Aminoglycosides in urology

REVIEW ARTICLE

AMINOGLYCOSIDES IN UROLOGY BURKE A. CUNHA, M.D. From the Winthrop-University Hospital and School of Medicine, State University of New York at Stony Brook, New York

Prompt management of serious urologic infections is extremely important. Kreger e t a l . 1 have ~emonstrated that early therapy with an effective antibiotic will result in improved survival ~nd a lower frequency of shock associated with :gram'negative baeteremia. As part of an effort ~6 achieve these therapeutic goals, empiric ~minoglyeoside therapy has been used s u e c e s s Iully for more than two decades. In addition, :aminoglycosides have been used prophylaeti}ally with urologic procedures and implant surlivery.2 ~ The selection of an antimierobial agent in a patient with a urinary tract refection (UTI) is :ibased on several factors. These include the !elini6al setting (i.e., if the infection is eommu!hity~ or hospital-acquired), whether or not it is !60Nplieated by host conditions, the severity of !he:infection, local susceptibility patterns for ~he potential pathogen(s), the appropriate ~ha~maeokinetie/pharmaeologie characteristics ~)f the agents, and cost. ii~ The choice of antibiotic for urosepsis is aided i~') examination of gram-stained urine, which igsu~ly reveals direct organism(s) involved in the ii~fectious process. When gram-positive cocci ~d, treatment with ampicillin, is Lhe patient who is not allergic to :e patient allergic to penicillin, 'ith or without an aminoglycoentamiein), is the usual therave. If the clinician suspects that bacilli are the causative or~lonephritis/urosepsis, a parenactive against these organisms ..........:. . . . . . . . . . . dequate concentrations in the }~lg6d, urine, and kidneys should be chosen. !A'gefits such as aminoglycosides, third-generation cephalosporins, aztreonam, and trimethoiPri:m~sulfamethoxazole might be utilized in this ~if:6ation. tf a nonfermenting gram-negative

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bacillus, such as Pseudomonas aeruginosa, is suspected, then an antipseudomonal penicillin/ eephalosporin, eiprofloxacin, aztreonam, or an aminoglyeoside would be a logical choice. Aminoglyeosides are especially useful in the treatment of gram-negative pyelonephritis because they achieve high renal concentrations. Historical Background The first aminoglyeoside used for parenteral therapy of a systemic infection in a human was streptomycin. This event involved the treatment of a patient with tuberculosis in November 1944. a Subsequently, the other aminoglyeosides were developed and released for use in the United States, including kanamyein in 1957, gentamiein in 1969, tobramyein in 1975, amikaein in 1976, and netilmiein in 1983. 4 Streptomycin has little activity against important gram-negative pathogens such as the Enterobaeteriaeeae and P. aeruginosa; its primary clinical utility is in the treatment of tuberculosis. Kanamyein manifests appreciably less activity against gram-negative pathogens as compared with the other aminoglyeosides, and is clinically much less useful than gentamiein, tobramyein, or amikaein, the primary aminoglyeosides currently in use. 4 Mechanism of Action of the Aminoglycosides Aminoglycosides are bactericidal against susceptible strains of bacteria by binding irrever= sibly to the ribosomal 30S subunit, thereby inhibiting protein synthesis and cellular metabolism. 5-7 Because entry of these drugs into the cell requires an oxygen-dependent active transport system, 5'8's anaerobic conditions strongly inhibit their activity2 1

TABLE I.

In vitro antimicrobial activity o] aminoglycosides* against common uropathogens "MICgo Values (~g/mL) Gentamicin Tobramycin Amikacin Microorganism Gram-negative bacteria Acinetobaeter spp. 6.2 6.3 6.2 Citrobacter spp. 4.0 4.0 16.0 Escherichia eoli 1.25 4.0 4.0 Enterobacter spp. 1.3 0.78 2.7 Klebsiella pneumoniae 4.0 4.0 8.0 Proteus mirabilis 4.0 4.0 4.0 Proteus (indole-positive) 1.2 6.3 6.3 Pseudomonas aeruginosa 8.0 6.3 16.0 Serratia spp. 0.25 6.3 3.1 Gram-positive bacteria Enterococci 50.0 50.0 100.0 Adapted from Ristuccia and Cunha. 1. *Netflmicin was not included in this table because it is not used at Winthrop-University Hospital. TOn the basis of approved break points, isolates having MICs of < 4 tzg/mL are considered susceptible to gentamiein and tobrarnyein, and those with MICs of < 16 #g/mL are susceptible to amikaein.

The ribosomal activity of aminoglycosides provides opportunity for additive or synergistic activity with other antibiotics having different mechanisms of action. Synergistic activity against some bacterial strains has been demonstrated with aminoglyeosides in combination with vaneomyein, penieillins, eephalosporins, quinolones, maerolides, and elindamyein. 1° Since synergism is most useful and desirable when treating resistant strains of bacteria, the combination of an aminoglyeoside with another agent is most commonly indicated for serious systemic infections due to P. aeruginosa, the enteroeoeei, or for extended-spectrum coverage. H Spectrum of Activity The aminoglyeosides are most useful aqgainst aerobic and faeultative gram-negative bacilli, including Pseudomonas. 4,7,1° Table I shows the usual in vitro activity of these agents against uropathogens. ~2 Importantly, significant variations in patterns of resistance can occur from one center to the next, therefore necessitating attention to changes in resistance patterns. The activity of the aminoglycosides against other strains of bacteria is variable. All streptococci, including enteroeoeei, are resistant at achievable concentrations, but are rapidly killed when exposed to an aminoglycoside in the presence of a penicillin. 7,n'13 Aminoglycosides have moderate anti-staphylococcal activity. All aminoglycosides, however, are inactive against all anaerobic organisms.

"2

Resistance Acquired resistance by bacterial strains previously susceptible to the aminoglycosides may occur via one of three different mechanisms: ~ enzymatic modification of the drug, decreased permeability of the organism to the antibiotie~: or altered binding to the ribosome. 14,15 Enzy-i matic-mediated resistance is the most .impor! tant and common mechanism of bacterial re-:! sistance] 5 and is most commonly acquired byi plasmid transfer. 16,17 Enzymes inactivation oc-i curs via adenylation or phosphorylation of one of several amino or hydroxyl groups on th~ aminoglycoside molecule (Fig. 1). Howevel since amikacin contains only one inactivatio~ focus, compared with gentamicin or tobram tin, which have six potential inactivation foci~ bacteria are less likely to develop resistance ti amikacin by this mechanism.iS A recent summary of resistance mechanismi regarding the aminoglycosides indicates thai gentamiein is susceptible to inactivation by a! least seven enzymes, tobramyein and netilmici~ are susceptible to at least six, and amikacin i affected by two enzymes. 1° The tendency f0 development of resistance to occur by enzy matie mechanisms occurs in the following of der: amikaein < netilmicin < tobramycin ~ gentamiein. During periods in which resistanc~ to commonly employed aminoglyeosides has i~~] creased in a hospital or on a regional level, anai~l kacin-resistanee has generally not developei~

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:P

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,9ncurrentlv. and conversion of amino I cos~de :seto primarily amikacin has led to a reduction iS:this resistance profile to other aminoglyco:~!deSwithout reducing the effectiveness of ami-

i:Uri~IiOCY / JULY 1990 / VOLUME XXXVI, NUMBER 1

As a result of these findings, much investigation has centered on the potential for the development of significant changes in hospital s u s ceptibility patterns with routine chronic use of the various aminoglyeosides in the hospital 3

100

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Relationship between aminogtycoside use and resistance in 7138 isolates of P. -so aeruginosa at Winthrop-University Hospital. Tobramycin accounted for less than 5 per-70 cent of total aminoglycoside usage• Thus increase in gen-60 ~ tamicin use in 1987, which is shown as decrease in amikacin use, correlated with striking E increase in resistance to gen- 50 ~ tamicin. (--O amikacin, --~ '• gentamicin, amikacin usage .) Adapted from ~'0 Cunha. 11

24-

1987

1988

~me(Years)

TABLE II. Pharmacokinetic characteristics of aminoglycosides Kinetic Parameters Gentamiein Tobramycin Amikaein Volume of distribution (L/kg) Elimination half-life (hrs) Healthy volunteers Anuric patients Usual adult dose (mg/kg) Serum level (/xg/mL) peak (usual/recommended) * Trough (recommended)* Protein binding (%) Removal by dialysis Hemodialysis ( % ) Peritoneal dialysis (rag/L)

0.25-0.30

0.25-0.30

0.25-0.30

2 80-60

2 50-70

2 30-90

1.5

1.5

7.5

4-6/< 12 <2 0

4-6/< 12 <2 0

25-30/< 35 < 10 0-3

50-60 0.5

50-60 0.5

50-60 1.0-1.5

Adapted from Ristuccia and Cunha. I~ *Recommended serum concentrations on the basis of safety considerations. Prolonged, excessive peak and trough concentrations are associated with increased risks of ototoxieity and nephrotoxicity, respectively.

population. These studies have shown that widespread use of gentamiein and tobramycin will ultimately result in an inereased incidence of resistant strains, particularly P. aeruginosa.26 In contrast, data regarding the widespread use of amikaein indieate that no change in resistanee patterns will oeeur, 2~ or that these changes will be delayed or of less significance (Fig. 2).27 Pharmacology/Pharmacokinetics The aminoglycosides exhibit similar pharmacologic properties. Although amikacin and kanamyein are not as potent as gentamicin, tobramycin, and netilmiein, amikaein and kanamyein are less toxic by weight than the other agents. The lower toxicity of amikaeirt and

4

kanamyein is offset by a need for higher doses, thus yielding a generally similar risk/benefit ratio as compared with the other aminoglyeosides. Table II summarizes the pharmaeokinetie characteristics of these agents. The aminoglyeosides are all water-soluble polar molecules that exhibit optimal activity at a pH of 6 to 8. 28,29Significant alterations in pH or the presence of divalent cations will alter the activity of these drugs. 28,29 Thus, a number of laboratory and clinical problems may arise. Susceptibility testing requires careful definition of the culture media. 1° This parameter may signifieantly eonfound the ability to compare the results of in vitro studies conducted under different conditions. Clinieally, these properties result in relatively poor function in the acidic

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environment of bronchial secretions or abscesses, and in the cation-containing environment produced by tissue necrosis and large quantities of organic debris. 2a,29

Absorption The aminoglyeosides are absorbed poorly when given orally, and are therefore useful for the treatment of systemic infections only when administered parenterally. 12 Intramuseular administration results in rapid and complete absorption with peak plasma eoncentrations oeeurring between thirty and ninety minutes after injection. 3° As with any intramuscular injection, impaired tissue perfusion (as occurs during shock) may limit the absorption of these agents. Other routes of administration result in variable degrees of absorption. Aminoglyeosides administered either intraperitoneally or into the pleural cavity are well absorbed, with resultant serum coneentrations dependent on the eoneentration of drug placed into the cavity. 31.a2 Finally, bladder irrigation, 33 intratraeheal or aerosolized administration, 34,3s and intratheeal or intraventrieular injectiona6 all lead to minireal absorption with negligible plasma eoneentrations.

Distribution The aminoglyeosides appear to be distributed into extraeellular fluids, since the volume of distribution (0.25-0.3 L/kg) most closely approx:imates that physiologic space.12 Diffusion into i~terstitial fluid is good, but concentrations are lower~ than those achieved concurrently in the serum. 37 Protein binding is very low (< 25 % ). 38 These agents do not penetrate into the cerebral S~inal fluid (CSF) of patients with normal meninges, 39 and achieve only low eoneentrati6ns in the presence of inflamed meninges ~ h e n usual doses are given. Penetration into ~mnehial secretions is low, 4°,41 but is somewhat more efficient in patients with parapneumonie effusions. 42 Distribution into bile and the gallbladder wall generally yields concentrations below those seen in the serum. 4a Synovial fluid c0neentrations generally exceed 50 percent of Concurrent serum concentrations. 44 Aminoglyeosides penetrate well into renal tissue, particularly the renal cortex. Coneentra~ons may easily exceed 100 /xg/g of tissue. 45 geabsorption of drug from the proximal renal tiibule is believed to produce these levels. This it6ndeney of aminoglyeosides to eoneentrate in t~e kidneys produces a favorable therapeutic

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advantage, 46 but also may be responsible for nephrotoxieity. Concentrations are also high in urine, often exeeeding 700-800/xg/mL for amikacin and 100-200 # g / m L for the other aminoglyeosides.4

Elimination Elimination of the aminoglycosides occurs virtually exclusively through glomerular filtration of active drug. Excretion is directly related to ereatinine clearance and will dramatieally decrease when the creatinine clearance falls below 40 mL/min. 47,48 Concentration-Response Relationships Since the development of reliable and relatively low-cost analytieal techniques, research has foeused on the concentration-response relationships of the aminoglycosides. Recent studies have revealed a correlation between peak serum concentrations, 49,5° clinical response of patients with gram-negative infections, and/or the ratio of the serum concentration to minimal inhibitory concentration (MIC).5~ Approximate dosing is complicated by the unreliability of various nomograms 52 and the significant interpatient variability in dosage required to attain target concentrations. 53,54 Undue reliance on dosing nomograms; i.e., Hull-Srubbi, Dettli method, in patients with changing renal function is a common mistake since precise calculation today cannot accurately be made on the basis of yesterday's ereatinine. Furthermore, all nomograms assume a constant volume of distribution (Vd), which is invalid in sick patients and inconstant between individuals. Approximations based on the degree of renal dysfunction, i.e., ereatinine clearance, are preferred. Serum levels must be carefully interpreted in view of the clinical setting. Peak levels should be obtained immediately post-infusion, and trough levels prior to the next dose once steadystate (usually five half-lives) has been achieved. Peak/trough levels vary according to the severity of illness and special kinetic considerations in the host. "Breakthrough baeteremias" due to suboptimal dosing in sick patients have been assoeiated with gentamiein, but not amikaein. Therapeutic levels after the first dose are achieved in approximately 60 percent of patients who receive gentamiein whereas >90 percent of patients who receive amikaein are immediately in the therapeutic range 51 (Fig. 3). The use of monitoring to avoid toxicity is also a commonly misunderstood area. After the 5

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FIGURE 3. Typical aminoglycoside serum levels and MIC values against P. aeruginosa (MICgo 16 and 8 izg/mL for amikacin and gentamicin, respectively). Elimination hal]-li]e o] two hours was used ]or both aminoglycosides. Adapted from Cunha. 11

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therapeutic levels have been determined by peak levels, serial troughs are the most useful determination to monitor nephrotoxicity and are superior to peak-trough pairs. 55 Since peak tissue levels are not achieved for > ten clays of aminoglycoside therapy, serial troughs better reflect post-distribution blood/tissue kinetics. Stable trough concentrations argue against potential nephrotoxicity, but elevated trough levels over two to four days presage subsequent tissue damage. Therefore, single peak-trough pairs are not cost-effective and should be discouraged. Similarly, elevated peak levels do correlate with ototoxic potential. Persistent, very elevated peaks are of concern, but single peaks, regardless of the degree of elevation, are not ototoxic. Guidelines for peak and trough aminoglyeoside levels are presented in tabular form (Table III). Toxicity Multiple adverse effects produced by the aminoglycosides have been identified. Perhaps the best known of these include nephrotoxicity and ototoxicity. Other significant reactions include skin rash, neuromuscular paralysis, mental confusion, and peripheral neuritis (rare). Interestingly, neuromuscular paralysis associated TABLE

III.

with the aminoglycosides is augmented by curare-like drugs, succinyleholine, magnesium, the presence of botulinus toxin in patients with botulism, and by myasthenia gravis. 56-59 This reaction is linked to high concentrations of drug at the neuromuscular junction (as seen with rapid intravenous administration of a bolus dose of drug), and is treated by prompt therapy with calcium. 6° Ototoxicity caused by the aminoglycosides is relatively uncommon, but is a difficult problem when it occurs. This side effect of therapy is apparently a result of selective destruction of the outer hair cells of the organ of Corti. 81-6~ Ultimately, this effect results in retrograde degeneration of the auditory nerve. 64 With more extensive damage, inner hair cells and cells of the stria vascularis are affected. When ceils in the ampullar cristae are damaged, vestibular toxicity results. ~5 Importantly, these ototoxic effects of the aminoglycosides are usually irreversible, since neither cochlear nor ampullar cells can regenerate after destruction. It is difficult to describe a specific timecourse for development of ototoxicity, in part because most studies do not report on this adverse event, and because there have been reports of ototoxicity occurring fairly early after treatment (i.e., 7-10 days) as well as after lengthy therapy. At least two trials have correlated the length of therapy with increased risk of this reaction. 66,67 Bendush and Weber 66 reported a significantly increased risk of ototoxicity in patients who received tobramycin for more than ten days. These findings were corroborated by Moore, Smith, and Lietman 67 who evaluated 135 patients for the occurrence of o t o t o x i c i t y f o l l o w i n g a m i n o g l y c o s i d e

Guidelines ]or optimal serum concentration

Peak and Trough Values*

Gentamiein

Tobramycin

Amikaein

P e a k s (/zg/mL) Serious i n f e c t i o n s Life-threatening infections

6-8 8-10

6-8 8-10

20-25 25-:30

0.5-1 1-2

0.5-1 1-2

Troughs (#g/mL) Serious infections Life-threatening infections

1-4 4-8

Adapted from Zaske2 ~ *Higher peak and trough values have also been suggested.

6

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therapy. They reported that the mean duration of therapy in those in whom ototoxieity developed was 9.1 days, versus 6.6 days in those in whom this reaction did not develop (p = 0.005). Aminoglyeoside ototoxieity is related to prolonged, high-dose aminoglyeoside therapy. Aminoglyeoside ototoxieity may be cochlear or vestibular, or a combination of both. Clinically, high-frequency hearing loss is not uneommon with audiometry, but gross hearing loss is unusual; i.e., cochlear toxieity occurs in < 5 percent of patients. Vestibular toxieity is uncommon, occurring in < 1 percent of patients ;regardless of t h e a m i n o g l y e o s i d e used. Aminoglyeoside ototoxieity has been associated :with high sustained peak levels that are maintained for an extended period of time. Single high levels have not been associated with ototoxicity. Ototoxieity does not manifest itself be:fore one week of aminoglyeoside therapy, and occurs almost exelusively in patients receiving aminoglyeosides for more than two weeks. Sinee ototoxieity changes may be permanent, aminoglyeosides should be avoided, if possible, n patients with pre-existing ear disease.l° i~ Nephrotoxieity associated with the aminoglycosides is believed to oeeur as a result of avid !ubular uptake, prolonged retention, and sub;equent cellular damage induced by these ~gents. Concentrations of drug in the renal eor!ex can reach levels five to fifty times greater !han those in plasma. ~8 The highest eoneentra!ions of aminoglyeosides are found in the proximal renal tubular cells. 69,7° Proximal cell damige occurs as a result of either lysosomal fffeets.6S 7o Clinically, late nephrotoxieity may ~e indirectly inferred as a reduced glomerular iltration rate (indirectly reflected as a de}reased ereatinine clearance), which occurs in i-25 percent of all eases. 71 74 The onset of eliniially deteetable nephrotoxieity generally oeeurs en to fourteen days after initiation of therapy, vith a subsequent inerease in glomerular dysruction. 55,75-78The risk faetors for nephrotoxiety are noted in Table IV. Aminoglyeoside nephrotoxieity also occurs !ate in the course of therapy, usually between Seek 1 and week 2, rising progressively thereafier. Aminoglyeosides cause proximal tubular ~ysfunetion resulting in a reversible acute tubu~ar necrosis-like syndrome in the following ~hirty days Nephrotoxieity is likely to occur in ~ritieally ili, debilitated patients who are vol~rne depleted, who receive aminoglyeosides for i[JROLOGY / JULY 1990 /

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TABLE IV. Risk ]actors associated with ototoxicity and nephrotoxicity OTOTOXICITY

Advanced age Renal insufficiency Dehydration Elevated peak eoneentrations Persistently elevated trough eoneentrations Coneurrent ototoxie drugs Duration of treatment NEPHROTOXICITY

Advaneed age Renal insuffieieney Elevated trough eoneentrations High total daily dose and eumulative dose Other nephrotoxie drugs Hypovolemia more than two weeks. The eoneomitant use of other potentially nephrotoxie agents may potentiate aminoglyeoside nephrotoxieity. Persistently high trough levels have been associated with nephrotoxieity. Aminoglyeosides should be avoided, if possible, in patients with significant renal disease. The serum ereatinine is a poor guide or predictor of aminoglyeoside-indueed renal dysfunction and should not be relied on to assess aminoglyeoside nephrotoxieity. The glomerular filtration rate (GFR) decreases as a proteetive response to failing proximal tubular function, and oeeurs five to ten days later. After cessation of aminoglyeoside therapy, GFR usually returns to pretreatment levels < sixty days. Serial urinary east eounts are a sensitive and specific indieator of proximal tubular dysfunction and are easy and inexpensive to perform, but diffieult to interpret. If aminoglyeosides must be used in patients with changing renal function, dosing should be performed only with expert supervision. 10 At present, the best way to avoid nephrotoxieity is to: (1) use aminoglyeosides only to treat serious gram-negative infections sueh as R aeruginosa, endoearditis, or gram-negative pyelonephritis; (2) limit aminoglyeoside therapy to no more than two weeks; (3) avoid aminoglyeosides in patients with pre-existing ear/renal disease; (4) avoid dehydration and hyponatremia in patients receiving aminoglyeoside therapy; and (5) administer aminoglyeosides in a single daily dose rather than in multiple doses (e.g., amikaein 1 g IV q 24 h, gentamiein 240 mg IV q 24 h) in selected patients. 55 In summary, elinieians should try to avoid aminoglyeosides when treating patients with pre-existing ear or renal diseases as well as those 7

with changing renal function, and in situations with increased nephrotoxie potential. A nonaminoglycoside almost always can be used in the majority of these treatment situations. Cost Considerations The low acquisition cost of the aminoglycosides often makes these drugs cost-effective for therapeutic use, especially as compared with some of the newly released agents. However, one must also consider such faetors as expenditures for monitoring and the cost of significant nephrotoxieity. Certain guidelines, however, may be used to minimize the cost of therapy with these agents. These include use of prolonged dosing intervals (i.e., _> q 24 hour intervals), use of the intramuscular route of administration, judicious application of therapeutic drug monitoring, use of other laboratory values used in monitoring, limiting the course of therapy, and eonsideration of acquisition cost w h e n selecting the particular aminoglycoside to be used. This last consideration must be balaneed against hospital-specific sensitivity and resistance patterns and reliable pharmacokinetics. Evaluation of Therapy The results of therapy in UTI may be classified as cure, relapse, reinfection, or failure. Patients who are cured have elimination of the initial pathogen(s) and achieve a satisfactory elinieal response. Patients who relapse have initial elimination of the pathogen, but later, the same pathogen reappears. This generally occurs after discontinuation of antibiotic therapy and may indicate that an inadequate course of therapy was given. Reinfection occurs when the initial pathogen is eliminated, but is replaced by a different organism(s) following discontinuation of therapy. Failure occurs when the pathogen(s) is never eliminated and the patient does not respond to treatment. In e v a l u a t i n g the effectiveness of UTI therapy, it is important that an adequate period of post-therapy follow-up occurs so that relapse and reinfection eases become apparent. For complicated UTI, this follow-up period usually lasts at least one month. Comparative Clinical Trials The clinical efficacy of the aminoglycosides in the treatment of UTIs has been evaluated in a number of randomized trials. 79-s6 Gentamicin

8

and tobramyein have been compared in two studies. 79,8° Walker and Gentry 79 administered each agent intramuscularly in a dose of 1 mg/kg every eight hours for a mean duration of 6.5 days. Forty symptomatic patients with >10 s efu/mL of bacteria in the urine were randomized to each treatment group. Fifteen patients in the gentamiein group and thirteen in the tobramyein group had anatomic abnormalities of the urinary tract and/or obstructive disease. The predominant causative pathogen was Escheriehia eoli, which occurred in 28 gentamitin and 25 tobramycin recipients, followed by Klebsiella spp., which was isolated in 7 eases in each group. The overall response to therapy at the fourteen-day post-treatment follow-up visit was similar in the two groups. In the gentamitin group, 32 (80 %) were cured and 8 (20 %) relapsed, while in the tobramyein group, 39. (80 %) were cured, 6 (15 %) relapsed, and 2 (5 %) became reinfected. The response rate for UTIs in patients without underlying abnormalities was slightly higher than that in patients with obstruction or other anatomie abnormalities. In a randomized trial, Madsen, Kjaer, and Mosegaard a° treated 75 patients wth either gentamiein or tobramyein in a dosage of 1 mg/kg every eight hours for seven days. Thirty-seven patients were randomized to receive gentamitin and 38 received tobramycin. UTIs' in this study were complicated by the presence of obstruction, prostatic hypertrophy, strieture, or urologic malignancy. Causative pathogens in the gentamiein group included E. eoli (n = 16), Klebsiella-Enterobaeter spp. (n = 5), Proteus spp. (n = 6), Pseudomonas spp. (n = 7), and Staphylococcus spp. (n = 3). In the tobramycin group, pathogens included E. coli (n = 19), Klebsiella-Enterobacter spp. (n = 7), Proteus spp. (n = 4), Pseudomonas spp. (n = 7), and Staphylococcus spp. (n = 5). At the end of therapy, 89 percent of UTIs were cured in each treatment group. However, at one week posttherapy, the results were 64 pereent cured, 17 percent relapsed/persisted, and 19 percent reinfected/superinfeeted in the gentamicin group. The corresponding figures for the tobramyein group were 64 percent, 19 percent, and 17 percent, respectively. Gentamiein and amikacin have been compared in three randomized studies evaluating UTI therapy, sl-sa In the largest of these studies, Cox sl treated 63 patients with either gentamitin 60-80 mg every eight hours for a mean of

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eight days, or amikaein 150-9.00 mg every eight hours for a mean of seven days. Cases were complicated by prostatic hypertrophy (n = 18), calculi (n = 12), urologic malignancy (n 15), strieture (n = 4), neurogenie bladder (n 5), and other eonditions (n = 5). Fifty-three patients had unspecified UTI, 9 had pyelonephritis, and 1 had cystitis. Pathogens in the amikaein group included E. eoli (n = 10), multiple organisms (n = 8), Pseudomonas spp. (n = 5), Klebsiella spp. (n = 5), Proteus spp. (n = 2), and other gram-negative rods (n = 2), while those in the gentamicin group ineluded Pseudomonas spp. (n = 3), Proteus spp. (n = 6), E. eoli (n = 5), multiple organisms (n = 4), Klebsiella spp. (n = 3), and other gram-negative rods (n = 3). Clinically, the satisfactory response rate was 9.6/32 (81% ) with amikaein and g6/31 (84%) with gentamiein. Microbiological response rates eorrelated with elinieal response. ! n the amikacin group, 26/32 (81%) were ieured, 5/32 (16%) relapsed, and 1/32 (3%) !were reinfeeted. In the gentamiein group, 26/ !31 (84%) were cured, 2/31 (6%) relapsed, and ii3/31 (10 % ) were reinfected. Gilbert, Eubanks, and Jackson 82 treated 30 ~patients who had UTIs in association with bladider catheters and other urologic abnormalities iwith either gentamiein 3-4 mg/kg/d (n = 15) ~0r amikaein 9 mg/kg/d (n = 15). Twenty-two i~atients had pyelonephritis; 18 of these were ini~fected with R aeruginosa. In the amikacin ~group, 10/15 (67 %) were cured, 1/15 relapsed, ~and 4/15 (27 % ) had reinfeetion/superinfection. iln the gentamicin group, 9/15 (60%) were l~ured, 3/15 (20%) had bacterial persistence, !imd 3/15 (20 % ) had superinfection/reinfeetion. These data suggest that in patients with eomplilcated urologic conditions, recurrence of baete:lriuria is relatively common. Smith et al. 83 compared gentamicin with i~'amikaein in 174 ~atients with various infec~ions. Of these, on~ly 71 eases were evaluable. ilFhere were 18 cases of UTI in the gentamiein t~oup and 24 cases in the amikaein group. I Fhere was no difference in response rates beliween these agents. Gentamiein has also been compared with sis5miein in the treatment of patients with eom~lieated UTIs. 84 These agents were adminis~tered in a dose of 1 mg/kg intramuscularly ~wiee daily for a mean duration of approximately seven days. In the sisomicin group (n = ~egu)s_~atohv?g22simclpudepnE=c~1)1' (Klebsile~'ay~°_

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terobaeter spp. (n = 5), and E aeruginosa (n = 2). In the gentamiein group (n = 21), pathogens ineluded E. eoli (n = 9), Proteus-Provideneia spp. (n = 6), Klebsiella-Enterobaeter spp. (n = 1), and R aeruginosa (n = 5). At two weeks post-therapy, cure was achieved in 22/25 (88 %) sisomiein- and 13/21 (61%) gentamieintreated patients (p = 0.05). Two failures and 1 relapse occurred with sisomiein therapy, and 2 failures, 2 reinfeetions, and 4 superinfeetions occurred with gentamiein therapy. No relationship between patient, disease, or bacterial species characteristics eould be found to aeeount for this difference. However, initial antibiotic sensitivity of the pathogen did have an influence on outcome. Two of 3 unfavorable sisomicin and 3/8 unfavorable gentamicin responses o c c u r r e d w h e n t h e MIC of t h e pathogen was > 3/xg/mL of the antimierobial. In these eases, the baeterieidal activity in the urine was < 1:2 despite adequate urine concentrations of the antimierobial, reflecting the high MIC of the pathogen. Netilmicin has been eompared with amikaein in a randomized study of 21 patients with unspecified types of UTI. 85 Amikaein was given in a dose of 7.5 mg/kg every twelve hours (n = 6), while netilmiein was administered in a dose of 2 mg/kg every eight hours (n = 15). In the amikaein group, 3 were cured, 1 failed, and 1 was reinfeeted, while in the netilmiein group, 7 (47 % ) were eured, 5 failed, and 3 beeame reinfeeted. One patient who received amikaein died of other causes and was not included in the assessment. In another study, netilmiein was eompared with amikaein in 57 eases of UTI in male patients with underlying prostatic hypertrophy, strieture, urologic malignancy, or obstruction. 8~ The dose of amikaein was 7.5 mg/kg every twelve hours for seven to ten days while that of netilmiein was 2 mg/kg every twelve hours. At the end of therapy, 9.8/29 (97 % ) netilmiein- and 25/28 (89%) amikaein-treated patients had a negative urine culture. At one week follow-up in the netilmiein group, 69 percent (20/29) were eured, 17 percent (5/29) had relapsed, and 14 percent (4/9.9) became reinfeeted/superinleered. In the amikaein group, the figures were 57 pereent (16/29), 11 pereent (3/28), and 32 pereent (9/28), respeetively. Comparative randomized clinical trials with aminoglyeosides have primarily addressed the treatment of complicated UTI. With the exception of one study, s4 the aminoglyeosides were of 9

equal efficacy in producing a bacteriologic cure. Due to the underlying urinary tract abnormalities in many of these cases, relapse or reinfection after an initial favorable response was common, indicating the need for close follow-up during the post-treatment period. Noneomparative Clinical Trials Amikacin

A summary of the experience with amikacin in the treatment of UTI has been published. 87 A total of 322 cases including unspecified UTI (n = 238), acute UTI (n = 45), and chronic UTI (n = 39) were reviewed. The amikacin dose, duration of therapy, and underlying urologic conditions were not specified. The overall response rate was 289/322 (90 %), and consisted of cure in 90 percent of unspecified UTIs, 95 percent of acute UTIs, and 79 percent of chronic UTI cases. Fifty-two cases of chronic UTI involved gentamicin-resistant pathogens. Ninety percent (47/52) were cured with amikatin. The response rates for all pathogens were excellent. The clinical response rate by pathogen was 75 percent (9/12) for Provideneia spp., 80 percent (44/55) for P. aeruginosa, and 87 percent (33/38) for Proteus spp. (indole-positive). The clinical response rate for all pathogens (E. eoli, P. mirabilis, Klebsiella spp., Enterobacter spp., Serratia spp., Citrobacter spp., Pseudomonas spp., multiple pathogen infections) exceeded 90 percent. The successful use of amikacin in treating complicated UTI has been reported. 81,ss 91 Mathias et al. 88 used amikacin in a dose of 7.5 mg/kg given every twelve hours to treat 29 cases of UTI, including acute pyelonephritis (n = 19, 5 bacteremic) and catheter-related UTI (n = 10). The latter cases all involved patients with paralysis, while an additional 3 patients had structural abnormalities and 2 had diabetes. Twelve cases of pyelonephritis were caused by E. coli, while catheter-related UTIs w e r e caused by Pseudomonas spp. (n = 6) and Providencia/Morganella spp. (n = 4). Clinically, all 19 patients with pyelonephritis responded (although 5 received oral antibiotic following amikacin). Microbiologically, 16/17 cases with an initial pathogen responded; in 1 patient with R aeruginosa resistance developed. At four-week follow-up, 13/17 evaluable cases had no clinical recurrence. However, 1 became reinfected, 1 relapsed (with E. coli), 1 died of other causes

10

before follow-up, and 1 was the prior bacteriologic treatment failure. In the catheter-related UTI group, 8/9 suseeptible pathogens were eradicated with treatment; in 1 resistance to the antibiotic developed, 4/8 patients with initial eradication became reinfeeted; and 1 relapsed (R aeruginosa). Doughty, Martin, and Greenberg 89 used amikaein 12-15 mg/kg/d for a mean of 12.9 days to treat 39 eases of UTI. Thirty-three eases were associated with complicating urinary tract conditions. Pathogens included R rettgeri (n = 29) and E. coli (n = 10), all of which were resistant to gentamiein and tobramycin. The pathogen was eradicated in 33/39 (85%) eases and persisted in 6/39 (15 %) eases. Hoeffler, Koeppe, and Demers ~° used an amikaein dose of 250 mg four times daily for ten days to treat 22 eases (9 males) of UTI associated with chronic uropathy or nephropathy. Pathogens were not specified. Sixty-four pereent (14/22) were cured at the fourteen-day follow-up. Leonard, McGee, and Alford Q1used an amikaein dose of 15 mg/kg/d to treat 10 symptomatic UTIs (3 bacteremie) in patients with bladder catheters (n = 10), calculi/strictures (n = 6), or urinary tract abscesses (n = 2). Clinically, all 10 responded to therapy, while bacteriologically 6/10 had the pathogen eradicated at follow-up. In 4 patients, the initial pathogen returned in a colonizing capacity (they relapsed during the first month after therapy). Cox 8~ used amikacin 7.5 mg/kg every twelve hours for a mean of 8.3 days to treat 50 eases of complicated UTI in 36 male patients. Eighteen cases were classified as lower tract and 32 as upper tract UTIs. Infecting organisms included Pseudomonas spp. (n = 15), E. coli (n = 12), and other gram-negative bacilli (n = 23). All but 4 patients had underlying urologic abnormalities. At the completion of therapy, the clinical cure rate was 43/50 (86%), while the microbiological cure rate was 46/50 (92 %). At the six-week follow-up visit, 3 eases had relapsed and 4 had become reinfeeted, for a longterm cure rate of 86 percent (43/50). Tobramycin

A summary of UTIs treated with tobramycin has been reported. 6~ Most were serious, complicated or reeurrent, and eonsisted of pyelonephritis (n = 282), cystitis (n = 177), and unspecified UTI (n = 287). The dose of tobramyein varied between less than 1 to greater than 3 mg/kg/d administered once, twice, or three

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times daily. The most common pathogens were E coli (n = 277), Pseudomonas spp. (n = 157), and Klebsiella Enterobaeter-Serratia spp. (n = 111). At five to fourteen-day follow-up, the overall satisfactory clinical response rate was 691/746 (93 %) in pyelonephritis, 170/177 (96 % ) in cystitis, and 258/287 (90 %) in unspecified UTI. The microbiological response was evaluated in 691 cases. There was an 84 percent (579/691) eradication rate, an 8 percent (54/ 691) recurrence rate, and an 8 percent (58/691) reinfection rate. Patients with asymptomatic bacteriuria were also treated with tobramyein; there was a 78 percent (57/73) non-recurrence rate and a 22 percent (16/73) recurrence rate. :Tobramycin therapy has been evaluated in ~hree other studies2 T M Landes 92 administered tobramyein 160-200 mg IM every twenty-four hours for fifteen days to 90 patients with UTI. Patients had serum ereatinine values < 1.5 mg/ !dL and blood urea nitrogen (BUN) _<25 mg/ idL. The overall clinical response rate was satisifaetory in 80/90 (89 070) cases. The mierobiologihal cure rate was 75 percent (68/90), the recur~ence rate was 7 percent (6/90), 9 percent (8/90) Sere reinfected, and 9 percent (8/90) persisted. i} Twenty-five cases of severe UTI (cystitis, n = 3; pyelonephritis, n = 6; epidido-orchitis, n !~ 4'' other, n = 2) were treated with tobramy~'m 3 mg/kg/d in two divided doses. 93 Patients ~ith renal impairment were not included in the !~iudy. Thirteen cases were uncomplicated, i~hlle 3 had bacteremia and 9 had urinary tract !'~bstruction E coli (n = 8), R mirabilis (n = 16ii R aeruginosa (n = 5), and other bacteria (n : ~ 2 ) were the causative pathogens. At the eom~i~Ietion of therapy, 24/25 patients (96 °7o) had a !inical cure, while all 25 had a microbiological are. : Altueei et al. 9 4 used tobramyein 80-120 mg ~iee daily for seven to fifteen days to treat 21 ases of UTI. E. eoli (n = 10), P. aeruginosa (n i 5), indole-positive Proteus spp. (n = 4), and her gram-negative bacilli (n = 2) were the ~usative bacteria. The satisfactory response ~ate was 15/21 (71% ), with 3/21 failures and 3/ 1 reinfections at follow-up. ?tilmicin

Jahre, Fu, and Neu 9~ administered netilmicin mg/kg every twelve hours for five to ten days ii~ the treatment of UTI in 13 patients. Caus!a i e bacteria included P. aeruginosa (n = 5), ~i marcescens (n = 4), E. coli (n = 2), and i~her (n = 4) Treatment resulted in cure in 11/

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13 cases and failure in 2/13 cases. Panwalker et al. 96 used netilmicin doses of 4.5-7.5 mg/kg/d in 12 cases of UTI (3 cases of pyelonephritis). All 15 pathogens (Klebsiella-Enterobacter spp., n = 7; E. coli, n = 4; other, n = 4) were eradicated, with no relapse at four-week follow-up. Five of these cases involved bacteremia. Gentamicin

Cox 97 reported the results of gentamicin therapy in 58 cases (34 males) of UTI (acute pyelonephritis, n = 9; chronic pyelonephritis, n = 30; chronic cystitis, n = 12; chronic prostatitis, n = 7). Doses ranged between 1.0-5.4 mg/kg/d given for five to thirty-three days (80% received treatment for 6-10 days). The overall clinical response rate at the end of therapy was 41/58 (71%) cured, 14/58 (24 %) improved, and 3/58 (5 %) failed. Microbiological outcome was not stated. Labovitz, Levison, and Kaye9s treated 21 cases of UTI with gentamicin doses of either 160 mg every twenty-four hours (n = 11) or 60-80 mg every eight hours (n = 10) for eight to f i f t e e n days. All p a t i e n t s h a d s e r u m creatinine levels < 1 . 5 mg/dL. The predominant pathogen was E. coli (n = 13). Overall, the cure rate was 10/11 with the once-daily regimen and 8/10 with the thrice-daily regimen. The open clinical trials with aminoglycosides confirm the usefulness of these agents in the treatment of UTIs. Response rates in some studies appeared higher t h a n those reported in the comparative clinical trials. In studies in which the inclusion of complicated UTIs was documented or the outcome at one or more weeks post-therapy was assessed, results were comparable to those obtained in the comparative clinical trials. Conclusion Recently, n u m e r o u s parenteral fl-lactam antibiotics have challenged the role of the aminoglyeosides in the treatment of UTIs. The fi-laetams are relatively safe agents and possess potent antimierobial activity. However, they are not optimal pharmaeokinetieally for the treatment of complicated urologic infections (e.g., pyelonephritis). In the infected patient with a complicating underlying urologic condition or an indwelling catheter, the microbiology of UTI may be complex. Multiple pathogens may be involved, ineluding P. aeruginosa and enteroeoeeus. However, m a n y of t h e n e w e r fl-laetams are

11

TABLE V. Feature

Distinguishing features of aminoglycosides Gentamicin

Tobramycin

+ + + + + + + + + + + + + +

+ + + + + + + + + + + + + + +

+ + + + + + + +

+ + + + + + +

Microbiology E. eoli Serratiaspp. P. aeruginosa Enzyme stability Synergy Toxic potential Nephrotoxieity Vestibular toxicity Coehlear toxicity Adapted from Cunha. n

ineffective against R aeruginosa. Beeause of prior antibiotie exposure and institutional resistance problems, the patient w i t h complicated nrologie infections m a y also be infected w i t h multiply resistant pathogens. In these situations, an aminoglycoside provides r a p i d and complete baeterieidal aetivity against susceptible baeteria. In addition, inducible fl-laetamases m a y render initially effective fl-laetam agents useless. Aminoglycosides, however, are not subjeet to these problems. T h e aminoglycosides reach high concentrations intrarenally in the urine, and even w h e n relatively low doses are administered, provide a w i d e therapeutie index at the site of infection in the urinary tract. TABLE VI.

Netilmicin + + + + +

+ + + + +

+ + + + +

+ + + + + + +

Amikaein + + + + +

+ + + + +

+ + + + +

+ + + + +

+ + + + + + +

W h e n given at systemic doses that reach target t h e r a p e u t i c levels, aminoglycosides are also effective in treating the b a c t e r e m i a t h a t frequently accompanies eomplieated urinary tract infections. T h e initial antibiotic choice in patients w i t h pyelonephritis m a y be guided b y a gram stain of the urine. If organisms other than gram-negative baeilli (such as enterococei) are present, then a c o m b i n a t i o n of an aminoglyeoside and a penicillin derivative or v a n c o m y c i n will generally provide optimal coverage until the p a t h o g e n is identified. T h e choice of a particular aminoglyeoside for empiric use depends on pharmaeokinetics, organism involved, institutional suseeptibility

Current perspectives on aminoglycoside usage in urology

Type of Therapy Prophylaxis Monotherapy Combination therapy

Treatment of suspected or established infection Monotherapy

Combination therapy Urosepsis

Definitive

Indications Positive urine culture in patients undergoing transurethral resection of prostate Procedures (e.g., urinary catheterization, prostateetomy) associated with enteroeoeeal endocarditis in high-risk patients (e.g., heart disease, prosthetic heart valve, prior history of infective endocarditis) (with ampicillin or vancomyein) Cardiac prosthetie valve surgery (with vaneomyein) Gram-negative urosepsis G r a m - n e g a t i v e p e r i t o n i t i s associated w i t h chronic ambulatory peritoneal dialysis

Sepsis (organism unknown) from GU traet (with ampieillin or vaneomyein) Serious enteroeoccal infections (e.g., endoearditis, urosepsis) (with ampieillin, penieillin or vancomyein). Any serious pseudomonal infection (with an antipseudomonal ~-laetam)

Adapted from Cunha31

lg

UROLOGY / JULY 1990 / VOLUMEXXXVI, NUMBER 1

patterns, toxicity potential, and cost to the institution (Table V). Aminoglycosides have proved effective and reliable for the initial empiric management of serious and complicated cases of urinary tract infections. Although newer parenteral agents continue to vie with the aminoglycosides for a place in the therapeutic armamentarium, it is doubtful that aminoglycosides will be displaced in urology in the near future. Current perspectives on aminoglycoside usage in urology are summarized in Table VI. Infectious Disease Division Winthrop-University Hospital Mineola, New York 11501 References i!i. Kreger BE, et ah Gram-negative bacteremia: IV. Reevaluali~fl of clinical features and treatment of 612 patients, Am J Med ~i~8:344 (1980). !~2. Childs 8J: Perioperative prevention of infection in genitourinary surgery, Anhblot Chem 33:1 (1985). ~ 3 Daniel TM and Selman A. Waksman and the first use of :t~eptomycin, J Lab Clin Med 95:133 (1988). ~i}}4. Pancoast SJ: Aminoglycoside antibiotics in clinical use, Med {~iin North Am 72:581 (1988). : 5 , Hancock RE: Ammoglycoslde uptake and mode of action ~tth special reference to streptomycin and gentamicin. I. Antago{~i}tSand mutants, J Antimicrob Chemother 8:249 (1981). !!~6. Hancock RE: Aminoglycoside uptake and mode of action i~i[h special reference to streptomycin and gentamicin. II. Effects !~6f aminoglycosides on cells, J Antimicrob Chemother 8 : 4 2 9 ~i 71 Moellering RC: In-vitro antibacterial activity ot the i~ ~inoglycoside antibiotics, Rev Infee Dis 5:212 (1983). 8. Bryan LE, and Van Den Elzen HM: Effects of membrane~ iergy mutations and cations on streptomycin and gentamiein in tsceptibte and resistant bacteria, Antimicrob Agents Chemother

i163 (1977). ~, Verklin RM, and Mandell GL: Alteration of effectiveness of !ibiotics by anaerobiasis, J Lab Clin Med 89:65 (1977). 10. Moellering RC Jr: Clinical microbiology and the in-vitro :ivity of aminoglycosides, in Whelton A, and Neu HC (Eds): e Aminoglycosides: Microbiology, Clinical Use, and Toxicity. ~wYork, Marcel Dekker, Inc, 1982, pp 65-96. !!. Cunha BA: Aminoglycosides: current role in antimicrobial !~~rapy, Pharmacotherapy 8 : 3 3 4 (1988). ~2. Ristuccia AM, and Cunha BA: The aminoglycosides, Med in Nortrh Am 66:303 (1982). il}?I3: Sanders CC, Sanders WE Jr, and Goering RV: In-vitro i~idies with Sch 21420 and Sch 22591: activity in comparison ~ '[h Six other aminogly cosides and syner gy with penicillin a gainst g~erococci Antimicrob Agents Chemother 14:178 (1978). i~i4. Courvalin t~ and Carlier C' Resistance towards aminogly~¢iside-aminocvelitol: ~ antibiotics in bacteria, J Antimicrob Che~other 8:57 (1981). . , !I~51 Davies J. Resistance to aminoglycosides: mechanisms and equency, Rev Infect Dis (suppl 2) 5:s261 (1983). !6. Bryan LE Shahrabadi MS, and Van Den Elzen HM: Gen~icin resistance in Pseudomonas aeruginosa: R-factor mediated i!stance, Antimicrob Agents Chemother 6:191 (1974). t7. Dickie P Bryan LE, and Pickard MA: Effect of enzymatic ~nylation on'dihydrostreptomycin accumulation in Escheriehia ! ~arrying an R-factor: model explaining aminoglycoside resist~ b y inactivating mechanisms Antimicrob Agents Chemother ~569 (1978).

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18. Jackson GG: Recent status of aminoglycoside antibiotics and their safe, effective use, Clin Ther h 200 (1977). 19. Hare RS, and Mller GH: Mechanisms of aminoglycoside resistance, Antimicrob Newslett 1:77 (1984). 20. Young LS, and Hindler J: Aminoglycosides: a worldwide experience, Am J Med 80:15 (1986). 21. PhiIips I, King A, and Shannon K: Prevalence and mechanisms of aminoglycoside resistance, Am J Med 8 0 : 4 8 (1986). 22. Mayer K: Review of epidemic aminoglycoside resistance worldwide, Am J Med 8 0 : 5 6 (1986). 23. Saavedra S, Vera D, and Ramirez-Ronda CH: Susceptibility of aerobic gram-negative bacilli to aminoglycosides--effeets of 45 months of amikacin as first-line aminoglycoside therapy, Am J Med 80:65 (1986). 24. Ruiz-Palacios GM, et ah ControI of emergence of multiresistant gram-negative bacilli by exclusive use of amikaein, Am J Med 80:71 (1986). 25. van Lnduyt HW, et ah Surveillance of aminoglycoside resistance-European data, Am J Med 80:76 (1986). 26. Gerding DN, and Larson TA: Resistance surveillance programs and the incidence of gram-negative bacillary resistance to amikacin from 1967 to 1985, Am J Med 80:22 (1986). 27. Levine JF, et al: Amikacin-resistant gram-negative bacilli: correlation of occurrence with amikacin use, J Infect Dis 151:295

(1985). 28. Miles AA, and Maskell JP: The neutralization of antibiotic action by metallic cations and iron chelators. J Antimicrob Chemother 17" 481 (1986). 29. Bodem CM, et ah Endobronchial pH. Revelance of aminoglycoside activity in gram negative bacillary pneumonia, Am Rev Resp Dis 127:30 (1983). 30. Barza M, and Lauermann M: Why monitor serum levels of gentamicin? Clin Pharmacokinet 3:202 (1978)• 31. Somani P, et ah Unidirectional absorption of gentamicin from the peritoneum during continuous ambulatory peritoneal dialysis, Clin Pharmacol Ther 32:113 (1982). 32. de Paepe M, et ah Peritoneal pharmacokinetics of gentamiein in man, Clin Nephrol 19:107 (1983). 33. Chamberlain G, and Needham P: The absorption of antibiotics from the bladder, J Urol 116:172 (1976). 34. Lifschitz MI, and Denning CR: Safety of kanamycin aerosol, Clin Pharmacol Ther 12:91 (1971). 35. Odio W, Vanleier E, and Klastersky J: Concentrations of gentamicin in bronchial secretions after intramuscular and endotracheal administration, J Clin Pharmacol 15:518 (1975). 36. Rahal JJ Jr, et ah Combined intrathecal and intramuscular gentamicin for gram-negative meningitis, N Engl J Med 290:1394

(1974). 37. Tan JS, and Salstrom SJ: Levels of carbenicillin, ticarcillin, cephalothin, cefazolin, cefamandole, gentamicin, tobramycin and amikacin in human serum and interstitial fluid, Antimicrob Agents Chemother 11:698 (1977). 38. Gordon RC, Regamey C, and Kirby WMM: Serum protein binding of the aminoglycoside antibiotics, Antimicrob Agents Chemother 2:214 (1972). 39. Briedis DJ, and Robson HG: Cerebrospinal fluid penetration of amikacin, Antimicrob Agents Chemother 13:1042 (1978). 40. Pennington JE: Penetration of antibiotics into respiratory secretions, Rev Infect Dis 3:67 (1981). 41. Alexander MR, et al: Bronchial secretion concentrations of tobramycin, Am Rev Resp Dis 125:208 (1982). 42. Taryle A, et ah Antibiotic concentratiorts in human parapneumonic effusions, J Antimicrob Chemother 7:171 (1981). 43. Bermudez RH, et al: Amikacin sulfate levels in human serum and bile, Antimicrob Agents Chemother 19:352 (1981). 44. Dee TH, and Kozin F: Gentamicin and tobramycin penetration into synovial fluid, Antimicrob Agents Chemother 12:548 (1977). 45. Contrepois A, et ah Renal disposition of gentamicin, dibekacin, tobramyein, netilmicin, and amikacin in humans, Antimicrob Agents Chemother 27:520 (1985). 46. Bergeron MG: Therapeutic potential of high renal levels of aminoglycosides in pyelonephritis, J Antimicrob Chemother 16:4

(1985).

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47. Jaffe G, Meyers BR, and Hirschman SZ: Pharmacokineties of tobramyein in patients with stable renal impairment, patients undergoing peritoneal dialysis, and patients on chronic hemodialysis, Antimierob Agents Chemother 5:611 (1974). 48. Madhaven T, et ah Effect of renal failure and dialysis on the serum concentration of the aminoglyeoside amikacin, Antimierob Agents Chemother 10:464 (1976). 49. Moore RD, Smith CR, and Lietman PS: The association of aminoglyeoside plasma levels with mortality in patients with gram-negative baeteremia, J Infect Dis 149:443 (1984). 50. Moore RD, Smith CR, and Lietman PS: Association of aminoglyeoside plasma levels with therapeutic outcome in gramnegative pneumonia, Am J Med 77:657 (1984). 51. Moore RD, Lietman PS, and Smith CR: Clinical response to aminoglyeoside therapy: importance of the ratio of peak coneentration to minimal inhibitory concentration, J Infect Dis 155: 93 (1987). 52. Lesawr TS, et ah Gentamicin dosing errors with four commonly used nomograms, JAMA 248:1190 (1982). 53. Zaske DE, et al: Wide interpatient variations in gentamicin dose requirements for geriatric patients, JAMA 248:3122 (1982). 54. Zaske DE, Cipolle RJ, and Strate RJ: Gentamicin dosage requirements: wide interpatient variations in 242 surgery patients with normal renal function, Surgery 87:164 (1980). 55. Tulkens PM: Nephrotoxicity of aminoglyeoside antibiotics, Toxicol Lett 46:107 (1989). 56. L'Hommedieu CS, Huber PA, and Rasch DK: Potentiation of magnesium-induced neuromuscular weakness by gentamicin, Crit Care Med l h 55 (1983). 57. L'Hommedieu C, et al: Potentiation of neuromuscular weakness in infant botulism by aminoglycosides, J Pcdiatr 95: 1065 (1979). 58. Sanders DB, et ah Intercostal muscle biopsy studies in myasthenia gravis: clinical correlations and the direct effects of drugs and myasthenic serum, Ann NY Acad Sci 377:544 (1981). 59. Pittinger CB, and Adamson R: Antibiotic blockade of neuromuscular function, Ann Rev Pharmacol 12:169 (1972). 60. Lietman PS: Aminoglycosides and spectinomycin: aminoeyclitols, in Mandell GL, Douglas RG Jr, and Bennett JE (Eds): Principles and Practice of Infectious Diseases. 2nd ed, New York, John Wiley & Sons, 1985, pp 192-206. 61. Brummett RE, Meilde MM, and Vernon JA: Ototoxicity of tobramycin in guinea pigs, Arch Otolaryngol 94:59 (1971). 62. Theopold HM: Comparative surface studies of ototoxic effects of various aminoglycoside antibiotics on the organ of corti in the guinea pig, Acta Otolaryngol (Stockh) 84:57 (1977). 63. Johnsson L-G, et ah Aminoglycoside-induced cochlear pathology in man, Acta Otolaryngol [Suppl] (Stockh) 383:1 (1981). 64. Koitchev K, et ah Spiral ganglion changes after massive aminoglycoside treatment in the guinea pig, Acta Otolaryngol (Stockh) 94:431 (1982). 65. Igarashi M: Vestibular ototoxicity in primates, Audiology 12:337 (1973). 66. Bendush CL, and Weber R: Tobramycin sulfate', a summary of worldwide experience from clinical trials, J Infect Dis 134:219 (1976). 67. Moore RD, Smith CR, and Lietman PS: Risk factors for the development of auditory toxicity in patients receiving aminoglycosides, J Infect Dis 149:23 (1984). 68. Edwards CQ, et ah Concentrations of gentamicin and amikacin in human kidneys, Antimicrob Agents Chemother 9: 925 (1976). 69. Kuhar MJ, Mak LL, and Lietman PS: Localization of 3Hgentamicin in the proximal renal tubule of the mouse, Antimicrob Agents Chemother 15:131 (1979). 70. Silverblatt F], and Kuehn C: Autoradiography of gentamicin uptake by rat proximal tubular cell, Kidney Int 15:335 (1979). 71. Smith CR, et ah Controlled comparison of amikacin and gentamiein, N Engl J Med 296:349 (1977). 72. Smith CR, et ah Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin, N Engl ] Med 302:1106 (1980).

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UROLOGY

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JULY 1990

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VOLUME XXXVI, NUMBER 1