A Meta-Analysis of the Relative Efficacy and Toxicity of Single Daily Dosing Versus Multiple Daily Dosing of Aminoglycosides

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1 796 A Meta-Analysis of the Relative Efficacy and Toxicity of Single Daily Dosing Versus Multiple Daily Dosing of Aminoglycosides Mirza Zaki Ali and Matthew Bidwell Goetz From the Department ofmedicine, Wilkes-Barre Veterans Affairs Medical Center, Wilkes-Barre, Pennsylvania; and the Department of Medicine, West Los Angeles Veterans Affairs Medical Center, Los Angeles, California We performed a meta-analysis of the efficacy and toxicity of single daily dosing (SOD) vs. multiple daily dosing of aminoglycosides and summarized the results of the four previously published metaanalyses on this subject. Our analysis showed that the overall clinical response rate favored son therapy (mean difference, +3.06%; 95% confidence limit [CLl, +0.17% to +5.95%; P =.04). However, we found no significant difference in the overall microbiological response rates (mean difference, +1.25%; 95% CL, -0.40% to +2.89%) or in the clinical response rates (mean difference, +0.62%; 95% CL, -2.48% to %) when patients who received adjunctive antimicrobial therapy were excluded from the analysis. No significant differences were found in the incidences of nephrotoxicity, ototoxicity, or vestibular toxicity; the summary differences in the rates of these toxicities were -0.18% (95% CL, -2.17% to +1.81%), +1.38% (95% CL, -0.99% to +3.75%), and -3.05% (95% CL, % to +4.59%), respectively. These results are similar to those of the previously published meta-analyses. The use of aminoglycosides for the treatment of gram-negative infections is associated with important advantages including rapid bactericidal activity, synergy with,b-lactam agents, and low acquisition costs. On the other hand, the use ofaminoglycosides is limited by their nephrotoxicity and ototo.~icity, the need for frequent dosing, and the cost of monitoring serum drug concentrations. Consequently, there has been considerable interest in devising strategies that might preserve the antimicrobial activity, reduce or eliminate the toxicity, and simplify the administration of these antibiotics. In particular, investigators have focused on alternative dosing schemes, wherein the total daily dosage of aminoglycosides is given as one dose per day (single daily dosing [SDD]) rather than as the conventional multiple daily dosing (MDD) regimen. See editorials on pages Data from in vitro studies, animal studies, and clinical trials indicate the potential usefulness of SDD of aminoglycosides. The higher peak serum concentrations achieved with SDD are associated with increases in the rate and magnitude of aminoglycoside microbicidal activity as well as the duration of inhibition of bacterial regrowth after the aminoglycoside concentration falls below the MIC for susceptible gram-negative pathogens (the postantibiotic effect [PAE]) [1-8]. Similarly, Received 6 March 1996; revised 12 September Reprints or correspondence: Dr. Matthew;Bidwell Goetz, Chief, Infectious Diseases, West Los Angeles Veterans Affairs Medical Center (liif), Wilshire Boulevard, Los Angeles, California Clinical Infectious Diseases 1997;24: This article is in the public domain. animal models of gram-negative pneumonia [3, 9] and softtissue infection [5, 10] have demonstrated that the same total daily aminoglycoside dose can be more effective when given as a single large dose than as frequent small doses. In addition, the intracellular accumulation of aminoglycosides by the proximal renal tubular cells and cochlear hair cells demonstrate saturable kinetics [11, 12]. Indeed, it has been observed that less drug accumulates in the renal cortex when patients undergoing elective nephrectomy are given a single dose of an aminoglycoside rather than the equivalent dose in a continuous infusion over 24 hours [13, 14], and animals receiving SDD regimens rather than MDD regimens manifest less nephrotoxicity [15-18] and ototoxicity [19-21]. The routine use of SDD of aminoglycosides requires robust evidence that such therapy is no less clinically or microbiologically effective and no more toxic than is traditional MDD therapy. Only when such evidence is available can the decreased costs of administration and drug preparation and the increased convenience of SDD justify its use. Despite the publication of numerous prospective randomized clinical trials of SDD vs. MDD of aminoglycosides, substantial questions remain as to clinical usefulness of SDD-particularly regarding difficult-to-treat infections such as those due to Pseudomonas aeruginosa or those in neutropenic patients. Furthermore, since the incidence of aminoglycoside-related nephrotoxicity is -15% and that of ototoxicity is -10% [22-24], only studies that include patients can assure with an 80% probability that SDD does not result in a doubling ofthe rates ofthese toxicities [25]. To gain further insights as to the relative usefulness of SDD vs. MDD of aminoglycosides, we performed a meta-analysis of the published clinical literature. We also compared the results of our meta-analysis with those of the previous analyses.

2 em 1997;24 (May) SDD vs. MDD ofaminoglycosides 797 Table 1. Criteria for inclusion or exclusion of studies in a metaanalysis of the relative efficacy of single daily dosing vs. multiple daily dosing of aminoglycosides. Inclusion criteria Aminoglycosides used for treatment of infection (at any site) rather than for prophylaxis SDD of an aminoglycoside vs. dosing of the same agent two-tothree times per day Intravenous or intramuscular administration of aminoglycosides Equal daily aminoglycoside doses in patients receiving SDD and MDD regimens Prospective, randomized allotment of patients to SDD or MDD regimens Exclusion criteria Inclusion of children < I year of age Duplicate reporting (only final or most detailed report included) Failure to separately report complete numerator and denominator outcomes data for patients receiving SDD and MDD regimens NOTE. MDD = multiple daily dosing; SDD = single daily dosing. Although four prior meta-analyses have been published [26-29], these analyses vary in terms of the criteria used to select studies for evaluation and the statistical methodologies used to assess the relative efficacy and toxicity of SDD vs. MDD. Materials and Methods We performed searches of MEDLINE for all Englishlanguage citations published between 1966 and January 1996 with use of the key words aminoglycosideslonce-a-day, oncedailylsingle-doselsingle-daily-dose; we also searched for articles about specific aminoglycosides (i.e., gentamicin, tobramycin, netilmicin, amikacin, and kanamycin). Two medical librarians performed the search independently. In addition, we searched the published literature, including the reference lists of the four previously published meta-analyses [26-29], for references that did not appear in the MEDLINE searches. Finally, we sought the advice ofother experts in the field regarding the existence of other manuscripts and abstracts. All studies of humans treated with an SDD regimen were examined. The criteria used to include or exclude studies for further analysis are shown in table 1. We separately analyzed the clinical and antimicrobial efficacy of SDD and MDD of aminoglycosides. In an effort to more accurately gauge the efficacy of SDD versus MDD for serious infections, we performed separate analyses of patients who did or did not receive other antimicrobials with potential activity against aerobic gram-negative bacteria. We also reanalyzed the data after excluding studies in which aminoglycosides were administered intramuscularly, the use of adjunctive antimicrobial therapy was uncontrolled, the majority ofpatients were treated for urinary tract infections, or the response to antimicrobial therapy per se was difficult to assess because of concomitant surgical intervention for the treatment of acute intra-abdominal infections. We separately analyzed the rates of nephrotoxicity, auditory toxicity, and vestibular toxicity among patients who received an SDD or MDD regimen. We analyzed only toxicity data from studies that provided explicit definitions for the categorization of the development of toxicity. For all outcome categories, we required that specific numerator and denominator data be separately reported for patients receiving an SDD or MDD regimen. All data were extracted by both of us, and we held discussions to resolve all disputes regarding the quality of the studies and data extraction. Unless otherwise specified, all summary statistics were generated with use of the random effects model for combining evidence [30]. We chose this approach to avoid assumptions regarding the homogeneity of the designs, sample sizes, and patient populations enrolled in the various studies [30, 31]. However, as among-study variance increases, this method tends to weight au studies equally, regardless of sample size [31]. Thus, for purposes of comparison, we also used a fixed effects model [30]. We assessed the rate differences in outcomes to measure the actual differences in efficacy and toxicity with SDD vs. MDD regimens [30]. To include studies in which all patients responded clinically or microbiologically or in which there were no nephrotoxic or ototoxic reactions to either SDD or MDD, we used a continuity correction for which a value of one-half was added to the observed number of events in both exposed and control groups [32]. We used the Q statistic, a X 2 measure ofthe null hypothesis of inhomogeneity, to assess for the heterogeneity of treatment effects across the studies included in this meta-analysis [30]. We used both the Qu statistic (which assumes that the sampling variances of the individual studies are equal) and the Qw statistic (which makes no such assumption). When either Q statistic indicated that there was significant interstudy heterogeneity (P <.05), we excluded outlying studies and assessed whether such changes affected the summary estimate of the difference between the efficacies or toxicities of SDD and MDD. All P values were two tailed. Results We identified 26 studies that met our inclusion and exclusion criteria [33-58] and that provided evaluable data. We also included data from a preliminary report of one study [59], which provided microbiological outcomes that were not available in the final report [49]. One evaluable study included data on patients < 12 months of age [45]; however, we excluded these data from our analysis (the average age of the remaining patients in that study was 33 years). No other study explicitly evaluated SDD vs. MDD of aminoglycosides in children. In another instance [47], additional demographic data and infor-

3 798 Ali and Goetz em 1997;24 (May) Table 2. Studies of patients receiving single daily dosing (SDD) vs. multiple daily dosing (MDD) of aminoglycosides that were excluded from meta-analysis of SDD vs. MDD. Reference [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] [72] Reason for exclusion Preliminary reporting of data in [49] Recapitulation of data in [47] Recapitulation of data in [47] Preliminary reporting of data in [47] SDD group received 160 mg of gentamicin daily, whereas MDD group received mg of gentamicin daily SDD group received 150 mg of netilmicin daily, whereas MDD group received 300 mg of netilmicin daily Preliminary reporting of data in [38] Recapitulation of data in [42] Inability to separately analyze outcomes associated with therapeutic vs. prophylactic use of aminoglycosides Inability to separately analyze outcomes for patients>12 months of age vs. those < 12 months of age Preliminary reporting of data in [58] Systematic use of different adjunctive therapy in patients receiving SDD or MDD; no evaluable toxicity data Preliminary reporting of data in [36] Preliminary reporting of data in [48] mation regarding study design were obtained from other sources [60, 61]. Finally, supplemental information was obtained from the authors of one study ([54]; 1. Leggett, personal communication). Table 2 lists all studies that we excluded and that were not listed in the references to the previous meta-analyses [26-29] as well as studies that were evaluated in these previous reports but failed to meet our inclusion criteria. The inclusion and exclusion criteria for the studies included in our analyses are shown in table 3. Intramuscular therapy was given to some or all patients in six of these studies [35, 37, 38, 40, 42, 44]. All patients in three studies [35, 38, 41] and the majority of patients in one study [40] underwent primary surgical intervention for the treatment ofintra-abdominal infections. All patients in two studies [33, 44] and the majority of patients in two other reports [46,49] had urinary tract infections. All patients in two studies [50, 53] and more than half of all patients in another [37] were neutropenic. In one study each, all patients had gram-negative bacteremia [39] or pelvic inflammatory disease [47] or required treatment in an intensive care unit [45]. Finally, 90% of enrolled patients in one study had either a urinary tract infection or pelvic inflammatory disease [56]. Only three studies specified that no adjunctive antimicrobial therapy could be administered [33, 39, 44]. In seven other studies [35, 37, 38,41,43,47, 54), all patients received identical adjunctive antimicrobial therapy. In one study, the patients receiving an SDD regimen were systematically given antimicrobial therapy different from that given to those receiving an MDD regimen [50]. We excluded the data from this study from our efficacy analyses but included them in our analyses of toxicity. Receipt of an SDD or MDD regimen was not the basis for administrating differing adjunctive antimicrobials in any other study. Various algorithms were used to adjust aminoglycoside dosing in accordance with serum aminoglycoside concentrations in 16 studies [34-36, 39, 41-43, 45, 48-50, 52, 54-58]. Table 4 summarizes the demographic data and the designs ofthe evaluable studies. Although no demographic data were provided in one study [49], the authors reported that these data were similar to those presented in an interim report [59]. The treatment allocation was blinded in only two studies [38, 57]. Studies represented both single-center [33-35, 37, 39, 42-48, 51-53,56-58] and multicenter investigations [36,38,40,41, 49, 50, 54, 55]. Clinical outcomes. Twenty-one evaluable studies [35-43, 45-49, 51-56, 58] provided data comparing the clinical outcomes for patients who received either SDD or MDD ofaminoglycosides. In several ofthese studies, patients were explicitly excluded if they had infections due to aminoglycoside-resistant microorganisms [36-39, 49], if they were retrospectively deemed not to have a bacterial infection [36,40-42,49,53], or ifthey died ofnoninfectious causes [51]. Four studies provided clinical outcome data for patients with gram-negative infections who received no antibiotic with activity against gram-negative bacteria other than the aminoglycoside under study [35, 38, 39,41]. We considered patients documented to have superinfections [43] and postoperative wound infections [35, 38] to have been treated successfully and patients for whom clinical outcomes were "indeterminant" [54-56] to have been treated unsuccessfully. Otherwise, we accepted the original criteria for clinical success used in each study. All but two studies [47, 52] provided objective criteria defining clinical success. As shown in figure 1, the rates offavorable clinical outcomes for patients with gram-negative infections who received SDD ofaminoglycosides as the sole effective antimicrobial treatment were equivalent to those for patients who received MDD (mean difference, +0.62% in favor of SDD; 95% confidence limit [CL], -2.48% to +3.71%). In contrast, analysis of studies in which patients did receive effective adjunctive antimicrobial therapy revealed that the summary response rate significantly favored SDD (mean difference, +4.58%; 95% CL, +0.89% to +8.26%; P =.02). When the results ofall studies were pooled, the clinical response rates continued to favor SDD (mean difference, +3.06%; 95% CL, +0.17% to +5.95%; P =.04). The clinical outcomes in all studies and in the subset of studies of patients with gram-negative infections that were treated with aminoglycosides alone were homogeneous, as judged by both the Qw and Qu statistics. However, the Qw statistic indicated that there was significant heterogeneity (P <.05) in the subset of studies of patients who received effective adjunctive antimicrobial therapy. Exclusion of one study [37] eliminated the heterogeneity without significantly altering the results of this analysis.

4 em 1997;24 (May) SDD vs. MDD of Aminoglycosides 799 Table 3. Design of studies analyzed in meta-analysis of single daily dosing vs. multiple daily dosing of aminoglycosides. Reference Inclusion criteria Exclusion criteria [33] [34] [35] [36] [37] [38] [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] [49] [50] [51] [52] [53] [54] [55] [56] [57] [58] UTI in cancer patients receiving radiation or cytostatic therapy Suspected infection warranting treatment with an aminoglycoside Gangrenous or perforated appendix in patients undergoing appendectomy Severe bacterial infection Suspected sepsis; temperature, > 38SC; and myelodysplasia, leukemia, lymphoma, or other malignancy Purulent skin/soft-tissue infection, septicemia, intra-abdominal infection, or radiographically documented lower respiratory tract infection Clinically suspected bacteremia (specifically included patients with septic shock) Sepsis or intra-abdominal infection, upper urinary tract infection, lower respiratory tract infection, or obstetrical/gynecologic infections warranting aminoglycoside therapy Bacteriologically proven intra-abdominal infections or gross perioperative intra-abdominal soiling with intestinal contents Adult with sepsis or bone infection, joint infection, soft-tissue infection, intra-abdominal infection, or "severe" upper urinary tract infection Suspected or confirmed infection for which aminoglycoside and cephalosporin therapy was indicated Urinary tract infection in cancer patients Confirmed gram-negative bacteremia; lower respiratory tract infection; wound infection in ICU patients Confirmed gram-negative infection Laparoscopically documented uncomplicated PID Suspected or confirmed infection warranting aminoglycoside therapy Suspected or confirmed gram-negative infection warranting aminoglycoside therapy Temperature, ;" 38 C; PMNs, < 1.0 X 10 9 /L Probable gram-negative infection warranting aminoglycoside therapy Serious infection Temperature, >38 C; suspected infection; PMNs, < 1.0 X 10 9/L. Suspected gram-negative infection Suspected infection warranting treatment with an aminoglycoside Suspected gram-negative infection Suspected gram-negative infection Suspected or confirmed infection warranting aminoglycoside therapy NA Creatinine level, >3.4 mg/dl; creatinine clearance, <20 mlimin NA Previous renal failure; age, < 18 years; pregnancy; netilmicin-resistant pathogen; aminoglycoside allergy Creatinine level, > 4.0 mg/dl; prior auditory or vestibular disease; aminoglycoside therapy within the previous 14 d; antibiotic therapy within the previous 2 d; pregnancy; nursing; body weight, < 45 kg; aminoglycoside allergy; or age, < 18 y "Severely abnormal renal function"; prior auditory or vestibular disease; pregnancy; PMNs, < 1.0 X 10 9/L; age, < 15 y* Creatinine level, > 2.7 mg/dl; dialysis dependent; prior auditory or vestibular disease; PMNs, < 1.5 X 10 9/L; pregnancy; life expectancy, < I mo; aminoglycoside allergy; age, <18 y Creatinine level, > 1.3 mg/dl; body weight, < 50 kg or > 75 kg; age, < 16 Y Preexisting renal insufficiency; progressive auditory or vestibular disease; PMNs, 1.5 X 10 9/L; aminoglycoside therapy within the prior 5 d; pregnancy; nursing; aminoglycoside allergy; age, < 14 Y Estimated creatinine clearance, < 60 mlimin; pregnancy Creatinine level, > 3.4 mg/dl; effective antibiotic therapy within prior 72 h; life expectancy, < I month; age, < 19 y Creatinine level, > 2.0 mg/dl Creatinine level, > 1.8 mg/dl; creatinine clearance, < 50 mlimin; dialysis; prior auditory, vestibular, or neuromuscular disease; concomitant gram-positive infection or fungal infection; aminoglycoside or,b-iactamallergy; age, < I Y Creatinine level, > 2.0 mg/dl; PMNs, < 1.0 X 10 9/L; aminoglycoside therapy within the prior 2 w; aminoglycoside allergy; "critically ill patients" Creatinine level, > 12.0 mg/dl; preexisting hearing loss (;" 50 db); "severe unrelated pathology"; aminoglycoside therapy within the prior 15 d; concurrent therapy with nephrotoxic or ototoxic drugs; active UTI or middle ear infection Creatinine level, > 3.4 mg/dl; estimated creatinine clearance, < 30 mlimin; prior auditory or vestibular disease; PMNs, < 1.0 X 10 9 /L; pregnancy; aminoglycoside allergy; age, < 16 y Creatinine clearance, < 25 mlimin; prior auditory disease; aminoglycoside therapy within prior mo; PMNs, < 1.0 X 10 8/L; life expectancy, < 1 mo Creatinine level, > 3.4 mg/dl; dialysis; parenteral antibiotic therapy within the preceding 4 d; pregnancy; nursing; obvious noninfectious cause of fever; aminoglycoside or,b-iactam allergy Creatinine level, > 2.0 mg/dl; PMNs, < 1.0 X 109/L;prior hearing loss or vestibular disease; aminoglycoside therapy within the prior 2 w; pregnancy; aminoglycoside allergy; life expectancy, < 2 w Creatinine level, > 1.5 mg/dl; known renal disease; diabetes mellitus; severe immunosuppressive disease; diuretic use Creatinine level, > 1.4 mg/dl; known otologic disease; receipt of aminoglycoside or other nephrotoxic drugs within the preceding 4 w; aminoglycoside allergy; age, <18 y or >75 y Creatinine clearance, < 30 ml/min; penicillin allergy; age, ~ 18 Y Creatinine level, > 1.5 mg/dl; known auditory disease; aminoglycoside treatment within the preceding 4 w; pregnancy; aminoglycoside allergy; age, < 16 y Creatinine level, > 1.5 mg/dl; known auditory disease; PMLs, < 0.5 X 10 9 /L; receipt of aminoglycoside or other nephrotoxic drugs within the preceding 4 w; pregnancy; septic shock; age, < 16 Y Creatinine level, > 2.4 mg/dl; otologic disease; neutropenia; shock; pregnancy; meningitis Creatinine level, > 2.0 mg/dl; allergy to gentamicin or tobramycin NOTE. ICU = intensive care unit; NA = data not available; PID = pelvic inflammatory disease; PML = polymorphonuclear leukocyte; PMN = polymorphonuclear neutrophil; UTI = urinary tract infection. * Two of the three study sites excluded patients with life expectancies of < 1 month.

5 800 Ali and Goetz em 1997;24 (May) Table 4. Demographic data and design ofstudies included in meta-analysis ofsingle daily dosing vs. multiple daily dosing of aminoglycosides. Minimum duration Minimum duration Mean Dosing Mean initial Mean (d) of therapy for (d) oftherapy for age interval Route of serum creatinine Mean dosage duration of evaluation of evaluation of Reference Aminog1ycoside (y)* (h)* administration level (mg/dl)* (mg/[kg d])* therapy (d)* efficacy toxicity [33] Sm 64/66 24/12 im NA 2/2 t 7.6/7.0 ND NA [34] Amik 65/64 24/12 iv 1.2/1.1 15/15 t ND ND ND [35] Net 37/45 24/8 im 1.1/ /4.5 t 7.0/ [36] Net 69 24/12 iv NA 4.7/ / [37] Net 61/62 24/8 iv NA 4.6/ / [38] Net 40/37 24/8 iv,im NA 4.5/ / [39] Net 59/64 24/8 iv 1.2/ / / [40] Net 39/41 24/8 iv,im NA 5.6/ / [41] Net 51/53 24/8 iv 94/1MI: 5.6/ / [42] Net, Gm 55/60 24/8 im NA 4.5/4.5 t 9.5/ [43] Net 71/70 24/12 iv 61/58 3.9/ / [44] Net 66/66 24/8 iv,im NA 6.0/ /7.0 ND 1 [45] Amik 37/29 24/12 iv 1.1/ / /6.8 3 NA [46] Amik 56/59 24/12 iv NA 15/15 t 9.6/10.4 NA NA [47] Net, Amik 28/28 24/8,12 iv 0.8/ ,14.5/6.6, / [48] Gm 59/59 24/8 iv 1.0/ / / [49]11 Amik 62/62 24/12 iv 1.2/1.1 15/15 t NA 3 NA [50] Amik 30/28 24/8 iv 0.7/ /19.5 t 8.5/8.0 ND 1 [51] Amik 69/63 24/12 iv NA 13.5/ / [52] Gm NA 24/8 iv NA 313 t NA NA NA [53] Net 48/50 24/8 iv 0.8/ / / [54] Gm 53/53 24/8 iv 80/86 287/258# 8.7/ [55] Net 48/48 24/8 iv 1.1/ / / [56] Gm 53/53 24/8 iv NA 4.5/4.5 t 5.6/ ~ [57] Amik, Gm, Tm NA 24/12 iv NA NA NA ND 5 [58] Gm,Tm 70/68 24/12 iv 1.0/0.9 4/4 t 8.7/ NOTE. Amik = amikacin; Gm = gentamicin; NA = data not available; ND = not done; Net = netilmicin; Sm = sisomicin; Tm = tobramycin. * Data for patients receiving single daily dosing/data for patients receiving multiple daily dosing. t Planned rather than actual daily dose. ~ Percentage of normal creatinine level. Creatinine clearance. II Data derived from preliminary report [58]. #Total dose (mg) per patient per day. We did not observe any statistically significant differences in clinical outcomes when we excluded all studies in which intramuscular therapy was given [35, 37, 38,40,42], adjunctive antimicrobial therapy was uncontrolled [36, 40, 42, 45, 46, 48, 49,51-53,55,56,58], or all or most patients had urinary tract infections [49] or surgically treated intra-abdominal infections [35, 38, 40, 41]. All comparative analyses of the clinical response to therapy by the fixed effects model yielded results that were similar to those based on the random effects model. Microbiological outcomes. Sixteen studies provided evaluable data regarding the microbiological outcomes for patients with documented bacterial infections [33, 37-40, 43-46, 48, 51, 54-56, 58, 59]. Several studies excluded patients who had infections due to aminoglycoside-resistant pathogens [37-39, 46, 48, 59] or who died of noninfectious causes [44]. Five studies reported microbiological outcomes for patients with r gram-negative infections who received no antibiotics with activity against gram-negative bacteria other than the aminoglycoside under study [33, 38, 39, 44, 48]. In several studies [38-40,43,45,48,54,55, 59], the microbiological outcomes were explicitly described as indeterminate for reasons including the inability ofthe investigators to reculture a wound that had healed or the inability to obtain further sputum specimens; we counted such patients as microbiological successes. Similarly, we considered patients who were explicitly identified as having had superinfections [33, 38, 40, 43, 48] or as having developed microbial colonization of infected sites [38, 40, 48] to have had successful microbiological responses to treatment of the original infection. Otherwise, we acceptedthe original criteriaused in each study to define microbiological success. As shown in figure 2, the rates of favorable microbiological outcomes among patients with gram-negative infections who received SDD as the sole effective antimicrobial treatment were equivalent to those among patients who received MDD (mean difference, +0.04%; 95% CL, -5.84% to +5.91%). Furthermore, we did not observe any significant differences in the microbiological response rates with SDD vs. MDD of amino-

6 em 1997;24 (May) SDD vs. MDD of Aminoglycosides 801 Clinical response Difference in response rates (±95% Cl) -40% -20% 0% 20% 40% 60%!! [35J [39J [38J [41J Sub-mean (R) [51J [42J [52J [37) [46] [48J [58] [47J [55J [36J [56J [43J [53J [54] [45] [40J [49J Sub-mean (R) Overall mean (R) Overall mean (F) f-- -, e ; ;! the microbiological response to therapy by the fixed effects model yielded results that were similar to those based on the random effects model. Nephrotoxicity. The incidence of nephrotoxicity was reported in all 26 evaluable studies [33-58]. However, we included only the 18 studies that provided objective diagnostic criteria for nephrotoxicity and that specified a threshold for nephrotoxicity of a 0.3 mg/dl increase or a 25% increase in the serum creatinine level. As shown in figure 3, analysis of these studies revealed no significant difference between the incidences of nephrotoxicity in patients who received an SDD regimen rather than an MDD regimen. The summary difference '[48] [44] [33] [39J [38] Sub-mean (R) Microbiological response Difference in response rates (±95% Cl) -40% -20% 0% 20% 40% 60% - Figure 1. Each bar represents the mean difference (2::95% CL) between the clinical response rates to single daily dosing (SDD) and multiple daily dosing of aminoglycosides in a single study. Positive values indicate that the clinical response rates were greater in patients receiving SDD therapy. The top group of bars represents studies of patients with gram-negative infections who received no other active antimicrobials, whereas the lower group depicts the response rates of patients who received adjunctive antimicrobial therapy. The submean presents the summary rate differences for each group of studies, and the overall mean presents summary rate differences for all studies. (R) denotes the random effects mean and (F) denotes the fixed effects mean. From top to bottom within each group, the studies are presented in ascending order of the size of the study population. A total of 378 patients and 1,657 patients were evaluated in the upper group and lower group of studies, respectively. CL = confidence limit. [58] [37J [51J [46] [55J [45] [56J [43] [54] [59] [40J Sub-mean (R) Overall mean (R) Overall mean (F) -,...- -f- -f--- r- - - glycosides in any of the studies in which patients received effective adjunctive antimicrobial therapy (mean difference, %; 95% CL, -0.85% to +3.90%) or when all studies were pooled (mean difference, %; 95% CL, -0.40% to %). Exclusion of studies in which intramuscular therapy was given [37, 38, 40, 44], adjunctive antimicrobial therapy was uncontrolled [40,45,46,48, 51, 55, 56, 58, 59], or all or most patients had urinary tract infections [33, 44, 46, 59] or surgically treated intra-abdominal infections [38, 40] did not alter the conclusions of any of these analyses. The microbiological outcomes of both categories of studies individually and when pooled were homogeneous, as judged by both the Qu and Qw statistics. All comparative analyses of Figure 2. Each bar represents the mean difference (±95% CL) between the microbiological response rates to single daily dosing (SDD) and multiple daily dosing ofaminoglycosides in a single study. Positive values indicate that the microbiological response rates were greater among patients receiving SDD therapy. The top group of bars represents studies of patients with gram-negative infections who received no other active antimicrobials, whereas the lower group depicts the response rates of patients who received adjunctive antimicrobial therapy. The submean presents the summary rate differences for each group of studies, and the overall mean presents summary rate differences for all studies. (R) denotes the random effects mean and (F) denotes the fixed effects mean. From top to bottom within each group, the studies are presented in ascending order by the size of the study population. A total of 351 patients and 915 patients were evaluated in the upper group and lower group of studies, respectively. CL = confidence limit.

7 802 Ali and Goetz em 1997;24 (May) [34] [52] [46] [57] [37] [39] [58] [48] [36] [56] [55] [53] [43] [54] [45] [41] [49] [50] Overall mean (R) Overall mean (F) Nephrotoxicity Difference in response rates (±95% Cl) -40% -20% 0% 20% 40% r- - f- +- -f- -f- Figure 3. Each bar represents the mean (:±:95% CL) of the difference between the incidence of nephrotoxicity in patients receiving single daily dosing (SDD) and multiple daily dosing of aminoglycosides for each study that provided defined criteria for the diagnosis of nephrotoxicity. Positive values indicate that the rate of nephrotoxicity was higher for patients receiving SDD therapy. (R) denotes the random effects mean and (F) denotes the fixed effects mean. From top to bottom within each group, the studies are presented in ascending order by the size of the study population. A total of 2,519 patients were evaluated in these studies. CL = confidence limit. in the rates ofnephrotoxicity was -0.18%, favoring SDD (95% CL, -2.17% to +1.81%). We also observed equivalent rates of nephrotoxicity after we excluded studies in which patients were given intramuscular therapy [46] or uncontrolled adjunctive antimicrobial therapy [34, 36, 45, 46, 48-50, 52, 53, 55-58]. The Qw and Qu statistics showed homogeneity in all analyses, and all comparative analyses performed with the fixed effects model yielded the same conclusions as those based on the random effects model. Reported risk factors for nephrotoxicity included the trough serum aminoglycoside level [41,43,48,49], prolonged duration of therapy [41, 48, 49], relative renal insufficiency on initiation of therapy [48-50], increased patient age [41, 50], the severity ofunderlying diseasesj41], and the use of diuretics [49]. In one study [43], increased trough serum concentrations of aminoglycosides were a risk factor for nephrotoxicity in patients receiving SDD but not in those receiving MDD. An- other study [58] showed that increased peak serum concentrations were a risk factor for nephrotoxicity with SDD but not with MDD. Finally, in one study the onset of nephrotoxicity occurred later in the course of therapy with SDD than with MDD [50]. Ototoxicity. The incidences of auditory toxicity were provided in 17 reports [33, 35-38, 40, 42-44, 46-50, 54-56]. However, we included in our analysis only the 12 studies that provided objective diagnostic criteria for auditory toxicity and that specified at least a 15-dB hearing loss at any frequency as the threshold for auditory toxicity. As shown in figure 4, analysis ofthese studies revealed no significant difference between the incidences of auditory toxicity among patients who received SDD regimens and those who received MDD regimens. The summary difference in the rates of auditory toxicity was +1.38% (95% CL, -0.99% to +3.75%), favoring MDD therapy. [57] [44] [48] [36] [42] [54] [46] [43] [47] [55] [50] [49] Overall mean (R) Overall mean (F) Auditory toxicity Difference in response rates (±95% Cl) -40% -20% 0% 20% 40% ~ Figure 4. Each bar represents the mean (:±:95% CL) ofthe difference between the incidence of auditory toxicity in patients receiving single daily dosing (SDD) and multiple daily dosing of aminoglycosides for each study that provided defined criteria for the diagnosis of auditory toxicity. Positive values indicate that the rate of auditory toxicity was higher for patients receiving SDD therapy. (R) denotes the random effects mean and (F) denotes the fixed effects mean. From top to bottom within each group, the studies are presented in ascending order by the size of the study population. A total of793 patients were evaluated in these studies. CL = confidence limit.

8 em 1997;24 (May) SDD vs. MDD of Aminoglycosides 803 Equivalent rates of ototoxicity were also observed after studies in which patients were given intramuscular therapy [46] or uncontrolled adjunctive antimicrobial therapy [36, 42, 46, 48-50, 55, 57] were excluded. The incidences of auditory toxicity were homogeneous, as judged by both the Qu and Qw statistics. In the one study that addressed the issue of serum aminoglycoside concentrations and ototoxicity, there was no association between the peak or trough serum aminoglycoside concentrations and the development of ototoxicity in patients receiving SDD or MDD regimens [50]. Comparative analyses performed with the fixed effects model also demonstrated equivalent rates ofauditory toxicity in patients receiving either SDD or MDD regimens. Objective testing for vestibular toxicity was assessed in only two studies [42, 49], whereas subjective, or undefined, testing was done in three others [33, 37, 50]. The summary difference between the rates of vestibular toxicity in the two studies that included objective testing favored SDD therapy, but this difference was not statistically significant (mean rate difference, %; 95% CL, % to +4.59%). None of the patients receiving SDD or MDD aminoglycoside regimens in either of these studies received controlled adjunctive antimicrobial treatment. In addition, one study of comprehensive vestibular function found equivalent toxicity in healthy volunteers given single daily doses or multiple daily doses oftobramycin for 9 days [73]. Other data. We found that there were no differences in the incidences of hepatotoxicity [39, 50], nausea or vomiting [40, 50], hypokalemia [50], or neuromuscular toxicity [43, 45, 53] among patients receiving single daily doses of aminoglycosides vs. those receiving multiple daily doses. No significant correlation was observed between any outcome and the specific choice of aminoglycoside therapy or between any outcome and the age of the patients in the study. Serum aminoglycoside concentrations. Although the rates of toxicity were not significantly increased for patients receiving single daily doses of aminoglycosides, as expected, these patients did have higher peak serum concentrations ofthe drug than did patients who received multiple daily doses. Amikacin serum concentrations were reported in six studies [45-47, 49-51]. Peak amikacin serum concentrations in patients receiving SDD ranged from 24.0 j1g/mlto 55 j1g/ml, whereas MDD resulted in peak concentrations that ranged from 5.5 j1g/ml to >40 j1g/ml. Trough concentrations for amikacin varied from 0.8 j1g/ml to 10.1 j1g/ml with SDD and from 1.5 j1g/ml to 4.7 j1g/ml with MDD. In the nine studies in which serum netilmicin concentrations were reported [35, 38, 39, 41, 43, 44, 47, 53, 54], peak netilmicin concentrations ranged from 12.4 j1g/ml to "-'30 j1g/ml with SDD, whereas they ranged from 4.9 j1g/ml to 15.3 j1g/ml with MDD. The trough concentrations for netilmicin ranged from 0.2 j1g/mlto 1.7 j1g/mlwith SDD and from < 1 j1g/ml to 3.0 j1g/ml with MDD. In the studies that reported gentamicin serum concentrations [48,52,54,56,58], the mean peak concentrations ranged from 7.7 j1g/ml to 22.0 j1g/ml with SDD and from 3.3 j1g/ml to 7.3 j1g/ml with MDD, whereas the corresponding trough values ranged from 0.6 j1g/ml to 0.9 j1g/ml with SDD and from 0.9 j1g/ml to 2.5 j1g/ml with MDD. Discussion For our primary examination of the studies included in this meta-analysis, we used a random effects model to assess differences in efficacy and toxicity ofsdd vs. MDD of aminoglycosides. With use of this model, we found a small but statistically significant difference in clinical response rates, which favored the use of SDD rather than MDD (mean difference, +3.06%; 95% CL, +0.17% to +5.95%; P =.04). A significant difference was also observed in the subset of studies in which effective adjunctive antimicrobial therapy was given (mean difference, +4.58%; 95% CL, +0.89% to +8.26%; P =.02) but not in the studies in which aminoglycosides were given as the sole effective therapy (mean difference, +0.62%; 95% CL, -2.48% to +3.71%). Although the subset of studies that included patients who did receive adjunctive antimicrobial therapydemonstrated significant interstudy heterogeneity, this heterogeneity was entirely due to the inclusion of one study [37] that demonstrated a superior clinical response rate among patients who received an SDD regimen. When we excluded this study from the analysis, the differences between the clinical response rates to SDD vs. MDD of aminoglycosides remained significant. None of our other analyses based on the random effects model demonstrated any statistically significant difference in efficacy and toxicity between SDD and MDD regimens. We found no difference in the microbiological response rates among patients who did or did not receive additional effective antimicrobial therapy for infections due to aerobic gramnegative bacteria. In addition, we found no statistically significant difference between the incidences ofnephrotoxicity, auditory toxicity, and vestibular toxicity among patients who received single daily doses rather than multiple daily doses of aminoglycosides. Finally, no studies demonstrated differences in the incidences ofhepatotoxicity, nausea or vomiting, hypokalemia, or neuromuscular toxicity. We also evaluated the relative efficacy of SDD vs. MDD after we excluded all studies in which patients received intramuscular therapy or studies in which the majority of patients had urinary tract infections or surgically treated intra-abdominal infections. All these analyses showed that SDD and MDD were clinically and microbiologically equivalent. To control for variations due to concomitant antimicrobial therapy, we also assessed the relative efficacy and toxicity of SDD vs. MDD after we excluded studies in which patients receiving single daily doses or multiple daily doses of aminoglycosides were given uncontrolled adjunctive antimicrobial therapy. Once again, we found no significant difference in the efficacy

9 804 Ali and Goetz em 1997;24 (May) Table 5. Inclusion and exclusion criteria used in previous meta-analyses of single daily dosing vs. multiple daily dosing of aminoglycosides. Reference [26] [27] [28] [29] Inclusion criteria Randomized trials of SDD vs. MDD of aminoglycosides Randomized trials of SDD vs. MDD of aminoglycosides in infected immunocompetent patients Randomized trials of SDD vs. MDD of aminoglycosides in infected patients Randomized trials of SDD vs. MDD of aminoglycosides in infected nonneutropenic adults with clinical or bacteriologic symptoms of infection (published in English) Exclusion criteria NA Studies in which > 50% of patients had lower UTIs; trials of antimicrobial prophylaxis Trials with different total daily doses in the treatment arms and trials of antimicrobial prophylaxis; trials in which patients receiving SDD and MDD of aminoglycosides were systematically given differing adjunctive antimicrobial therapy were excluded from efficacy analyses; trials in which patients were allowed to receive amphotericin B were excluded from the meta-analysis of nephrotoxicity Case reports, reviews NOTE. MDD = multiple daily dosing; SDD = single daily dosing; UTI = urinary tract infection. and toxicity of SDD vs. MDD. Finally, we did not find a correlation between increasing age and the relative incidence of nephrotoxicity or auditory toxicity among patients receiving SDD regimens rather than MDD regimens. In comparative analyses, we used a fixed effects model to assess differences in the efficacy and toxicity of SDD vs. MDD of aminoglycosides. This approach demonstrated the clinical superiority of SDD when all study results were pooled, as well as the clinical and microbiological superiority of SDD when effective adjunctive therapy was given. In all ofthe previously mentioned subanalyses, the fixed effects model yielded similar results with respect to the direction of differences between SDD and MDD, as did the subanalyses based on the random effects model. The previous meta-analyses of SDD regimens vs. MDD regimens differ in several regards. First, the authors of the other meta-analyses reported the difference between SDD andmdd in terms of a risk or odds ratio, whereas we analyzed the absolute percent difference in outcome. Furthermore, as shown in table 5, the authors of all prior meta-analyses used different criteria for the selection of evaluable studies. Because of the differences in selection criteria and time frames used to select evaluable studies, each of these meta-analyses was an assessment of a unique set of studies (table 6). Finally, the previous meta-analyses differed in terms of outcome measures. For all of these analyses, the original investigators' definitions of clinical and/or microbiological success were used, with little or no modification. Two analyses [26, 28] were based on the definitions ofauditory toxicity used in the original reports, and one analysis [26] was based on the definitions of nephrotoxicity used in the original investigations. Otherwise, all of the meta-analyses, including the,' present one, required that nephrotoxicity be defined as an increase in the serum creatinine level of ~0.3 mg/dl or ~25% and that auditory toxicity be defined as a hearing loss of ~ 15 db at any frequency. As shown in table 6, we explicitly included several studies that other investigators either did not cite [55, 57, 58] or excluded because aminoglycosides were administered intramuscularly [35,42], randomization was not applied [47], data were reported inadequately [54], or patients with neutropenia [33, 37, 50, 53] or urinary tract infections [46] were included. It is important to note that we obtained further data on one preliminarily reported study [54] and used ancillary sources [61] to ensure that patients were randomized [47]. We also performed subanalyses after we excluded studies in which the majority of patients had urinary tract infections or surgically treated infections so that we could better assess the efficacy of SDD regimens vs. MDD regimens for more-difficult-to-treat infections. Finally, several studies [59, 61, 63, 64, 67, 68, 71, 72] that we excluded for the reasons shown in table 2 were included in other meta-analyses. A summary of the findings, as reported in each study of the four previous published meta-analyses, is presented in table 7. Where available, we present summary statistics based on both the random and fixed effects models are shown. Each of the analyses indicated that when assessed, clinical response, mortality, and rates of microbiological cure tended to be greater with SDD than with MDD. In several of the reports, the difference between the two regimens in terms of clinical response was statistically significant [28, 29, and the present study]. Similarly, the incidence of nephrotoxicity was consistently lower with SDD and reached statistical significance in one analysis [29]. We did not find any significant differences in the rates of auditory and vestibular toxicity. The clinical applicability of the conclusions of our analysis and those of other meta-analyses is necessarily limited by the design, execution, and reporting of the original investigations. These studies provided little information regarding the outcomes of infections due to specific pathogens, or, other than urinary tract infections [33, 44], of infections at specific ana-

10 cm 1997;24 (May) SDD vs. MDD of Aminoglycosides 805 Table 6. Studies and endpoints evaluated in five meta-analyses of single daily dosing vs. multiple daily dosing of aminoglycosides. Meta-analysis Ferriols-Lisart and Reference Present report Galloe et al. [26] Hatala et al. [27] Barza et al. [28] Alos-Almifiana [29] Comment [33] N C,N,O C,N Excluded Some patients may have been neutropenic [34] N N,O N Excluded [35] C C, N,O Excluded C [36] C,N,A C,M,N,A [37] C,M,N C,N,O C,N Excluded > 50% ofpatients were neutropenic [38] C,M C,N,O C,M C,N C [39] C,M C,N C,M,N,A C,N C,N [40] C,N C,N,O C,M,N C,N C [41] C,N C,N,O C,N,A C,N C,N [42] C,A, V C,N,O Excluded C,N C,N,A [43] C,M,N,A C,N,O C,M,N,A C,N C,N,A [44] M,A Excluded C,N C Some patients may have been neutropenic [45] C,M,N C,M,N C,N C,N [46] C,M,A C,N,O,A Excluded C,N C,N,A [47] C,A Excluded C,A [48] C,M,N,A C,M,N,A C,N C,N,A [49] C,M, N,A, V C,N,A C,N C,N,A [50] N, At Nt Excluded Neutropenic patients [51] C,M C,M C,N C [52] C,N C,N C,N [53] C,N C,N Excluded Neutropenic patients [54] C,M,N,A Excluded [55] C,M,N,A [56] C,M,N C,A [57] N,A [58] C,M,N [59] Excluded C,N,O,A Excluded Excluded Preliminary reporting of data in [49] [61] Excluded C,N,O,A Preliminary reporting of data in [47] [62] Excluded C,M,A C,N Excluded Preliminary reporting of data in [47] [63] Excluded C,N,O Excluded Excluded. [64] Excluded C,N,O Excluded C [67] Excluded Excluded Excluded C [68] Excluded C,N Excluded [71] Excluded Excluded C,N C,N Preliminary reporting of data in [36] [72] Excluded C,N,O,A Excluded Preliminary reporting of data in [48] NOTE. Excluded indicates that the reference was explicitly reviewed and considered not to meet the stated criteria for inclusion of studies in the relevant meta-analysis. Barza et al. [28] indicated that 11 studies were included in analyses of auditory toxicity and eight studies were included in analyses of vestibular toxicity, but these authors did not specifically identify which studies were used in these analyses. Endpoint abbreviations: A = auditory toxicity; C = clinical; M = microbiological; N = nephrotoxicity; 0 = ototoxicity (auditory and/or vestibular); V = vestibular toxicity. Ellipses indicate that reference was not cited. t Included only in toxicity analyses. t Included in subanalyses of nephrotoxicity. Used only for supplemental data not available in the full report [49]. tomic sites. Only one study each provided detailed data regarding clinical or microbiological outcomes for patients with neutropenia [53], those requiring treatment in an intensive care unit [45], or those with gram-negative bacteremia [39]. Although analysis of each of these studies failed to demonstrate a statistically significant difference in the clinical and microbiological outcomes with SDD vs. MDD of aminoglycosides, the confidence limits for these conclusions were broad. In addition, few studies have assessed the relative clinical and microbiological efficacy of monotherapy with SDD regimens or MDD regimens for gram-negative infections [33, 35, 38, 39, 41, 44, 48]. Furthermore, for three of these studies, the efficacy of antimicrobial therapy was augmented by surgical treatment ofintra-abdominal infections [35,38,41], and in two other of these studies, all patients were treated for urinary tract infections [33, 44]. Finally, SDD of aminoglycosides has not been critically evaluated with respect to synergy when it is combined with,b-iactams for the treatment of gram-positive bacteremia. This information is relevant, as some data indicate that MDD of aminoglycosides may provide superior synergy

11 806 Ali and Goetz em 1997;24 (May) Table 7. Summary of outcomes in meta-analyses of single daily dosing vs. multiple daily dosing of aminoglycosides. No. of Outcome studies Microbiological Reference measure included Clinical response* Mortality response Nephrotoxicity Auditory toxicity Vestibular toxicity [26] Relative risk ( ) ND ND ( ) ( ) ND (95% CL)t [27] Risk ratio 17 NDt 0.91 ( ) 1.02 ( ) 0.87 ( ) 0.67 ( ) ND (95% CL) [28] Risk ratio ( ) 0.87 ( ) ND 0.78 ( ) 1.09 ( ) 1.11 ( ) (95% CL) Risk ratio ( ) 0.87 ( ) ND 0.74 ( ) 1.09 ( ) 1.11 ( ) (95% CL)# [29] Odds ratio ** ( ) ND ND 0.60" ( ) 0.56 ( ) ND (95% CL)# [PRJ Percent ( ) ND 1.25 ( ) ( ) 1.38 ( ) ( ) difference (95% CL)* Percent 4.64" ( ) ND 3.03 ( ) ( ) 1.60 ( ) ( ) difference (95% CL)# NOTE. ND = not done; PR = present report. * Differences in success rates were assessed in four studies [26,27,29, PRJ, whereas failure rates were compared in another study [28]. The superiority of SDD therapy is indicated by values of> I in three studies [26, 27, 29], by positive values in the present report, and by values of < I for another study [28]. t Model not specified. t Not calculated because of the large degree of interstudy heterogeneity. Random effects model used. lip <.05. #Fixed effects model used. ** p <.01. in combination with {3-lactams in experimental models of enterococcal endocarditis [74]. Concerns have been raised regarding the efficacy of SDD regimens in patients with neutropenia and in those with infections caused by P. aeruginosa. The PAE of aminoglycosides is decreased in neutropenic animals [1, 2, 75], and unless an SDD regimen is combined with an effective {3-lactam, SDD of aminoglycosides is less efficacious for the treatment of P. aeruginosa infections in neutropenic animals than in nonneutropenic animals [3]. However, we did not find a significant difference in clinical outcomes with SDD vs. MDD in the one evaluable study that included only neutropenic patients [53]; all patients in this study received adjunctive therapy with an antipseudomonal {3-Iactam. In another evaluable study, > 50% of the patients were neutropenic, and all patients were given cefuroxime; the rate of clinical response to a single daily dose of an aminoglycoside was superior to the rate of response when multiple daily doses were given, and the microbiological response rates were equivalent [37]. Furthermore, in another study [50] no significant difference was found in the clinical outcomes for neutropenic patients randomized to SDD p)us ceftriaxone vs. MDD plus ceftazidine. Finally, in regression analyses of the clinical efficacy of SDD vs. MDD, Barza ~t 'at [28] found that the relative advantage of an SDD regimen ~as increased in studies that included neutropenic patients or in which an increased proportion of all infections was caused by P. aeruginosa. SDD of aminoglycosides has not been extensively assessed as monotherapy or as adjunctive antimicrobial therapy for patients who are critically ill or pregnant or have significant prior renal or otologic dysfunction. However, many other patients receive aminoglycosides in combination with other antimicrobials that have activity against aerobic gram-negative pathogens. It is for such patients that our analysis and other metaanalyses have demonstrated that the use of an SDD regimen has at least equivalent clinical and bacteriologic efficacy and no greater nephrotoxicity or ototoxicity (table 7). Although the causes of nephrotoxicity and ototoxicity in patients receiving aminoglycosides are multiple, the narrow confidence limits in these analyses provide reasonable assurance that SDD of aminoglycosides is not intrinsically more toxic than MDD when used for patients who do not have serious preexistent renal or otologic dysfunction. For patients who need therapy with an aminoglycoside, SDD offers potentially important advantages. These advantages include a greater probability of obtaining optimal peak serum concentrations of drug, decreased time spent administrating and preparing the drugs, a decrease in the number of serum assays required due to the superfluity of measuring peak concentrations, and lower expenditures for consumable items used in the daily administration of antimicrobials. The achievement of uniform peak serum aminoglycoside concentrations may be especially important. Previous studies have demonstrated a correlation between the achievement of peak serum drug

12 em 1997;24 (May) SDD vs. MDD of Aminoglycosides 807 concentrations during the first days of therapy and a favorable clinical outcome [76-78]; however, subtherapeutic dosing of aminoglycosides is common [79]. The decreased reliance on peak aminoglycoside concentrations may have an additional benefit: although the timing of these concentrations is critical, 16%-45% of antibiotic administrations differ from the prescribed time by > 1 hour [79]. Despite the relative simplicity of SDD regimens, implementation of these regimens requires selection of dosing regimens for patients with renal impairment and development of protocols for monitoring aminoglycoside serum concentrations [80]. Several guides with respect to these factors have recently been published [81-84]. Despite the reproducible nature ofaminoglycoside peak and trough concentrations with SDD, patients with abnormal renal function who receive therapy for > 5 days as well as those in whom the drugs are eliminated rapidly (e.g., the very young and burn patients) or those in whom the volumes ofdistribution are large may still require monitoring ofaminoglycoside serum concentrations [81]. Since the expected serum concentrations will be higher than the usual range in these patients, care should be taken to use an appropriate assay to measure serum aminoglycoside concentrations [85]. Note Added in Proof Since the submission of this manuscript, two other meta-analyses of the efficacy and toxicity of SDD vs. MDD aminoglycoside dosing have been published [86, 87]. 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