosides, amikacin also has a nephrotoxic potential, which, adjusted for the higher doses given, approximates that of netilmicin and must be judged more favorable than that of gentamicin [23,44]. The vestibulotoxic potency appears to equal that of gentamicin and tobramycin; however, cochleotoxicity is somewhat greater [23].

Gerding and Larson [45] and Bet% and co-workers [46] reported the interesting and important observations that the resistance of gram-negative organisms to gentamicin and tobramycin declined significantly in numerous hospitals when amikacin was used alone, while amikacin resistance itself did not increase significantly. Although there are centers that regard amikacin as a reserve aminoglycoside, other centers employ it as first-line aminoglycoside therapy and find no substantial increase in resistance [47-491. Netilmicin. A semisynthetic derivative of sisomicin, netilmicin was introduced in 1975. This aminoglycoside is primarily modified by three acetyltransferases, but not by adenyltransferases or phosphotransferases [4]. Therefore, sisomicin-, gentamicin-, and tobramycin-resistant E. coli, Klebsiella species, Serratia species, and even P. aeruginosa are often still eradicated by netilmicin. Nevertheless, cross-resistance with gentamicin is not uncommon in P. aeruginosa strains [50-521. In animal studies, netilmicin shows a lower nephrotoxicity than gentamicin and amikacin [53,54], and clinical trials indicate that the fewest cochlear and vestibular side effects occur with netilmicin [23].
INDICATIONS FOR AMINOGLYCOSIDES

Before discussing specific indications for aminoglycoside therapy, we should consider some of the advantages and disadvantages of these antibiotics (Table Ill). The advantages include chemical stability without metabolic changes, broad antibacterial spectrum, rapid bactericidal action, and comprehensive experience over many years. This experience has shown that the efficacy and success rate can be improved by the use of controlled, optimal serum concentrations. Two other advantages are the very rare occurrences of allergic side effects, and the synergism demonstrated when used along with beta-lactam antibiotics. Some disadvantages include the potential for nephrotoxicity and ototoxicity and the associated narrow therapeutic range between suboptimal serum concentrations and toxic values. Other disadvantages are the lack of activity against anaerobic organisms; the relatively low concentrations in cerebrospinal fluid and bile; the markedly variable pharmacokinetics influenced by age, renal function, fever, ascites, and obesity; the lack of correlation between the administered dose and the measured serum concentration; and, finally, the inactivation of aminoglycosides by reversible binding to lysed granulocytes, low pH, anaerobic environment, high concentrations of calcium and magnesium ions, and beta-lactam antibiotics. The last factor, however, probably plays a role only in vitro, and is rarely of clinical importance except during concomitant administrations and when renal function is severely impaired [55,56].

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Clinically, aminoglycosides are used in infections caused by pathogens resistant to other less toxic antibiotits (Table IV). When used empirically or as specific therapy in severe gram-negative, hospital-acquired infections, especially in neutropenic patients, aminoglycosides are often combined with beta-lactam antibiotics because of the possible synergy. This article briefly discusses some infections in which aminoglycosides are frequently used
(Table V).

TABLE

IV

Principal Indications Aminoglycosides

for
to other infections, less toxic especially in

Infections caused by pathogens resistant antibiotics Severe gram-negative, hospital-acquired neutropenic patients

Among the important infections of the upper respiratory tract is malignant otitis externa caused by P. aeruginosa. It can lead to severe complications, such as osteomyelitis, basal meningitis with cranial nerve involvement, cerebritis, and venous sinus thromboses, and therefore requires combined therapy with an antipseudomonal penicillin or a third-generation cephalosporin with an aminoglycoside. Hospital-acquired bronchopneumonias are generally caused by Pseudomonas, E. coli, Klebsiella, Enterobacter, Serratia, Proteus, Providencia, and Acinetobacter species, and, rarely, S. aureus. Depending on the bacterial resistance pattern of the particular hospital and the status of host-defense mechanisms, an aminoglycoside must be added to an antipseudomonal penicillin or a thirdgeneration cephalosporin. The pathogenic spectrum of bacterial pneumonias acquired outside the hospital has clearly changed in recent years. The pneumococci that were predominant until about 1970 have been less commonly isolated in recent years. According to a study in Connecticut, the frequency of pneumococci isolated during 1980 to 1981 was 30 to 40 percent, while Legionella pneumophila, Hemophilus influenzae, P. aeruginosa, and other aerobic/anaerobic organisms were isolated more frequently [57-601. Severe pyelonephritis with septicemia that is due to P. aeruginosa or Enterobacteriaceae can develop in hospitalized patients, especially those undergoing urologic intervention or those with urogenital anomalies, including obstruction, malformation, or neurogenic bladder. In these cases, the newer and less toxic third-generation cephalosporins offer a valuable alternative to the aminoglycosides [61,62]. However, combination therapy with an aminoglycoside is advised when multiply resistant organisms are isolated. It should be remembered that aminoglycosides can be inactivated by high urine concentrations of calcium and magnesium ions and by a low urinary pH [63]. Endocarditis requires some special considerations. Approximately 80 to SOpercent of the endocarditis cases are caused by gram-positive cocci, i.e., the enterococci, viridans streptococci, other streptococci, and coagulasepositive or coagulase-negative staphylococci. Although aminoglycosides are not intrinsically very active against these organisms, they are indicated in this situation because of the severity of the infection. The frequency of endocarditis caused by gram-negative pathogens is about

TABLE

Infections

Treated

with Aminoglycosides

Malignant otitis externa hospital-acquired pneumonias Urogenital infections Endocarditis Intra-abdominal infections Gram-negative meningitis Infectious arthritis or osteomyelitis Nosocomial septicemia Infections in immunocompromised

patients

5 percent and appears to be increasing [64-701. Endocarditis exhibits special anatomic and functional features, such as an impaired local host-defense response with few phagocytes. In addition, large bacterial populations of IO* to 10 colony-forming units per gram of tissue, with reduced metabolic activity, are protected from the antibiotics by a fibrin network. For these reasons, corroborated by animal studies, endocarditis is generally treated with combined drugs: penicillin G plus streptomycin against enterococci, provided that the minimal inhibitory concentration for streptomycin is less than 2,000 mg/liter. If the minimal inhibitory concentration is greater, penicillin G plus gentamicin is used. Penicillin G is combined with streptomycin against viridans streptococci when the minimal inhibitory concentration for penicillin exceeds 0.2 mgiliter, or when the streptococci are fully sensitive (i.e., the minimal inhibitory concentration for penicillin is below 0.2 mg/liter) and a short, 14-day course of therapy is planned. Gentamicin is combined with a penicillinase-stable penicillin for treatment of S. aureus endocarditis. Bacteremia is cleared more rapidly by drug combinations, but the clinical course is not substantially influenced. Gentamicin plus vancomytin plus rifampicin is used in patients with Staphylococcus epidermidis endocarditis involving prosthetic heart valves. Finally, an aminoglycoside is generally used with a betalactam antibiotic against gram-negative endocarditis pathogens. In these cases, the best possible combination with regard to synergism should be sought in vitro [lo,71 -741. Empiric therapy of intra-abdominal infections should be effective against a mixed flora, including enterococci, Enterobacteriaceae, P. aeruginosa, and strictly anaerobic organisms. An aminoglycoside in combination with clindamycin, a 5nitroimidazole, or cefoxitin has been effective

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TABLE

VI

Combination Therapy Aminoglycosides

with

Aminoglycosides are combined to broaden the antimicrobial spectrum or to enhance antibacterial activity especially in situations in which other antibiotic groups or in combination are not as effective, i.e., in life-threatening infections with unknown pathogens in mixed aerobic/anaerobic infections in bacterial endoctirditis in systemic Pseudomonas infections in neutropenic or immunodeficient patients
l l l l l l l

alone

in these situations. Among drugs used as monotherapy, piperacillin and imipenem have the broadest spectrums of activity. According to a review by Kager and Nord [75], imipenem has already been proved very successful as monotherapy. The third-generation cephalosporins are strong competitors of the aminoglycosides in the treatment of gramnegative meningitis in patients of all ages [76-781. However, when combination therapy is needed to treat special pathogens, such as P. aeruginosa or Enterobacter species, or when ventriculitis is present, additional routes of administration may be necessary. For example, injection of the aminoglycoside directly into the ventricle via an Ommaya or Rickham reservoir may improve its efficacy [79-811. McCracken and co-workers [82] reported that intraventricular administration of gentamicin does not improve prognosis in newborns. Therefore, this form of therapy should not be used as routine treatment for neonatal meningitis caused by gram-negative enteric bacilli. If infectious arthritis or acute or chronic osteomyelitis develops in infants under one month of age or in patients more than 50 years of age, the differential diagnosis should consider Enterobacteriaceae and P. aeruginosa in addition to staphylococci as possible pathogens [83-851. Empiric therapy should, therefore, consist of combining an aminoglycoside with a beta-lactamase-stable penicillin. After causative organisms are identified, therapy should be modified. It is important to consider the spectrums of action of all available antibiotics-especially those of beta-lactam antibiotics and aminoglycosides-when choosing therapy for nosocomial septicemia. For newly developed substances such as monobactams, carbapenems, and 5-quinolones, there is still insufficient experience in this respect. Moreover, the therapeutic gaps with individual substances are important to know. For example, the aminoglycosides are inactive against anaerobes; the new beta-lactam antibiotics exhibit only limited activity against penicillinase-producing strains of S. aureus; and the thirdgeneration cephalosporins are inactive against entero-

cocci and also show inadequate activity against Bacteroides fragilis. Most penicillins are inactive against Klebsiella species. In addition, clinical trials have shown that during monotherapy with third-generation cephalosporins and antipseudomonal penicillins, Pseudomonas strains often become resistant, causing therapeutic failures [86911. Furthermore, the choice of substances has to be adapted based on the pathogens in an individual hospital. In general, a combination of a beta-lactam antibiotic with an aminoglycoside is used initially, then changed to monotherapy only after identification of the pathogen in a patient with normal host-defense mechanisms. As mentioned previously, the aminoglycosides have new competition in the monobactams (e.g., aztreonam), the carbapenems (e.g., imipenem), and the 5-quinolones (e.g., ciprofloxacin, ofloxacin, and norfloxacin). Some of these agents possess even broader activity than the aminoglycosides, primarily because they attack anaerobes. It may eventually be possible to use them with sufficient safety as monotherapy in immunocompetent patients with septicemia. A review of the many studies in which aminoglycosides have been used as monotherapy in septicemia reveals success rates of 24 to 100 percent. In neutropenic patients with septicemia, failures often occur. However, consistently positive results can be attained in patients with normal host defenses [92-981. Pathogens for which an aminoglycoside is the drug of choice are discussed later in this article, as are those compounds that are equally effective [99]. In infections with Acinetobacter anitratus or Iwoffi, an aminoglycoside, an antipseudomonal penicillin, or one of the new 5-quinolone preparations can all probably be considered equally effective as alternative therapy. Cefotaxime, ceftizoxime, ceftazidime, or imipenem (plus cilastatin) are the alternatives to an aminoglycoside in infections with Enterobacter species. In infections with Hafnia alvei, an aminoglycoside is the drug of first choice, and chloramphenicol is only the drug of second choice. Against Morganella species, imipenem (plus cilastatin) will most likely be as effective as an aminoglycoside. Amikacin is the drug of first choice against Providencia species, with the possible alternatives being cefotaxime, moxalactam, ceftizoxime, or imipenem (plus cilastatin). Streptomycin is the drug of choice against F. tularensis, with chloramphenicol the alternative. Amikacin is the drug of choice against Serratia marcestens, but the new 5-quinolone preparations are, in all likelihood, equally effective. Yersinia enterocolitica is most successfully treated with an aminoglycoside, but ceftizoxime, ceftriaxone, and moxalactam are also effective. Streptomycin continues to be the first-line drug for treatment of Y. pestis infection, with no equally effective alternative. Only prolonged clinical experience and controlled comparative studies will establish the relative reliability

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and value of a given drug against a specific pathogen. Combination Therapy with Aminoglycosides (Table VI). The need to broaden the spectrum of antibiotic therapy has led to the administration of antibiotic combinations. The rationale for combination therapy also includes the enhancement of antibacterial activity due to synergistic or additive interactions. Increased activity reduces the risk of therapeutic f&lure that might iesult when bacterial subpopulations develop resistance to one or both antibiotics. In addition, these synergistic or iddiiive effects often allow a reduction in dosage and in consequent tbxic side effects. The value of combining aminoglycosides with beta-lactam antibiotics is recognized worldwide. However, drug combinations may also hatie antagonistic interactions, increased side effects caused by both drugs, possipie provocation of multiply resistant organisms, misinterpretation of therapeutic safety, and finally, higher costs. Regardless of the potential disadvantages, in mavy clinical situations, the combination of an aminoglycoside with a beta-lactam antibiotic continues to be the optimal therapy. This is true in life-threatening infections with unknown pathogens, in mixed aerobic/anaerobic infections, in infections in neutropenic or immunodeficient patients, in bactbrial endocarditis, and in systemic Pseudomonas infections. Above all, clinical trials have shown that patients with cjranulocytopenia appear to benefit from combined antibiotic ttierapy. Young and co-workers [loo] and Love et al [IO11 reported a success rate of 80 p&cent in granulocytopenic patients with septicemia when both antibiotics us&d in the combination, a beta-lactam, plus an aminoglycoside, were individually active against the causative organisms. The success rate declined to about 60 percent when one of the antibiotics in the combination proved inactive icvhentested alone. If both antibiotics were inactive in vitro, the success rate dropped below 20 percent. There are now numerous animal and clinical trials that confirm the superiority of combined antibiotic therapy in appropriate indications [102-l 071, a fact that had been recognized as early as 1971 by Schimpff and co-workers [108]. Today, however, in various infections, new antibiotic groups alone or in combination show similar results, a fact that has to be considered when evaluating a therapeutic regimen. Monitoring Serum Concentratiok of Aknoglycosides. Suggested peak lgvels to be achieved at the end of a 60-minute infusion for gentamicin, tobramycin, and netilmicin are 6 to 8 mg/liter; trough levels before the next infusion should be between 0.5 and 2 mg/liter. For amikacin, the corresponding peak and trough values are 20 to 30 mg/liter and between 2 and 10 mg/liter, respectively (Table VII). These values can be obtained with a maintenance dose of 3 to 6 mg/kg per day for gentamicin, tobramycin, and netilmicin. For amikacin, they can be achieved by administration of 15 to 25 mg/kg per day, divided in two

TABLE

VII

Suggested Peak and Trough Aminoglycosides

Levels for

mg/liter Gentamicin, Tobramycin, Netilmicin Amikacin

7 (6-8) 8-12 ?0.5< 2 25 (20-30) PO-35 z2- < 10

Levels
Peak (end of 60-minute infusion) Pseudomonas infections, pneumonia Trough (before next infusion)

TABLE

VIII

Recommended Aminoglycosides

Dosages

bf

Gentamicin, Tobramycin, Netilmicin

Loading dose (mg/kg) Maintenance dose (mg/kg Infusion period (minutes) Dosage interval - 3 x t1/2 tlj2 = In 2 x At / In (C,&) per day) 2 3-6 60

Amikacin
8 15-25 60

TABLE

IX

Monitorihg of Serum Concentrations of

Aminoglycosides
aminoglycoside correlation doncentrations between serum concentration level and and and

Relationship between clinical ~efficacy Lack of reproducible administered dose Correlation of serum ototoxicity

serum

with nephrotoxicity

to four doses and administered over a period of one hour (Table VIII). Results of clinical and microbiologic studies indi,cate that during aminoglyco$ide therapy, drug serum concentrations should be monitored (Table IX). In vitro and in vivo studies show that there is a quantitative relationship between aminoglycoside serum concentrations and clinical efficacy. In 68 patients with gram-negative infections, Noone and colleagues [log] showed thtit 46 (84 percent) of 55 patients had cures with adequate gentamicin therapy, compared with only three (23 percent) of 13 patients who received inadequate therapy. If gram-negative Septicemia was assessed alone, 10 (91 percent) of 11 treatments were successful with adequate gentamicin therapy, whereas no success was recorded ih any of the four patients with suboptimal gentamicin concentrations. From case reports of 530 patients, Moore and co-workers [l IO,1 1I] also showed significailtly higher clire rates in patients with adequate serum levels of gentamicin, tobramycin, and amikacin than in patients with suboptimal drug concentrations. Finally, Anderson et al [112] demon-

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TABLE

Lack of Reproducible Correlation between Serum Level and Administered Dose

Infusion with Amikacin (9 mg/kgbodyweight) After 30 Minutes

Concentrations in the serum (mgiliter)
30.8-50.8

After 60 Minutes
17.6-30.8

After 120 Minutes

10.9-18.9

strated breakthrough bacteremia in 52 (22 percent) of 237 patients undergoing antibiotic therapy for gramnegative bacteremia; of 42 samples evaiuated, 20 showed subinhibitory drug concentrations when the positive blood cultures were takeri. Instead of measuring aminoglycoside concentrations in serum, some investigators have correlated clinical outcome with serum bactericidal titers [113,114]. Klastersky and co-workers [114] reported a success rate of more than 80 percent among 317 patients with tumors when the bacteriostatic activity in the serum equaled or exceeded 1:8. Another reason for measuring serum concentrations is the lack of a reproducible correlation between the serum level and the administered dose. Barza and colleagues [I 151 measured peak serum concentrations in 23 patients after intravenous or intramuscular administration of gentamicin at 1.2 to 1.7 mgikg bodyweight, and found that leveis ranged from 1.7 to 7.4 mg/liter. Kaye and co-workers [116] studied 23 patients in whom a gentamicin serum concehtration of 5 mg/liter was attained one hour after intramuscular injection of doses ranging from 0.9 to 2.35 mg/kg bodyweight. A dose of 2.35 mg/kg bodyweight given to two different patients yielded extremely different peak concentrations of 5.2 mg/liter and 14 mg/liter. Goodman et al [117] measured trough and peak concentrations and found, in agreement with other authors, a high degree of variability among patients. Moreover, patients given identical doses showed different serum concentrations at different times. In our institution, a, study by Ltithy (Table X) confirmed this variability [118]: 30, 60, and 120 minutes after starting an infusion of amikacin at 9 mg/kg bodyweight, the corresponding serum concentrations were 30.8 to 50.8 mg/liter, 17.6 to 30.8 mg/liter, and 10.9 to 18.9 mg/liter, respectively. Nephrotoxicity and ototoxicity associated with the aminoglycosides appear to be correlated with the area under the serum concentration-time curve, but there are also reports suggesting that ototoxicity depends more on peak concentrations. According to a major study by Kahlmeter and Dahlager [23], who reviewed data on about 10,000 patients over the period from 1975 to 1982, nephrotoxic side effects associated with gentamicin, tobramycin, netilmicin, and amikacin occurred at a rate of about 10 percent

(the differences among individual aminoglycosides discussed earlier should be considered here). Cochleotoxic side effects are even less frequent, and the occurrence of vestibulotoxic side effects are rare. Moore et al [119] analyzed the course of gram-negative infection and treatment iri 214 patients who had received either gentamicin or tobramycin in randomized prospective clinical studies. In the contrql group without aminoglycoside therapy, a 50 percent reduction in creatinine clearance (the criterion of nephrotoxicity) was observed only once; however, this side effect occurred in 30 (14.1 percent) patients receiving gentamicin or tobramycin. After investigation and statistical evaluation of various cofactors, the following circumstances were found to be significantly associated with nephrotoxicity. In the group that showed toxicity, the peak serum level of 7.2 -t 0.4 mgiliter was higher than in the group without toxicity, which had a level of 5.3 +- 0.1 mgiliter. The trough level of 3.4 -t 0.3 mg/liter in the group with toxicity was also higher than the trough level of 2.6 + 0.1 mgiliter in the group without side effects. Patients who experienced toxicity had a higher creatinine clearance before therapy. It is possible tliat the higher initial drug flooding to the tubular cells contributed to the development of nephrotoxicity. Some of the affected patients also had hepatic disorders, suggesting a connection between hepatic insufficiency, reduced renal blood flow, and activation of the renin-angiotensin mechanism. Shock states occurred more commonly in the group with toxicity and led to reduced organ perfusion. Finally, women were affected more often than men. The data from 135 patients receiving gentamicin and tobramycin were also analyzed by Moore and co-workers [120] with reference to ototoxicity. The total dose of aminoglycoside received was higher in, the group in which inipaired hearing developed. This group had received 3.06 ? 0.37 grams of aminoglycoside, compared with 2.01 -C0.15 grams in the group without side effects. The duration of therapy also differed. The group with side effects received aminoglycosides for 9.1 -I 0.8 days, compared with 6.6 + 0.1 days for the group without side effects. Patients with ototoxicity also had higher fever initially. It was suspected in these cases that the cytoprotective prostaglandins of class E are produced in smaller quantities under the influence of fever and aminoglycosides. More patients with ototoxicity had an initial bacteremia that could lead to direct cochlear injury by bacterial endotoxins and/or changes in the endolymph caused by these toxins. The peak and trough levels of aminoglycoside were, in contrast to the situation with nephrotoxicity, not significantly associated with the development of ototoxicity. This observation is in disagreement to some extent with the studies of Wilson and Ramsden [12lj, who described a reversible cochlear damage with peak tobramycin concentrations above 8 to 10 mgiliter.

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It is clear from all these studies that regular ment of aminoglycoside serum concentrations mize therapy in many ways. AMINOGLYCOSIDES AND THE FUTURE

measurecan opti-

regardless of which new agent was used, resulting apeutic failures [I 22-l 241. COMMENTS

in ther-

Results of numerous clinical studies with similar indications for aminoglycoside therapy are already available on new antibiotics such as carbapenems, monobactams, and 5-quinolones. Although the results regarding efficacy in most types of bacterial infections are consistently positive, it is also true that resistance to P. aeruginosa developed

Aminoglycosides have retained their place in the treatment of various infectious diseases, particularly those acquired in the hospital. Newly developed agents from other classes of antibiotics undoubtedly represent an enrichment of the clinicians therapeutic armamentarium and, at present, appear to be effective complements in different situations to the aminoglycosides.

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cosides. Ann Intern Med 1984; 100: 352-357. Moore RD, Smith CR, Lietman PS: Risk factors for the development of auditory toxicity in patients receiving aminoglycosides. J Infect Dis 1984; 149: 23-30. Wilson P, Ramsden RD: Immediate effects of tobramycin on human cochlea and correlation with serum tobramycin levels. Br Med J 1977; I: 259-261. Vivas JR, Creixems MR, Bouza E, et al: Evaluation of aztreonam in the treatment of severe bacterial infections. Antimicrob Agents Chemother 1985; 28: 222-226.

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