Once-daily aminoglycosides: practical guidelines

Netherlands Journal of Medicine 52 Ž1998. 1–9

Current practice: Invited article

Once-daily aminoglycosides: practical guidelines Jan M. Prins ) , Peter Speelman Academic Medical Centre, Department of Internal Medicine, DiÕision of Infectious Diseases, Tropical Medicine and AIDS, Room F4-221, Meibergdreef 9, Amsterdam 1105 AZ, Netherlands Received 3 April 1997; revised 26 August 1997; accepted 28 August 1997

Abstract There is ample evidence that once-daily dosing of aminoglycosides is preferable to the conventional regimens during the treatment of serious infections. Experimental and clinical studies also provide evidence that this regimen can be safely used in children, neutropenic patients and endocarditis. The use of once-daily tobramycin in cystic fibrosis merits further study, as the pharmacokinetics of the aminoglycosides are altered in these patients. The dose-adjustment strategy in patients with renal failure is still controversial, but reducing the daily dose whilst maintaining the q24-h interval has been demonstrated to be safe. Although the value of serum level monitoring in ensuring efficacy and avoiding toxicity has been overestimated in the past, especially in patients with renal failure, an undesirable accumulation of the aminoglycosides can occur. The best way to detect accumulation remains to be defined. q 1998 Elsevier Science B.V. Keywords: Aminoglycoside; Dosing schedule; Pharmacokinetics; Nephrotoxicity; Ototoxicity

1. Introduction Over the past decades, aminoglycosides have remained a mainstay of therapy for severe Gram-negative infections, with approximately 1–2.5 defined daily dosages ŽDDD. per 100 bed days in the Western European hospitals w1x. The major drawback of this class of antibiotics is their potential for nephroand ototoxicity. Especially the incidence of ototoxicity is often underestimated. For instance, 17.9% of ears screened for ototoxicity after aminoglycoside treatment showed hearing loss, as assessed by con-

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ventional audiometry, whilst this percentage increased to 47% when frequencies up to 20 kHz were also tested w2x. Neuromuscular blockade has been reported, but this is sufficiently rare that clinical concern has focused on nephro- and ototoxicity. An additional problem is the important interpatient variation in pharmacokinetics. Nomograms, which use body weight and estimated creatinine clearance, often result in elevated trough levels or subtherapeutic peak levels w3x. During the past decade, new insights have been gained into the pharmacodynamics, and the pathogenesis of nephrotoxicity of aminoglycosides. As a result, controversy has arisen with respect to the preferred dosage regimen. These antibiotics were usually given thrice daily, but many in vitro and animal studies suggested that a once-daily regimen

0300-2977r98r$19.00 q 1998 Elsevier Science B.V. All rights reserved. PII S 0 3 0 0 - 2 9 7 7 Ž 9 7 . 0 0 0 7 1 - 5

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J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

could reduce the risk of side effects, with equal or even improved efficacy.

2. Rationale for once-daily dosing In addition to the practical advantages Žless labour-intensive, fewer disposables needed., oncedaily dosing has a number of theoretical benefits w4–6x. First, the aminoglycosides display a concentration-dependent bactericidal activity in vitro w7,8x. This means that the higher the serum concentration, the greater the bactericidal activity against susceptible organisms. The aminoglycosides also possess a postantibiotic effect ŽPAE., i.e. a period of suppression of bacterial growth after cessation of exposure of the bacteria to an antibiotic w8,9x. The PAE theoretically protects against bacterial regrowth when the aminoglycoside concentrations fall below the minimal inhibitory concentration. The duration of the PAE appears to be dependent on the AUC andror the serum concentration of the aminoglycoside. The duration of the PAE is enhanced in vivo, but is substantially reduced in the case of granulocytopenia w10x. In summary, the administration of a large dose once daily could maximize the rate of bacterial killing, the PAE preventing regrowth of bacteria during the period of low antibiotic concentration in serum. In addition, with regard to toxicity, once-daily schedules appear to be of benefit. The renal cortical uptake of gentamicin, netilmicin and amikacin Žbut not tobramycin. is saturable, and the renal accumulation of these drugs in humans is less when given in one large dose, rather than in divided doses or by continuous infusion w11,12x. The uptake of tobramycin was not significantly lower in the oncedaily regimen w12x. In animals, the single daily dose resulted in less nephrotoxicity w13–15x. Finally, the observation in a number of animal studies that the uptake of gentamicin in the inner ear tissues is lower with a single injection as compared to the same dose given as a continuous infusion w16,17x also favours once-daily instead of multipledaily dosing or continuous infusion. In a number of animal studies, an advantage with regard to ototoxicity was found for once-daily dosing regimens of gentamicin and amikacin w18–20x. Data from animal

studies with different dosage regimens of tobramycin are conflicting w15,21x. In conclusion, these experimental data suggested that a once-daily regimen could reduce the risk of side effects, with equal or even improved efficacy.

3. Meta-analyses of clinical trials comparing onceand multiple-daily dosing During the past 10 years, a considerable number of clinical studies comparing multiple- versus oncedaily administration of gentamicin, netilmicin or amikacin have been published. During the past 2 years, these studies have been summarized in a number of meta-analyses ŽTable 1. w22–26x. Two meta-analyses concluded that once-daily dosing resulted in a greater rate of clinical cure w23,26x. One meta-analysis reported significantly less nephrotoxicity for once-a-day dosing w24x, while three analyses reported a non-significant trend towards less nephrotoxicity for once-daily regimens w23,25,26x. So, the results of these 5 meta-analyses differ, but none of them reported better results for multiple-daily dosing with respect to either efficacy or toxicity. The different results reached can be explained by the fact that different statistical methods were used, with different criteria for the selection of individual studies w27x. A few restrictions have to be made. In most studies, the number of patients which could be evaluated for ototoxicity was small. In the clinical studies which used audiometry to compare cochleotoxicity, no differences in ototoxicity were seen for the various dosage regimens w6,28–37x. However, in only two studies, more than 100 patients were included w33,36x, and in only three studies, high-tone audiometry was performed w6,28,30x. Differences in vestibulotoxicity were not noticed either. An adverse effect of once-daily as opposed to multiple-daily dosing is, based on these data, unlikely. Second, only three clinical studies comparing once- versus multiple-daily dosing of netilmicin or amikacin have been performed in children w36–38x, and with gentamicin, one small study was reported w39x. In one of these studies, a better clinical and microbiological efficacy was found for the once-daily dosing regimen w38x, whereas in two other studies, efficacy was comparable for the two dosing regi-

Ref. Cure

Nephrotoxicity

w22x Relative chance of cure a

1.03 Ž0.993–1.06.

w23x Clinical cure b

1041r1163 Ž89.5%. Nephrotoxicity b Ž . vs. 929r1097 84.7% P - 0.001

w24x Relative risk of clinical failurea

0.83 Ž0.57–1.21.

Avoidance of nephrotoxicity a

Ototoxicity 1.00 Ž0.980–1.02.

Avoidance of ototoxicity a

73r1617 Ž4.5%. Ototoxicity b Ž . vs. 86r1564 5.5% P s 0.20

1.00 Ž0.986–1.02. 28r674 Ž4.2%. vs. 34r636 Ž5.3%. P s 0.31

Risk of nephrotoxicity a 0.74 Ž0.54–1.00.

P s 0.05 Risk of ototoxicity a 1.09 Ž0.68–1.75.

w25x Relative chance 1.02 Ž0.99–1.05. of bacteriological cure a

Risk of nephrotoxicity a 0.87 Ž0.60–1.26.

Risk of ototoxicity a 0.67 Ž0.35–1.28.

w26x Clinical cure b

Nephrotoxicity b

Ototoxicity b

a b

84.9% vs. 81.4%; difference 3.5% Ž0.5; 6.5%.

P s 0.32

P s 0.027

Relative chance Žor risk. of once-daily compared with multiple-daily treatment. Once- versus multiple-daily treatment.

4.7% vs. 5.9%; diff. 1.3% Žy3.1; 5%.

P s 0.20

6.2 vs. 5.5%; diff. 0.7% Žy3.1;4.5%.

P s 0.85

J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

Table 1 Meta-analyses of studies comparing once- and multiple-daily aminoglycoside dosing

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J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

mens w37,39x. The incidence of nephro- or ototoxicity was the same for both regimens w36–39x. All clinical data taken together, the use of oncedaily regimens seems justified. Less nursing time and therefore less delivery costs with once-daily dosing are additional advantages, and further savings may be achieved if serum-concentration monitoring is reduced Žsee below.. Certain issues have not yet been solved. In the first place, as most studies were performed in nonneutropenic adults, the question is whether once-daily dosing is also justified in neutropenic patients. The same holds true for the treatment of endocarditis and exacerbations of cystic fibrosis. Finally, an important question is how to adjust the daily dose in the case of renal failure and how to monitor therapy.

4. Special patient groups 4.1. Neutropenic patients The duration of the PAE is substantially reduced in the case of granulocytopenia w10x. Therefore, the question is whether it is safe to use a once-daily regimen in neutropenic patients. In three randomized trials in neutropenic patients, clinical and bacteriological cure rates were comparable for once- and multiple-daily regimens w36,40,41x. In all three studies, the aminoglycosides were given in combination with b-lactam antibiotics. These results suggest that in neutropenia, the aminoglycosides can safely be given once-daily, provided that they are combined, as is common practice, with b-lactams. 4.2. Endocarditis Once-daily dosing of aminoglycosides Žusually in combination with b-lactams. was as effective as thrice-daily dosing in a great number of animal models w42x. No comparative studies have been performed in humans. The only data available is a case series describing 52 patients with streptococcal endocarditis, who were treated with a 2-week course of ceftriaxone Ž2 g. plus netilmicin Ž4 mgrkg oncedaily. w43x. The clinical and bacteriological cure rates were comparable with results usually obtained with conventional regimens. Because the efficacy of the

conventional treatment is high in streptococcal endocarditis, and this disease is relatively rare, a comparative clinical trial is not easily feasible. 4.3. Cystic fibrosis Finally, concern has been raised with regard to giving tobramycin once-daily in cystic fibrosis. In the first place, with regard to nephrotoxicity, the reasons for once-daily dosing are less compelling for tobramycin as compared to the other aminoglycosides. In contrast to gentamicin and netilmicin, which have a saturable uptake w44x, the renal cortical uptake of tobramycin is, in animals, linearly related to the steady-state serum concentration w44x. In humans, the uptake of tobramycin was not significantly lower in the once-daily regimen as compared to multiple-daily dosing w12x. Hence, once-daily dosing of tobramycin probably does not result in less nephrotoxicity. Second, and more important, the pharmacokinetics of the aminoglycosides are altered in patients with cystic fibrosis. Especially the total body clearance is higher than in healthy volunteers w45,46x, and this could lead to prolonged low serum levels with oncedaily dosing. ŽTwo other patient categories with an exceptionally rapid elimination rate are intravenous drug abusers w47x and burn patients w48x.. Only a few comparative studies have been done in cystic fibrosis patients with a pulmonary exacerbation. In one study, comprising 29 patients, a conventional 8-h tobramycin regimen was compared with a 12-h regimen w49x. The efficacy and nephrotoxicity of both regimens were the same, whereas a difference in ototoxicity was established in favour of the 12-h regimen. In two other studies Žcomprising 31 and 44 episodes., the efficacy of once-daily dosing and continuous tobramycin dosing w13x, respectively, once- and thrice-daily dosing was the same w50x.

5. Dosing in once-daily regimens As the aminoglycosides are excreted by the kidneys w5x, adjustment of the daily dose in the case of a decreased renal function remains necessary in oncedaily regimens. Two strategies are possible: extension of the interval Žto 36, 48 or ) 48 h.; or a dose reduction whilst maintaining the 24-h interval. As

J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

justification of once- as opposed to multiple-daily dosing, with regard to both efficacy and toxicity, is based on studies in which in the case of renal dysfunction the daily dose was lowered w6,32–35x, we favour a dose every 24 h, with dose-de-escalation in the case of renal dysfunction in order to achieve low serum levels at the end of the dosing interval. Efficacy and safety of the alternative strategy, the use of a fixed dose with a drug administration interval based on estimated creatinine clearance Že.g. 7 mgrkg every 36–72 h w51x., has not been demonstrated in comparison to the former standard of treatment Žmultiple-daily dosing.. In addition, especially in the case of a decreased renal function, this regimen results in prolonged high aminoglycoside serum levels, which is opposed to the rationale of once-daily dosing, i.e the presence of a substantial drug-free interval every 24 h. So far, there is no established dosing schedule for once-daily dosing. We derived a simplified schedule from the Hull and Sarubbi nomogram, for which efficacy and safety in a once-daily dosing regimen was previously demonstrated w6x, and prospectively followed serum aminoglycoside levels in over 200 patients w52x. The standard treatment was gentamicin or tobramycin 4 mgrkg i.v. once daily. When the renal function was decreased, the daily dose was reduced ŽTable 2. w52x. First-trough levels above 2 mgrl were recorded in only 22 of the evaluable 204 patients Ž11%. and all these patients were characterized by a baseline creatinine clearance of less than 50 mlrmin or a substantial decrease in creatinine clearance between enrolment and the day the trough level was obtained. This confirmed earlier reports that in once-daily regimens, elevated trough levels occur especially in the case of deterioration of renal function w32,35,53x. A peak level of less than 6 mgrl

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Fig. 1. First serum trough and peak aminoglycoside concentrations Žmgrl. as a function of initial daily dose Žestimated creatinine clearance above 80 mlrmin, dose of 4 mgrkg; between 50 and 80 mlrmin, 3.25 mgrkg; between 30 and 50 mlrmin, 2.5 mgrkg; and below 30 mlrmin, 2 mgrkg.. The horizontal lines inside the boxes indicate the median value; the boxes represent the 25th to 75th percentiles, and the bars represent the 10th to 90th percentiles. Reprinted with permission from w52x.

Table 2 Reduction of standard daily dose in the case of renal failure

was observed in 11 out of the 185 evaluable patients Ž6%.. Five of them were patients in the group with the lowest daily dose Ž2 mgrkgrday. ŽFig. 1.. So, using this dosing schedule, serum levels are predictable in the vast majority of patients, but especially in patients with an impaired renal function, the monitoring of serum levels remains an important issue.

Estimated creatinine clearance Žmlrmin. a

Daily dose of gentamicin or tobramycin Žmgrkg.

6. Serum level monitoring in once-daily regimens

)80 50–80 30–50 - 30

4.00 3.25 2.50 2.00

a

Estimated by Cockcroft&Gault formula.

In multiple-daily regimens, it is common practice to monitor serum trough and peak levels. However, the importance of achieving these target levels has become a matter of controversy w54x, and recommen-

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J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

dations with regard to serum level monitoring depend on underlying beliefs and assumptions. The first assumption is that achieving sufficiently low trough levels is useful to avoid nephro- and ototoxicity. However, it has always been a question whether elevated serum levels are the cause or result of a declining renal function w6,55x. In an extensive review of the available literature, it was concluded that ‘‘Little evidence supports a direct or causal relation between a specific serum aminoglycoside concentration and the development of nephrotoxicity’’ w54x. Perhaps even more important, monitoring serum levels did not prevent nephrotoxicity either w54x. The assumption in aiming at sufficiently high peak levels is that low peak levels are associated with therapy failure w56–58x. However, in animal models, in the case of aminoglycosides, the most important parameter determining efficacy of bacterial killing is the log 10 AUC Žarea under the concentration–time curve. w59x. After scrutinizing the literature, McCormack and Jewesson concluded that the evidence was insufficient to support a causal relationship between low peak levels and poor treatment outcome w54x. Their objections against the abovementioned studies Žw56–58x. were due to the fact that in these studies, the breakpoint serum levels were determined retrospectively, and, therefore, were liable to bias, and that much of the evidence was conflicting. For instance, in one study, the maximal peak level was identified as the most important factor associated with therapeutic outcome w56x, whereas this was not found in the other two studies w57,58x. In addition, in very ill patients, the volume of distribution increases, resulting in lower peak levels, which may explain why patients with ‘low’ peak levels seem to do worse. So, the value of peak levels is uncertain, and as low peak levels are found in only a very low percentage of patients, it is questionable if it is useful to follow these levels at all. One can argue that these results have been obtained in patients treated with a multiple-daily regimen. We have recently assessed risk factors for nephrotoxicity in 200 patients treated with a oncedaily regimen w52x. Several risk factors for nephrotoxicity were identified, but after multivariate analysis, only the duration of treatment and the use of

other nephrotoxic antibiotics or high-dose furosemide, but not the trough level, were significant, independent risk factors. In two recent studies on once-daily aminoglycoside treatment, no association was found between serum peak levels and treatment outcome either w32,41x. So, also in once-daily regimens, the clinical value of monitoring peak and trough levels appears to be limited. Nevertheless, it remains necessary to identify patients in whom the aminoglycosides accumulate. Accumulation of aminoglycosides is undesirable with regard to ototoxicity, as in animals, total dose and total AUC Žarea under the concentration–time curve. in plasma and perilymph are predictive of ototoxicity w60,61x. One strategy to detect accumulation is to measure trough levels in patients with an estimated creatinine clearance of less than 50 mlrmin and in patients who develop a significant decline in renal function during therapy, as in these patients, trough levels exceeding 2 mgrl can be found w52x. An objection to this strategy could be that a trough level of - 2 mgrl, obtained 24 h after the last dose, does not preclude a significantly prolonged serum half-life and increased AUC, and a maximum acceptable trough level of 1 mgrl, as has been proposed w62x, does not preclude an excessive AUC either. Therefore, Begg et al. constructed a concentration–time curve, based on the maximal AUC permitted, and proposed to take one serum level between 6 and 14 h postdose. If this serum level falls below their curve, an excessive AUC would be unlikely w63x. In the case of renal dysfunction, an additional serum level is required 0.5 h postdose to calculate the AUC. In both cases, the daily dose should be lowered in the case of an excessive AUC. However, whether this is the best way to detect accumulation of aminoglycosides remains to be defined in a prospective study. More importantly, whether dose adjustment indeed prevents ototoxicity, and whether the daily dose should be lowered, or the dosage interval increased in the patients who have elevated ‘trough’ levels, respectively, an excessive AUC, remains to be established. 7. Most important conclusions Ø Once-daily dosing of aminoglycosides is justified in non-neutropenic adults and children.

J.M. Prins, P. Speelmanr Netherlands Journal of Medicine 52 (1998) 1–9

Ø In cystic fibrosis, once-daily dosing is still under investigation. Ø In the case of renal failure, the daily dose should be reduced. Ø Monitoring peak levels is not useful. Ø Monitoring trough levels can be restricted to patients with an impaired renal function.

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