Receiving Aminoglycoside Therapy Research Articles

2222. Impact of Empiric Aminoglycoside Usage on Outcomes in Bacterial Pneumonia

BackgroundAlthough aminoglycosides are recommended as part of empiric combination therapy in selected patients with healthcare-associated pneumonia, their efficacy and safety remains unclear. The objectives of this study were to evaluate the impact of empiric aminoglycoside treatment on microbiologic cure, recurrent pneumonia and death, and acute kidney injury (AKI) among hospitalized patients treated for pneumonia who were clinically cured.MethodsThis was a nested cohort study including 441 hospitalized subjects with confirmed bacterial pneumonia who achieved clinical cure. All subjects had positive respiratory cultures at the beginning of therapy and also had cultures obtained at the time of antibiotic completion. Subjects with the same pathogen present at both the beginning of and at the end of treatment were categorized as microbiologic failure and all others were categorized as microbiologic cure. Serum creatinine was measured at both the beginning and end of therapy, with an absolute increase in serum creatinine of 0.5 mg/L or greater defined as AKI. Composite outcomes of 30- and 90-day recurrent pneumonia or death following the clinical cure of the index pneumonia were captured. Patients who received empiric aminoglycoside therapy were compared with patients who did not receive aminoglycoside therapy.ResultsOf 441 included subjects, 14.5% (N = 64) received aminoglycoside therapy and 85.5% (N = 377) did not. The mean age was 54.7 years, with 70.5% male and 78.2% white. Characteristics of the two groups (including Charlson Comorbidity Indices and APACHE II scores) were similar. Rates of microbiologic cure, death/recurrent pneumonia at 30- and 90-days and AKI and were similar in both groups (table). In subgroup analyses restricted to different pathogen groups these associations remained unchanged.ConclusionAmong hospitalized patients with pneumonia who were clinically cured, empiric aminoglycoside therapy was not associated with an increased likelihood of microbiologic cure, death or recurrent pneumonia or AKI. Disclosures All authors: No reported disclosures.

Dose Timing of Aminoglycosides in Hemodialysis Patients: A Pharmacology View.

Aminoglycosides for patients undergoing intermittent hemodialysis (IHD) have traditionally been dosed at half the normal dose administered at the end of a hemodialysis session. Several investigations have suggested that administering higher doses preceding or with the initiation of dialysis would more readily optimize pharmacodynamic parameters. However, the selection of an optimal aminoglycoside dosing strategy in patients receiving IHD is complex and requires consideration of numerous factors, precluding a singular approach. By reviewing aminoglycoside pharmacokinetics, pharmacodynamics, risks for toxicity and resistance development, and practical considerations, we derive indication- and setting- specific recommendations. We identify some areas (definitive therapy of gram-negative infections in patients receiving predictable hemodialysis sessions, for example) where dosing preceding or with the initiation of dialysis is optimal and feasible, and others (gram-positive synergy, unstable patients with poor/unpredictable vascular access) where postdialysis dosing remains preferred. Finally, given the dearth of data exploring the pharmacodynamics and clinical outcomes of IHD patients receiving aminoglycoside therapy, we identify several key questions in need of investigation.

Prevalence of MT‐RnR1 in the General Population

Objective: Review the prevalence of MT-RNR1 genetic mutation and assess the need for neonatal screening prior to gentamicin therapy. A comprehensive search of MEDLINE, EMBASE, Cochrane Library, Clinical Evidence, and Cochrane Central Register of Trials was performed. The reference lists were cross-referenced. Review was restricted to human studies in English language. Method: Studies describing the prevalence/incidence of MT-RNR1 gene mutations (A1555G, C1494T, A7445G) in the population. Relevant studies screening for presence for MT-RNR1 in patients receiving aminoglycoside therapy were included. Results: Twenty-two articles out of 67 full papers and 206 abstracts from 1948 to November 2011 met the inclusion criteria. These included 9 prospective case-control studies, 12 case series, and a case report. There is weak evidence that MT-RNR1 is globally prevalent with racial bias especially in Chinese and Spanish populations. The prevalence/incidence ranged from 0.09%-2.9% in general population to 17% in the high-risk population. Weak evidence of neonatal sensorineural hearing loss following aminoglycoside exposure was also seen. Conclusion: There is a need for large national epidemiological studies to assess the prevalence of MT-RNR. Some evidence of a global prevalence of MT-RNR1 with racial bias and link between aminoglycoside exposure and NSHL among at risk group. It is difficult to justify routine screening of patients for MT-RNR1 with the available literature.

Treatment and Clinical Outcomes of Urinary Tract Infections Caused by KPC-Producing Enterobacteriaceae in a Retrospective Cohort

BackgroundOptimal treatment regimens for infections caused by Klebsiella pneumoniae carbapenemase (KPC)-producing Enterobacteriaceae are not well-defined. ObjectivesThis study describes the treatment and outcomes in patients with urinary tract infection (UTI) caused by KPC-producing Enterobacteriaceae. MethodsThis retrospective cohort study analyzed data from adult inpatients with bacteriuria caused by KPC-positive organisms treated at Barnes-Jewish Hospital from June 1, 2006, to February 1, 2008. KPC-positive isolates were identified utilizing disk-diffusion susceptibility testing and confirmed to contain blaKPC via molecular methods. ResultsTwenty-one patients met the inclusion criteria and all were classified as having symptomatic UTI. The majority of patients were female (15/21 [71%]), and the mean (SD) age was 62.4 (15.2) years. Successful clinical and microbiologic responses were observed in 16 patients (76%) for both outcomes. Patients with urinary catheters had them removed or replaced in 9 of 15 cases (60%). Antibiotics active against the isolated pathogen were provided in 14 of 21 cases (67%), often after considerable delay (median, 72.5 hours [range, 4–312 hours]). All 7 patients receiving aminoglycoside therapy had successful clinical and microbiologic responses, and in vitro testing of an extended antibiotic panel revealed high susceptibility rates for tigecycline (28/29 [97%]), minocycline (22/29 [76%]), and fosfomycin (25/29 [86%]) against the KPC-positive isolates. ConclusionsAlthough receipt of appropriate therapy was delayed in many cases, clinical outcomes investigated revealed high rates of successful response in this defined group of patients. Aminoglycosides and tetracycline derivatives suggested therapeutic promise in the treatment of KPC-producing Enterobacteriaceae UTI.

Combination therapy with an aminoglycoside for Staphylococcus aureus endocarditis and/or persistent bacteremia is associated with a decreased rate of recurrent bacteremia: a cohort study

Although limited data exist on the efficacy and potential risk of synergistic aminoglycoside therapy for persistent Staphylococcus aureus bacteremia and endocarditis, aminoglycosides are frequently used in clinical practice. As our study population, we included subjects fulfilling the modified Duke criteria for S. aureus endocarditis and/or having greater than 72h of S. aureus bacteremia. Among these subjects, we compared patients who did and did not receive aminoglycoside therapy for their S. aureus bloodstream infection. These groups were compared for the primary outcome of recurrent bacteremia, as well as for the duration of bacteremia, mortality, complication rate, and incident renal failure. Eighty-seven subjects fulfilled the inclusion criteria. Of these, 49 received aminoglycoside therapy, whereas 38 did not. There were no significant differences in the baseline characteristics when comparing groups who did or did not receive aminoglycoside therapy. Four (8.2%) subjects treated with aminoglycoside therapy experienced recurrent bacteremia versus nine (23.7%) who did not receive aminoglycoside therapy [relative risk and 95% confidence interval [RR (95%CI)]=0.51 (0.22-1.17), p=0.04]. In multivariable analyses, aminoglycoside use remained significantly associated with a decrease in recurrent bacteremia [adjusted odds ratio (OR) (95%CI)=0.26 (0.07-0.98), p=0.046]. No significant differences were seen between groups treated with and without an aminoglycoside in terms of the 6-month all-cause mortality (51.0 vs. 42.1%, p=0.41), complication rate (71.4 vs. 73.7%, p=0.82), or incident renal failure (54.5 vs. 46.9%, p=0.54). The use of combination therapy with an aminoglycoside in persistent S. aureus bacteremia and/or endocarditis may be associated with a lower rate of recurrent bacteremia without significant differences in the incident renal failure.

A 10-year survey of blood culture negative endocarditis in Sweden: Aminoglycoside therapy is important for survival

We estimated the prevalence of blood culture negative endocarditis (CNE) and described and analysed data with special attention to antibiotic treatment from patients with infective endocarditis (IE) reported to the Swedish endocarditis registry during the 10-y period 1995-2004. All 29 departments of infectious diseases in Sweden reported data to the registry. During the 10-y period, 2509 IE episodes (78% Duke definite) were identified in 2410 patients. 304 CNE episodes (25% Duke definite) were found. The proportion of CNE was measured to be 12% of all IE episodes. Fatal outcome occurred in 10.7% of all IE patients and in 5% of the CNE patients. The risk of dying was significantly increased in female (9%) compared to male (2%) CNE patients (OR 5.1). Mortality was significantly decreased in patients treated with an aminoglycoside (3%) versus patients without aminoglycoside therapy (13%), OR 0.2. In conclusion, the prevalence of CNE was 12% in Swedish IE patients in a 10-y survey. The mortality in IE was low (10.7%) and 4.6% for CNE. Women have higher mortality rates than men in CNE. CNE patients who received aminoglycoside therapy survived more frequently than CNE patients without this therapy.

Aminoglycoside-induced deafness in leukemic patients: Cost-effectiveness of prevention by genetic testing

9014 Background: Aminoglycosides are highly-effective, inexpensive antimicrobials widely used in empirical combination therapy for fever in children with severe neutropenia, including patients receiving treatment for acute leukemia. Some genetically predisposed individuals are exquisitely sensitive to the cochleotoxic effects of these drugs, even when levels are within the therapeutic range. This genetic susceptibility is maternally inherited and caused by mutation of the MT-RNR1 gene encoding mitochondrial 12S rRNA at base position 1555, termed m.1555A>G. Methods: Retrospective analysis of m.1555A>G positive cases in the Regional Diagnostic laboratory to determine how many were revealed by aminoglycoside treatment for cancer treatment-related sepsis. Results: Three unrelated mutation positive individuals were identified in a two year period. All were children with acute lymphoblastic leukemia who experienced rapidly progressive hearing loss during their treatment. Two of the three children have a post-lingual hearing loss of sufficient severity to merit cochlear implantation. None had a significant family history of deafness. Conclusions: Initial estimates of the prevalence of the m.1555A>G mutation were based upon extrapolation back from its contribution to the cause of hearing loss amongst hearing-impaired people and were thought to be low. However, recent small studies of the prevalence of m.1555A>G in the general population suggest that prevalence is much higher than previously calculated (1 in 206 in New Zealand (n=206), 1 in 1,161 in Texas (n=1,161)) but that penetrance, at least in the absence of aminoglycosides, is low. Using estimates of the lifetime cost of pediatric cochlear implantation we suggest that screening for the m.1555A>G mutation at the time of diagnosis of leukemia would be cost effective and therefore suggest that all children diagnosed with leukemia should be screened for this mutation prior to receiving aminoglycoside therapy. No significant financial relationships to disclose.

Rate of False-Positive Results for Threshold Shifts during Initial Treatment with Aminoglycosides

Specific recommendations from the American Speech-Language Hearing Association (1994) exist for the audiometric surveillance of patients receiving aminoglycoside therapy. However, these recommendations are not based primarily on test-retest repeatability in often seriously ill patients. The probability of ototoxicity is very low during the first three days of aminoglycoside therapy, and significant threshold shifts can be assumed to represent a false-positive result. Baseline thresholds were measured in 28 patients before or not later than 24 h after the beginning of aminoglycoside therapy. These measurements were repeated in 22 patients during the first three days of the drug administration. Three out of 22 patients fulfilled the American Speech-Language-Hearing Association’s (1994) criteria for cochleotoxicity making up a false-positive rate of 13%. In actual patients, the false-positive rate of audiometric surveillance during ototoxic drug administration may be substantially higher than in healthy subjects when these criteria are used.

アミノ配糖体抗生物質で治療を受けた入院患者における体内動態の個体内変動とＣ反応性蛋白質との相関性

To evaluate the correlation between the intra-individual variations in the pharmacokinetics of aminoglycoside (arbekacin and amikacin) and C-reactive protein (CRP), the serum concentrations of aminoglycoside and the CRP levels were monitored in 10 inpatients receiving arbekacin or amikacin therapy. The pharmacokinetic parameters of aminoglycoside were estimated using a one-compartment model.A significant difference was observed between the distribution volume at higher CRP levels and lower levels in inpatients receiving aminoglycoside (Vd, 0.442±0.134 vs 0.368±0.164 L/kg, P< 0.05), However, no significant relationship existed between the CRP levels and Vd of aminoglycoside, There was a significant difference in the half-life (t1/2) of seruim aminoglycoside between higher CRP levels and lower levels in inpatients receiving aminoglycoside (3.90±1.97 vs 4.46±2.02 hours, P< 0. 01).In the future, further examinations of serum aminoglycoside concentration monitoring are called for to check the intra-individual variations in the pharmacokinetics for aminoglycoside, when the CRP levels change in inpatients receiving aminoglycoside therapy.

Capability of serum to convert streptomycin to cytotoxin in patients with aminoglycoside-induced hearing loss

Individual variations in sensitivity to the ototoxic effects of aminoglycoside antibiotics are well documented. Our research demonstrates that there is an apparent difference in serum from patients who are resistant or susceptible to aminoglycoside ototoxicity. In the first study, the cytotoxicity of sera from patients with and without hearing loss after various time periods following the discontinuation of aminoglycoside treatment was assayed using the isolated outer hair cell toxicity assay. The results indicate that sera from patients with hearing loss were significantly more toxic than sera from patients with normal hearing or minimal hearing loss. This toxicity may persist for up to 1 year after discontinuation of aminoglycoside therapy. In a second study, sera were obtained from patients who had received aminoglycoside therapy several years previously. None of these sera was toxic to isolated outer hair cells in vitro. Streptomycin was then incubated with the sera or a protein fraction isolated from sera, and the incubation mixtures were tested for toxicity. The percentage of damaged outer hair cells was significantly higher when streptomycin had been treated with sera or a serum protein fraction from patients with hearing loss (58±10% and 68±9%, respectively) than with sera or a serum protein fraction from a control group (10±5% and 17±4%, respectively). In addition, several incubation mixtures were analyzed using high performance liquid chromatography. A new chromatographic peak was only found in the incubations of streptomycin with serum protein from patients with hearing loss. The results suggest that sera from individuals sensitive to aminoglycoside antibiotics may metabolize these drugs to cytotoxins.

A single 16S ribosomal RNA substitution is responsible for resistance to amikacin and other 2-deoxystreptamine aminoglycosides in Mycobacterium abscessus and Mycobacterium chelonae.

Twenty-six clinical isolates of Mycobacterium abscessus resistant to amikacin were identified. Most isolates were from patients with posttympanostomy tube placement otitis media or patients with cystic fibrosis who had received aminoglycoside therapy. Isolates were highly resistant (MICs > 1024 microg/mL) to amikacin, kanamycin, gentamicin, tobramycin, and neomycin (all 2-deoxystreptamine aminoglycosides) but not to streptomycin. Sequencing of their 16S ribosomal (r) RNA revealed that 16 (94%) of 17 had an A-->G mutation at position 1408. In vitro-selected amikacin-resistant mutants of M. abscessus and Mycobacterium chelonae had the same resistance phenotype, and 15 mutants all had the same A-->G substitution at position 1408. Introducing an rRNA operon from Mycobacterium smegmatis with a mutated A-->G at this position into a single functional allelic rRNA mutant of M. smegmatis produced the same aminoglycoside resistance phenotype. These studies demonstrate this 16S rRNA mutation is responsible for amikacin resistance in M. abscessus, which has only one copy of the rRNA operon.

Nonparametric approach to population pharmacokinetics in oncology patients receiving aminoglycoside therapy.

A nonparametric expectation maximization approach to the study of population pharmacokinetics is described for an aminoglycoside antibiotic. The method is used to explore population estimates for gentamicin clearance (liters per hour per creatinine clearance) and volume of distribution (liters per kilogram) in tumor patients. Joint and marginal probability distributions are plotted and further characterized by using standard descriptors such as mean, median, mode, standard deviation, skewness, and kurtosis. Results of additional analyses using hematologic or solid tumor subpopulations agree with those of a recent larger study which found no significant pharmacokinetic differences between these groups. Nonparametric maximum-expectation analyses are convenient and allow exploratory analysis of population estimates directly from routine laboratory information.

Aminoglycoside ototoxicity in cystic fibrosis. Evaluation by high-frequency audiometry.

In this study, we sought to determine the clinical usefulness of high-frequency audiometry (8000 to 20,000 Hz) in detecting aminoglycoside-induced increases in pure-tone hearing thresholds before they are noticed in conventionally tested frequencies. We measured hearing thresholds from 250 to 20,000 Hz in 22 patients with cystic fibrosis who were treated with aminoglycosides. The audiograms were age-matched and were compared with those from 13 patients with cystic fibrosis and 38 subjects without cystic fibrosis, all of whom had never received aminoglycoside therapy. In patients with cystic fibrosis who were treated with aminoglycosides (younger than 20 years), there were statistically significant elevations only in frequencies higher than 16,000 Hz. Patients with cystic fibrosis who were treated with aminoglycosides who were 20 years and older had elevated thresholds in all frequencies tested. Patients with cystic fibrosis who were not treated with aminoglycosides did not differ statistically from controls. High-frequency audiometry may serve as a useful measure of elevation in pure-tone hearing thresholds that precede noticeable loss of auditory acuity in patients with cystic fibrosis who are receiving long-term aminoglycoside therapy.

Impact of a Clinical Pharmacokinetic Service on Patients Treated with Aminoglycosides for Gram-Negative Infections

The present study was a retrospective, case-control design aimed at evaluating whether the clinical pharmacokinetic service (CPS) is cost-effective, as assessed by lengths of hospital stay and aminoglycoside therapy, incidence of a decrease in renal function, and time for resolution of infection as determined by vital signs. Forty-six patients were entered into this study, and were matched by defined criteria. The results of the study demonstrated a six-day difference in hospital stay for the CPS group (p less than 0.05). Length of aminoglycoside therapy was 33 hours shorter for the CPS group. Additionally, the time necessary for resolution of the infection was significantly shorter for this group, as assessed by vital signs returning to normal or baseline. Three patients in each group expired. Two patients in the CPS group and five in the control group developed aminoglycoside-associated increases in serum creatinine. No significant difference was found between the two groups in age, weight, or APACHE II score. Additionally, the two groups were similar with respect to concomitant diseases and concomitant antibiotics used. The approximate cost of the CPS was calculated as $56 per patient. Use of the CPS decreasing hospital stay by six days (mean $1875/patient) would translate to an annual savings of $654,375 in hospital charges, assuming 365 patients received aminoglycoside therapy per year.

A rapid method of assaying gentamicin and kanamycin concentrations in serum.

SUMMARY A simple method is described for the assay of gentamicin and kanamycin in human serum. It is a modification of the monosaccharide hydrolysis method of Faine and Knight (1968) and will estimate low concentrations of antibiotic accurately within 3 hours. The method gives results similar to those obtained by a double-row tube-dilution growth inhibition technique, is unaffected by the presence of penicillins or cephalosporins, and requires only standard laboratory equipment. Because the method gives readily reproducible results and is easy to perform, it should commend itself to all laboratories dealing with patients receiving aminoglycoside therapy.