Aminoglycoside-associated Nephrotoxicity Research Articles

2542. Attenuation of Polymyxin and Aminoglycoside-Associated Nephrotoxicity

Abstract Background The clinical use of aminoglycosides and polymyxins to treat multidrug-resistant Gram-negative bacterial infections is hindered by dose-limiting nephrotoxicity. Recently, there has been increased interest in reducing the nephrotoxic potential of these antibiotics to combat the antimicrobial resistance crisis. We identified zileuton, an FDA-approved anti-inflammatory drug, via a virtual screen indicating that it has desirable properties as a potential nephroprotectant. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. Methods Sprague-Dawley rats (n=10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Doses were chosen based on prior pharmacokinetic studies to achieve a systemic exposure comparable to that in humans after a standard dose. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 minutes before antibiotic administration each day. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥ 2x elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was conducted to characterize the extent of renal injury. Results Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100% within 10 days, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton 4 mg/kg and 10 mg/kg, respectively. Additionally, histopathology confirmed reduced renal injury in animals receiving concomitant zileuton. Conclusion This pilot study suggests that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat multidrug-resistant Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and characterize pharmacokinetics to correlate with clinical dosing in humans. Disclosures All Authors: No reported disclosures

The effect of gender on aminoglycoside-associated nephrotoxicity .

The kidney disease improving global outcomes (KDIGO) clinical practice guidelines for acute kidney injury (AKI) has endorsed the widely held belief that female gender is a risk factor for aminoglycoside-associated nephrotoxicity (AAN). In contrast, female gender is protective in animal models. In light of this dichotomy, we sought to explore this relationship in greater detail. We performed a meta-analysis of studies published between 1978 and 2015 which examined aminoglycoside nephrotoxicity and provided gender-specific data. 24 studies were identified that provided univariate gender-specific data. The incidence of AAN did not differ between the sexes (odds ratio (OR) for females vs. males 1.00 (0.81, 1.22), p=0.97, n=5,980). Twelve studies utilized logistic regression analysis with gender as a covariate. Meta-analysis of the 5 studies that utilized multivariate analysis and reported gender-specific OR found no effect of gender on the risk of AAN (OR 0.99 (0.58, 1.69), p=0.96, n=2,994). Similarly, gender was not an independent risk factor for AAN in the remaining 7 studies that utilized multivariate analysis with gender as a covariate but failed to report gender-specific OR (n=1,636). Our meta-analysis contradicts the generally held consensus that female gender is an independent risk factor for the development of AAN. Our findings may have much wider implications insofar as AAN cannot be used as an example to support the conclusion of the KDIGO Clinical Practice Guidelines that female gender is an independent risk factor for AKI. .

Chronopharmacokinetics of once daily dosed aminoglycosides in hospitalized infectious patients.

Background hospitalized patients with serious infections treated with aminoglycosides are at risk of developing nephrotoxicity. Previous clinical studies have shown that the pharmacokinetics of aminoglycosides in humans follow a circadian rhythm. Therefore, the time of administration could have important clinical implications with respect to the risk of developing aminoglycoside-associated nephrotoxicity in patients treated with once daily dosing regimens. Objective To examine the effect of the time period of administration on aminoglycoside exposure and the incidence of nephrotoxicity in a large population of hospitalized patients with serious infections. Setting General ward and intensive care unit of a teaching hospital. Method In this retrospective cohort study, patients treated with intravenous tobramycin or gentamicin were eligible for inclusion. Patients were divided into three groups by time of administration: morning, afternoon and night. Main outcome measure Pharmacokinetic parameters and the incidences of nephrotoxicity were compared between the morning, afternoon and evening groups. Results 310 general ward and 411 intensive care unit patients were included. No significant differences were found in patient characteristics between the morning, afternoon and night groups. The time period of administration did not affect aminoglycoside pharmacokinetics or the incidence of nephrotoxicity. Conclusion The time of administration has no effect on the pharmacokinetics or nephrotoxicity of once daily dosed aminoglycosides in hospitalized patients. Consequently, we advise aminoglycosides to be administered as soon as possible in case of (suspected) severe hospital-acquired infections and subsequent dosages to be based on therapeutic drug monitoring to optimize the efficacy/toxicity balance.

Aminoglycosides in Septic Shock

Aminoglycoside nephrotoxicity has been reported in patients with sepsis, and several risk factors have been described. Once-daily dosing and shorter treatment have reduced nephrotoxicity risk, and simplified aminoglycoside monitoring. This review focuses on nephrotoxicity associated with aminoglycosides in the subset of patients with septic shock or severe sepsis. These patients are radically different from those with less severe sepsis. They may have, for instance, renal impairment due to the shock per se, sepsis-related acute kidney injury, frequent association with pre-existing risk factors for renal failure such as diabetes, dehydration and other nephrotoxic treatments. In this category of patients, these risk factors might modify substantially the benefit-risk ratio of aminoglycosides. In addition, aminoglycoside administration in critically ill patients with sepsis is complicated by an extreme inter- and intra-individual variability in drug pharmacokinetic/pharmacodynamic characteristics: the volume of distribution (Vd) is frequently increased while the elimination constant can be either increased or decreased. Consequently, and although its effect on nephrotoxicity has not been explored, a different administration schedule, i.e. a high-dose once daily (HDOD), and several therapeutic drug monitoring (TDM) options have been proposed in these patients. This review describes the historical perspective of these different options, including those applying to subsets of patients in which aminoglycoside administration is even more complex (obese intensive care unit [ICU] patients, patients needing continuous or discontinuous renal replacement therapy [CRRT/DRRT]). A simple linear dose adjustment according to aminoglycoside serum concentration can be classified as low-intensity TDM. Nomograms have also been proposed, based on the maximum (peak) plasma concentration (Cmax) objectives, weight and creatinine clearance. The Sawchuk and Zaske method (based on the determination of Cmax and an intermediate aminoglycoside assay before minimum plasma concentration) and the Bayesian method were both classified as high-intensity TDM programmes. Given the mean cost of aminoglycoside nephrotoxicity, these programmes may be cost-effective if its prevalence is above 10%. However, none of these high-intensity TDM programmes have demonstrated a reduction of aminoglycoside-associated nephrotoxicity in patients with septic shock. Therefore, the questions remain as to, first, whether a TDM programme is relevant and, second, what intensity of TDM is achievable in the ICU, i.e. how it can be practically applied in the ICU setting where urgent care and high workload are substantial obstacles to a sophisticated, optimized aminoglycoside administration.

Mechanism-Based Urinary Biomarkers to Identify the Potential for Aminoglycoside-Induced Nephrotoxicity in Premature Neonates: A Proof-of-Concept Study

Premature infants are frequently exposed to aminoglycoside antibiotics. Novel urinary biomarkers may provide a non-invasive means for the early identification of aminoglycoside-related proximal tubule renal toxicity, to enable adjustment of treatment and identification of infants at risk of long-term renal impairment. In this proof-of-concept study, urine samples were collected from 41 premature neonates (≤32 weeks gestation) at least once per week, and daily during courses of gentamicin, and for 3 days afterwards. Significant increases were observed in the three urinary biomarkers measured (Kidney Injury Molecule-1 (KIM-1), Neutrophil Gelatinase-associated Lipocalin (NGAL), and N-acetyl-β-D-glucosaminidase (NAG)) during treatment with multiple courses of gentamicin. When adjusted for potential confounders, the treatment effect of gentamicin remained significant only for KIM-1 (mean difference from not treated, 1.35 ng/mg urinary creatinine; 95% CI 0.05–2.65). Our study shows that (a) it is possible to collect serial urine samples from premature neonates, and that (b) proximal tubule specific urinary biomarkers can act as indicators of aminoglycoside-associated nephrotoxicity in this age group. Further studies to investigate the clinical utility of novel urinary biomarkers in comparison to serum creatinine need to be undertaken.

Risk factors for aminoglycoside-associated nephrotoxicity in surgical intensive care unit patients

Background:Aminoglycosides are commonly used antibiotics in the intensive care unit (ICU), but are associated with nephrotoxicity. This study evaluated the development of aminoglycoside-associated nephrotoxicity (AAN) in a single surgical intensive care unit.Materials and Methods:Adult patients in our surgical ICU who received more than two doses of aminoglycosides were retrospectively reviewed for demographics, serum creatinine, receipt of nephrotoxins [angiotensin converting enzyme (ACE) inhibitors, angiotensin-II receptor blockers, diuretics, non-steroidal anti-inflammatory drugs, cyclosporine, tacrolimus, vasopressors, vancomycin and intravenous iodinated contrast] and the need for dialysis. AAN was defined as an increase in serum creatinine >0.5 mg/dL on at least 2 consecutive days. Univariate and multiple regression analyses were performed.Results:Sixty-one patients (43 males) receiving aminoglycoside were evaluated. Mean age, weight, initial serum creatinine, and duration of aminoglycoside therapy were 58.7 (±15) years, 83.3 (±24.4) kg, 0.9 (±0.5) mg/dL, and 4 (±2.3) days, respectively. Thirty-one (51%) aminoglycoside recipients also received additional nephrotoxins. Seven aminoglycoside recipients (11.5%) developed AAN, four of whom required dialysis and all had received additional nephrotoxins. Only concurrent use of vasopressors (P = 0.041) and vancomycin (P = 0.002) were statistically associated with AAN. Receipt of vasopressors or vancomycin were independent predictors of acute kidney insufficiency (AKI) with odds ratios of 19.9 (95% CI: 1.6–245, P = 0.019) and 49.8 (95% CI: 4.1–602, P = 0.002), respectively. Four patients (6.6%) required dialysis.Conclusions:In critically ill surgical patients receiving aminoglycosides, AAN occurred in 11.5% of the patients. Concurrent use of aminoglycosides with other nephrotoxins increased the risk of AAN.

Prevalence and risk factors for aminoglycoside nephrotoxicity in intensive care units.

In order to assess the prevalence of and risk factors for aminoglycoside-associated nephrotoxicity in intensive care units (ICUs), we evaluated 360 consecutive patients starting aminoglycoside therapy in an ICU. The patients had a baseline calculated glomerular filtration rate (cGFR) of > or =30 ml/min/1.73 m(2). Among these patients, 209 (58%) developed aminoglycoside-associated nephrotoxicity (the acute kidney injury [AKI] group, which consisted of individuals with a decrease in cGFR of >20% from the baseline cGFR), while 151 did not (non-AKI group). Both groups had similar baseline cGFRs. The AKI group developed a lower cGFR nadir (45 +/- 27 versus 79 +/- 39 ml/min/1.73 m(2) for the non-AKI group; P < 0.001); was older (56 +/- 18 years versus 52 +/- 19 years for the non-AKI group; P = 0.033); had a higher prevalence of diabetes (19.6% versus 9.3% for the non-AKI group; P = 0.007); was more frequently treated with other nephrotoxic drugs (51% versus 38% for the non-AKI group; P = 0.024); used iodinated contrast more frequently (18% versus 8% for the non-AKI group; P = 0.0054); and showed a higher prevalence of hypotension (63% versus 44% for the non-AKI group; P = 0.0003), shock (56% versus 31% for the non-AKI group; P < 0.0001), and jaundice (19% versus 8% for the non-AKI group; P = 0.0036). The mortality rate was 44.5% for the AKI group and 29.1% for the non-AKI group (P = 0.0031). A logistic regression model identified as significant (P < 0.05) the following independent factors that affected aminoglycoside-associated nephrotoxicity: a baseline cGFR of <60 ml/min/1.73 m(2) (odds ratio [OR], 0.42), diabetes (OR, 2.13), treatment with other nephrotoxins (OR, 1.61) or iodinated contrast (OR, 2.13), and hypotension (OR, 1.83). In conclusion, AKI was frequent among ICU patients receiving an aminoglycoside, and it was associated with a high rate of mortality. The presence of diabetes or hypotension and the use of other nephrotoxic drugs and iodinated contrast were independent risk factors for the development of aminoglycoside-associated nephrotoxicity.

Application of Bayes theorem to aminoglycoside-associated nephrotoxicity: comparison of extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing.

The objective of this study was to examine the incidence of aminoglycoside-associated nephrotoxicity related to extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing by applying Bayes theorem. An electronic literature search of MEDLINE (1966-2003) and a manual search of references from published meta-analyses and review articles were performed. Studies using extended-interval dosing, individualized pharmacokinetic monitoring, or multiple-daily dosing and reported aminoglycoside-associated nephrotoxicity for patients > or = 16 years of age were included. Quality scores were assigned based on the rigor of definition of aminoglycoside-associated nephrotoxicity, duration of therapy, and length of follow-up of renal function after completion of therapy. Inclusion criteria were then based on these quality scores. Quantitative data on the incidence of aminoglycoside-associated nephrotoxicity were abstracted. Twelve extended-interval dosing studies (n = 916), 10 individualized pharmacokinetic monitoring studies (n = 2066), and 27 multiple-daily dosing studies (n = 4251) met the inclusion criteria. Prior probabilities of aminoglycoside-associated nephrotoxicity were derived from a combination of a review of published studies and expert judgment. The maximum densities for the final posterior probabilities of aminoglycoside-associated nephrotoxicity for extended-interval dosing, individualized pharmacokinetic monitoring, and multiple-daily dosing were located at 12% to 13%, 10% to 11%, and 13% to 14%, respectively. Application of Bayes theorem demonstrates that aminoglycoside dosing by individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity than extended-interval dosing or multiple-daily dosing.

Aminoglycoside-associated nephrotoxicity in the elderly.

To determine whether there was an increased incidence of nephrotoxicity in elderly patients (> or =65 y) prescribed single-dose (SD) versus multiple-dose (MD) aminoglycosides and whether aminoglycoside-induced nephrotoxicity was associated with length of therapy and other risk factors. A prospective, observational audit at a university teaching hospital was conducted. Physician prescribing was used to stratify subjects according to dosing regimen: MD (n = 60) or SD (n = 26). Nephrotoxicity was defined as an increase in the serum creatinine level of 0.5 mg/dL sustained over 2 days. Eighty-six patients were included; 9.3% developed nephrotoxicity, of whom 62.5% received SD therapy. The incidence of nephrotoxicity did not differ between regimens (p = 0.051). There was an increased length of therapy in those who developed nephrotoxicity (mean +/- SD 6.1 +/- 6.2 vs. 3.7 +/- 2.8 d; p = 0.044). Additionally, patients who developed nephrotoxicity had an increased length of hospitalization (20.3 +/- 16.1 vs. 8.4 +/- 5.4 d; p < 0.001). Nephrotoxicity correlated with a diagnosis of diabetes mellitus (OR 15.1; 95% CI 1.11 to 205), concomitant angiotensin-converting enzyme (ACE) inhibitor therapy (OR 28.0; 95% CI 2.15 to 365), and SD therapy (OR 20.7; 95% CI 1.45 to 297). Our overall incidence of nephrotoxicity is consistent with that reported in the literature. A diagnosis of diabetes mellitus, concomitant use of ACE inhibitors, and SD regimens were risk factors for the development of nephrotoxicity. An adequately powered, randomized trial is needed to assess whether a difference in the incidence of nephrotoxicity exists between SD and MD therapy in the elderly.

Aminoglycoside-Associated Nephrotoxicity in the Elderly

Aminoglycoside-Associated Nephrotoxicity in the Elderly

Aminoglycoside-Associated Nephrotoxicity in the Elderly

Aminoglycoside-Associated Nephrotoxicity in the Elderly

PID28: COMPARING DIFFERENCES IN CLINICAL EFFECTIVENESS, NEPHROTOXICITY, AND COST-EFFECTIVENESS OF AMINOGLYCOSIDE THERAPY BETWEEN ALTERNATIVE DOSING PROTOCOLS

OBJECTIVE: The objective of this study was to develop a pharmacoeconomic model which compared the difference in cost-effectiveness (CE) between a Multiple-daily-dosing (MDD) protocol of aminoglycosides (AG) managed by a Clinical Pharmacokinetic Dosing Service (CPS) and a protocol for Once-daily-dosing (ODD), from the perspective of a Managed Care Organization. METHOD: Event rates for both clinical effectiveness and aminoglycoside-associated-nephrotoxicity (ANN) for MDD were determined by a retrospective chart review of 262 randomly sampled patients who received gentamicin for the treatment of serious gram-negative bacterial infections between January 1, 1990 and March 30, 1998. The incidence of ANN was 3.1%. Event rates for ODD protocol for both clinical effectiveness and ANN were determined to be 82.2% and 5.8%, respectively based on an extensive review of the current literature. Time-in-motion studies were performed to determine personnel costs for all nursing and pharmacy activities. Decision analysis was used to determine the CE of the two protocols. RESULTS: The results were unexpected based on reports in the literature predicting substantial cost savings with the use of ODD programs. In the base case analysis the expected per patient cost value for MDD with CPS and ODD protocols was $241 and $237 respectively. However, MDD with CPS was determined to be more cost-effective than ODD due to slightly increased rate of clinical effectiveness and a decrease in the rate of ANN (average CE ratios = $281 versus $287, respectively). Both one-way and two-way sensitivity analyses were performed by varying the two key parameters of clinical effectiveness and ANN. The model was robust to alterations in these key parameters. CONCLUSION: This CE analysis questions the benefit of implementing an ODD program when compared to a more traditional MDD protocol managed by a CPS for aminoglycoside dosing.

Individualized pharmacokinetic monitoring results in less aminoglycoside-associated nephrotoxicity and fewer associated costs.

To examine the impact of individualized pharmacokinetic monitoring (IPM) on the development of aminoglycoside-associated nephrotoxicity (AAN). Retrospective case-control study. Two teaching hospitals. Two thousand four hundred five patients who received aminoglycosides. Aminoglycoside therapy dosed by either IPM or physicians' directions. Patients receiving IPM were significantly less likely to develop AAN by both univariate (7.9% vs 13.2%, p=0.02) and multivariate methods (odds ratio 0.42, p=0.002). Female sex was protective against AAN. Age 50 years and above, high initial aminoglycoside trough, long duration of therapy, and concurrent piperacillin, clindamycin, or vancomycin increased risk of AAN. We estimated that IPM decreased AAN costs by $90,995/100 patients. Individualized pharmacokinetic monitoring significantly decreased the frequency of AAN and its associated economic costs.

Evaluation of Nephrotoxicity Associated with Once-Daily Administration of Aminoglycoside

Objective: To determine the potential risk factors associated with nephrotoxicity in patients receiving once-daily aminoglycoside (ODA) therapy. Design: Case series. Setting: Large community teaching hospital. Patients: Twenty-five patients considered nephrotoxic during ODA therapy. Main Outcome Measures: This study is a retrospective chart review of patients in whom nephrotoxicity developed during ODA therapy. Nephrotoxicity was defined as a rise in serum creatinine (SCr) concentration of 0.5 mg/dL or more above the preaminoglycoside baseline value. Patients were identified from our institutional ODA database. Based on the previously identified risk factors for aminoglycoside-associated nephrotoxicity with conventional aminoglycoside therapy published by Bertino et al., a data collection tool was developed. Collected data included demographic information, concurrently administered drugs, diagnostic agents used, and potential comorbidity risk factors. Results: Similar to what has been found in patients receiving conventional aminoglycoside regimens, numerous risk factors, such as the concomitant use of cephalosporins, loop diuretics, intravenous contrast dye, angiotensin-converting enzyme inhibitors, and nonsteroidal antiinflammatory drugs, may have been responsible for the rise in SCr observed in our study population. In addition, common comorbidity risk factors in this population were pleural effusion, pneumonia, decrease in systolic blood pressure to less than 80 mm Hg, and preexisting renal disease. Conclusions: Nephrotoxicity is the result of multifactorial processes and is not solely due to the ODA administration technique.

Aminoglycoside-associated nephrotoxicity in extrahepatic obstructive jaundice

Experimental data demonstrate that biliary obstruction increases renal sensitivity to gentamicin. In the present study the incidence of and risk factors for aminoglycoside nephrotoxicity were prospectively studied in patients with extrahepatic obstructife jaundice. Two hundred and thirty-seven hospitalized adult patients were classified into three groups. Group I consisted of 84 patients with extrahepatic obstructive jaundice, who received aminoglycoside (gentamicin or tobramycin). Group II consisted of 81 patients with extrahepatic obstructive jaundice, who received either antibiotics other than aminoglycoside or no antimicrobial therapy. Group III consisted of 72 noncholestatic patients receiving aminoglycosides for different disorders. Nephrotoxicity developed in 27 patients (32%) in group I vs 9 patients (11%) in group II and 4 patients (5.6%) in group III ( p<0.00001). In group I, a comparison of patients with and without nephrotoxicity revealed significantly higher values in the former for mean serum bilirubin concentration, initial steady-state trough aminoglycoside concentration and estimated half-life. Stepwise multivariate analysis with nephrotoxicity status as the dependent variable determined that the most significant variable for predicting nephrotoxicity was serum total bilirubin level. In extrahepatic cholestasis a high serum bilirubin level is a distinct factor predisposing to aminoglycoside nephrotoxicity.

Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring.

Incidence of and risk factors for aminoglycoside-associated nephrotoxicity (AAN) were evaluated in 1489 patients prospectively monitored with individualized pharmacokinetic monitoring (IPM). Incidence of AAN was 7.9% with individual (univariate) risk factors including advanced age, decreased albumin, poor nutritional status, pneumonia, concurrent furosemide, amphotericin B, vancomycin, cephalosporin, or piperacillin, intensive care unit treatment, leukemia, rapidly fatal illness, liver or renal disease, reduced aminoglycoside clearance, elevated initial steady-state trough concentration (Cminss), volume of distribution or half-life, duration of therapy, total dose, fever, male gender, shock, pleural effusion, and ascites. Multiple logistic regression revealed that Cminss, concurrent clindamycin, vancomycin, piperacillin, or cephalosporin, ascites, advanced age, male gender, decreased albumin, duration of therapy, and leukemia were significant independent risk factors for AAN. Positive predictive value of the model was 30.8%; negative predictive value was 91.7%. No identifiable risk factor alone or in combination was of sufficient sensitivity to reliably predict AAN, but use of IPM may lower the incidence of AAN.

Aminoglycoside-Associated Nephrotoxicity Increases Costs, Study Finds

Journal Article Aminoglycoside-Associated Nephrotoxicity Increases Costs, Study Finds Get access American Journal of Hospital Pharmacy, Volume 45, Issue 4, 1 April 1988, Page 742, https://doi.org/10.1093/ajhp/45.4.742 Published: 01 April 1988

What is the cost of nephrotoxicity associated with aminoglycosides?

We measured the economic impact of aminoglycoside-associated nephrotoxicity in a nested case-control study at six Philadelphia area hospitals. From the charts of 1756 patients who received aminoglycosides and met entry criteria, we collected data on patient demographics, clinical characteristics, and resource utilization for all patients with nephrotoxicity and for a sample of patients without nephrotoxicity. Of the 1756 patients, 129 (7.3%) developed aminoglycoside-associated nephrotoxicity. The component costs of nephrotoxicity were calculated by hospital accounting methods; room and board costs were enumerated with per diem rates. The additional cost of hospital ancillary services per case of nephrotoxicity was $446 (p less than 0.001); the additional cost of hospital stay was $825 for additional routine days (2.74 days) (p less than 0.02) and $1152 for intensive care days (1.50 days) (p less than 0.01). Additional consultations were $78 per patient. Therefore, the mean total additional cost of aminoglycoside-associated nephrotoxicity was $2501. The average additional cost per patient receiving aminoglycosides was $183.

CLINICAL PHARMACOKINETICS, TOXICITY AND COST EFFECTIVENESS ANALYSIS OF AMINOGLYCOSIDES AND AMINOGLYCOSIDE DOSING SERVICES

This article reviews the clinical pharmacokinetics, clinical toxicity and cost-effectiveness analysis of aminoglycosides and of dosing services for aminoglycosides. The reader is referred elsewhere for a review of the pharmacology, antimicrobial spectrum of activity and clinical use of these drugs. A critique of the more commonly used methods of aminoglycoside dosage determinations is included, based on the inter-individual variation in aminoglycoside disposition parameters. The advantages and disadvantages of arbitrary, predictive, and pharmacokinetic methods of dosing determination are summarized. Justification for the routine determination of serum aminoglycoside concentrations is reviewed. We review the lack of standardization of definitions for aminoglycoside-associated nephrotoxicity in published studies, and studies which illustrate these differences are highlighted. Evidence for the association between serum aminoglycoside concentrations and nephrotoxicity is examined. Ototoxicity is similarly reviewed. The concept of cost-effectiveness analysis is examined extensively in this review. We discuss the literature concerning the cost benefit analysis of drug dosing services.

Urinary alanine aminopeptidase and β2-microglobulin as measurements of aminoglycoside-associated renal impairment

The value of urinary alanine aminopeptidase (AAP) and urinary beta 2-microglobulin as predictors of aminoglycoside-associated nephrotoxicity was studied in 46 patients treated with gentamicin or tobramycin. In three patients serum creatinine increased by more than 50 mumol/l. Urinary AAP increased in virtually all patients. The degree of these increases could not be correlated to subsequent increases in serum creatinine. Increases in urinary beta 2-microglobulin were also seen in many patients who did not show subsequent increases in serum creatinine. Moreover, urinary beta 2-microglobulin was elevated before the onset of aminoglycoside treatment in many patients with septicaemia and malignant diseases, thus making an evaluation of antibiotic-induced changes impossible. These results indicate that neither urinary AAP nor urinary beta 2-microglobulin can be used to predict aminoglycoside-associated nephrotoxicity of clinical importance in individual patients.