Aminoglycoside Treatment Research Articles

Assessment of aminoglycoside dosing and estimated glomerular filtration rate in determining gentamicin and tobramycin area under the curve and clearance.

Aminoglycoside clearance depends on kidney function, but the Australian Therapeutic Guidelines for antibiotics (version 14, 2010) recommend initial dosing based on weight without consideration of kidney function. Other guidelines that modify dosing based on kidney function estimates often use the Cockroft-Gault equation, but the role of the estimated glomerular filtration rate equations for this purpose is unclear. To determine the performance of current guideline dosing in achieving target area-under-the-curve and examine the relative precision of the estimated glomerular filtration rate equations compared with traditional Cockroft-Gault creatinine clearance in predicting aminoglycoside clearance. We analysed 496 aminoglycoside treatment episodes involving 1377 infusions in adult patients. Conformity with antibiotic guideline dosing was achieved if the discrepancy between prescribed and recommended dose was less than 15%. Aminoglycoside clearance was determined from linear regression using a one compartment model with the Aminoglycoside Levels and Daily Dose Indicator programme. We assessed the precision of the Cockroft-Gault, Modification of Diet in renal Disease Study and Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations in predicting aminoglycoside clearance by correlation and linear regression. Conformity with guideline dosing was not associated with achieving target area-under-the-curve. The CKD-EPI estimated glomerular filtration rate adjusted for body surface area showed the highest correlation (gentamicin, r = 0.66; tobramycin, r = 0.82) and best predictive model for aminoglycoside clearance. Current guideline dosing may be suboptimal for achieving target area-under-the-curve. The CKD-EPI equation adjusted for patient body surface area best predicts aminoglycoside clearance, and could be evaluated as a covariate in determining initial aminoglycoside dosing.

Development of a User-Friendly Graphic Tool to Estimate Individualized Survival Curves for Advanced Cancer Patients in Hospice Care.

This prospective study aimed to develop an individualized prognostic tool for predicting the survival probability at any given point for a hospice patient with advanced cancer. A total of 286 patients with advanced cancer were included in the study. Median observational time was 18 days (range: 1 to 60 days). Cox proportional hazards regression analysis revealed that faster heart rate (hazard ratio [HR] = 1.01), jaundice (HR = 2.32), poorer performance status (HR = 2.01), and antifungal treatment (HR = 1.62) were independent predictors of shorter survival time. Patients with infections who received aminoglycoside treatments (HR = 0.45) were associated with longer survival times. Based on this model, we could construct a covariate-adjusted individualized survival curve for a given patient according to his or her clinical condition. This user-friendly tool for estimating the survival probability of patients with advanced cancer in hospice settings could facilitate clinical decision making and medical care planning.

Propensity-based study of aminoglycoside nephrotoxicity in patients with severe sepsis or septic shock.

To assess the risk of acute kidney injury (AKI) attributable to aminoglycosides (AGs) in patients with severe sepsis or septic shock, we performed a retrospective cohort study in one medical intensive care unit (ICU) in France. Patients admitted for severe sepsis/septic shock between November 2008 and January 2010 were eligible. A propensity score for AG administration was built using day 1 demographic and clinical characteristics. Patients still on the ICU on day 3 were included. Patients with renal failure before day 3 or endocarditis were excluded. The time window for assessment of renal risk was day 3 to day 15, defined according to the RIFLE (risk, injury, failure, loss, and end-stage renal disease) classification. The AKI risk was assessed by means of a propensity-adjusted Cox proportional hazards regression analysis. Of 317 consecutive patients, 198 received AGs. The SAPS II (simplified acute physiology score II) score and nosocomial origin of infection favored the use of AGs, whereas a preexisting renal insufficiency and the neurological site of infection decreased the propensity for AG treatment. One hundred three patients with renal failure before day 3 were excluded. AGs were given once daily over 2.6 ± 1.1 days. AKI occurred in 16.3% of patients in a median time of 6 (interquartile range, 5 to 10) days. After adjustment to the clinical course and exposure to other nephrotoxic agents between day 1 and day 3, a propensity-adjusted Cox proportional hazards regression analysis showed no increased risk of AKI in patients receiving AGs (adjusted relative risk = 0.75 [0.32 to 1.76]). In conclusion, in critically septic patients presenting without early renal failure, aminoglycoside therapy for less than 3 days was not associated with an increased risk of AKI.

Mitochondrial mutation m.1555A>G as a risk factor for failed newborn hearing screening in a large cohort of preterm infants.

BackgroundThe mitochondrial m.1555A>G mutation is associated with a high rate of permanent hearing loss, if aminoglycosides are given. Preterm infants have an increased risk of permanent hearing loss and are frequently treated with aminoglycoside antibiotics.MethodsWe genotyped preterm infants with a birth weight below 1500 grams who were prospectively enrolled in a large cohort study for the m.1555A>G mutation. Treatment with aminoglycoside antibiotics in combination with mitochondrial m.1555A>G mutation was tested as a predictor for failed hearing screening at discharge in a multivariate logistic regression analysis.Results7056 infants were genotyped and analysed. Low birth weight was the most significant predictor of failed hearing screening (p = 7.3 × 10-10). 12 infants (0.2%) had the m.1555A>G-mutation. In a multivariable logistic regression analysis, the combination of aminoglycoside treatment with m.1555A>G-carrier status was associated with failed hearing screening (p = 0.0058). However, only 3 out of 10 preterm m.1555A>G-carriers who were exposed to aminoglycosides failed hearing screening. The m.1555A>G-mutation was detected in all mothers of m.1555A>G-positive children, but in none of 2993 maternal DNA-samples of m.1555A>G-negative infants.ConclusionAntenatal screening for the m.1555A>G mutation by maternal genotyping of pregnant women with preterm labour might be a reasonable approach to identify infants who are at increased risk for permanent hearing loss. Additional studies are needed to estimate the relevance of cofactors like aminoglycoside plasma levels and birth weight and the amount of preterm m.1555A>G-carriers with permanent hearing loss.

Is single-dose prophylactic gentamicin associated with acute kidney injury in patients undergoing cardiac surgery? A matched-pair analysis

Although aminoglycoside treatment has been associated with nephrotoxic effects, single-dose gentamicin has been considered safe in surgery. However, the effect of a single-dose prophylactic aminoglycoside on the risk of acute kidney injury among patients undergoing cardiac surgery remains uncertain. A population-based cohort study with matched-pair analysis of 2892 consecutive patients undergoing cardiac surgery at Aarhus University Hospital, Denmark, was performed. Two different prophylactic antibiotic regimens were used during the study period. The patients exposed to a single dose of prophylactic gentamicin were compared with those had not received gentamicin. Statistical analysis for matched data was performed. The data were retrieved from the Western Denmark Heart Registry. Matching resulted in 668 patient pairs. Patients receiving gentamicin had higher maximum serum creatinine during the first postoperative 72 hours (median, 96 vs 90 mmol/L; P=.0002). Also, a greater fraction of patients receiving gentamicin developed acute kidney injury according to the Acute Kidney Injury Network criteria (22% vs 17%; P=.02). The hospital length of stay was shorter in the control group (5.0 vs 5.6 days; P<.0001). No difference was found in the incidence of patients requiring postoperative dialysis, 30-day and 1-year mortality, or the incidence of sternal infection between the 2 groups. A single-dose prophylactic aminoglycoside in adult cardiac surgery patients was associated with an increased risk of acute kidney injury but not with a greater frequency of postoperative dialysis or mortality. No differences in the incidence of sternal infections between groups were observed.

Aminoglycoside-mediated relaxation of the ductus arteriosus in sepsis-associated PDA.

Sepsis is strongly associated with patency of the ductus arteriosus (PDA) in critically ill newborns. Inflammation and the aminoglycoside antibiotics used to treat neonatal sepsis cause smooth muscle relaxation, but their contribution to PDA is unknown. We examined whether: 1) lipopolysaccharide (LPS) or inflammatory cytokines cause relaxation of the ex vivo mouse DA; 2) the aminoglycosides gentamicin, tobramycin, or amikacin causes DA relaxation; and 3) newborn infants treated with aminoglycosides have an increased risk of symptomatic PDA (sPDA). Changes in fetal mouse DA tone were measured by pressure myography in response to LPS, TNF-α, IFN-γ, macrophage-inflammatory protein 2, IL-15, IL-13, CXC chemokine ligand 12, or three aminoglycosides. A clinical database of inborn patients of all gestations was analyzed for association between sPDA and aminoglycoside treatment. Contrary to expectation, neither LPS nor any of the inflammatory mediators caused DA relaxation. However, each of the aminoglycosides caused concentration-dependent vasodilation in term and preterm mouse DAs. Pretreatment with indomethacin and N-(G)-nitro-L-arginine methyl ester did not prevent gentamicin-induced DA relaxation. Gentamicin-exposed DAs developed less oxygen-induced constriction than unexposed DAs. Among 488,349 infants who met the study criteria, 40,472 (8.3%) had sPDA. Confounder-adjusted odds of sPDA were higher in gentamicin-exposed infants, <25 wk and >32 wk. Together, these findings suggest that factors other than inflammation contribute to PDA. Aminoglycoside-induced vasorelaxation and inhibition of oxygen-induced DA constriction support the paradox that antibiotic treatment of sepsis may contribute to DA relaxation. This association was also found in newborn infants, suggesting that antibiotic selection may be an important consideration in efforts to reduce sepsis-associated PDA.

Influence of very short patch mismatch repair on SOS inducing lesions after aminoglycoside treatment in Escherichia coli

Low concentrations of aminoglycosides induce the SOS response in Vibrio cholerae but not in Escherichia coli. In order to determine whether a specific factor present in E. coli prevents this induction, we developed a genetic screen where only SOS inducing mutants are viable. We identified the vsr gene coding for the Vsr protein of the very short patch mismatch repair (VSPR) pathway. The effect of mismatch repair (MMR) mutants was also studied. We propose that lesions formed upon aminoglycoside treatment are preferentially repaired by VSPR without SOS induction in E. coli and by MMR when VSPR is impaired.

Dose-dependent effect of aminoglycoside treatments on hair cells of transgenic ET4 zebrafish

Dose-dependent effect of aminoglycoside treatments on hair cells of transgenic ET4 zebrafish

Normal hearing in a child with the m.1555A>G mutation despite repeated exposure to aminoglycosides. Has the penetrance of this pharmacogenetic interaction been overestimated?

The mtDNA m.1555A>G mutation causes increased susceptibility to aminoglycoside ototoxicity resulting in significant hearing loss in 100% of reported exposed cases. Genetic and audiological assessments were conducted in a sample of 59 children with cystic fibrosis (CF) undergoing aminoglycoside treatment. Of the two m.1555G patients identified one had severe-profound deafness. Surprisingly, the second m.1555G patient exhibited well-preserved hearing despite repeated exposure. This may be a rare case of intact hearing in an m.1555G individual with aminoglycoside use. Alternatively, its penetrance may have been previously overestimated due to recruitment bias. Further studies are required to determine the true penetrance to inform m.1555A>G genetic testing in similar clinical scenarios.

Sensorineural hearing loss in congenital diaphragmatic hernia survivors is associated with postnatal management and not defect size

Background/PurposeWe determined the incidence of sensorineural hearing loss (SNHL; >20dB at any frequency) in a contemporary cohort of congenital diaphragmatic hernia (CDH) survivors at a single tertiary care center and identified potential risk factors for SNHL. MethodsFrom 2000 through 2011, clinical and audiologic data were collected on 122 surgically-repaired Bochdalek CDH patients. CDH defect size, duration of ventilation, and cumulative aminoglycoside treatment were used for multivariate logistic regression. ResultsIncidence of SNHL was 7.4% (9/122). We identified one significant independent predictor of SNHL: cumulative length of aminoglycoside treatment (P<.001; OR 1.44, 95% CI: 1.13–1.83). ConclusionsOver the last decade, the incidence of SNHL in our CDH patients is low compared to previous reports in the literature (7.4%) and is not associated with CDH defect size or the need for extracorporeal membrane oxygenation. Prolonged duration of aminoglycoside treatment increases the risk of SNHL independent of defect size and duration of ventilation.

Identification of off-target effects of aminoglycosides on human genes

Introduction: All medically useful antibiotics should have the potential to distinguish between target microbes (bacteria) and host cells. Prolonged antibiotic treatment can lead to detrimental side-effects in patients, but the mechanisms underlying the effects of antibiotics in mammalian systems remain unclear. Understanding the molecular mechanisms of toxicity may aid in the design of adjunctive therapies to improve antibiotic tolerance. Aim and objective: The study aimed to characterize the mechanistic effects of clinically relevant bactericidal antibiotics on mammalian cells using publicly available data. Owing to the relatively frequent occurrence of nephrotoxicity and ototoxicity during aminoglycoside treatment, this study focused on this antibiotic group. Materials and method: Aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin and spectinomycin) were investigated for their effect on human genomes using the Comparative Toxicogenomics Database public website and research tool. For each drug, the drug – gene interactions were listed as either increased or decreased gene expression. The functions of those genes listed were searched using the GeneDecks (www.genecards.org) online tool. Results: Aminoglycosides were found to increase the expression of 1573 genes involved in mortality/ageing, cellular, immune system, and homeostasis/metabolism phenotypes. On the other hand, aminoglycosides decreased the expression of another 666 genes involved in in mortality/ageing, homeostasis/metabolism, cellular, growth/size, nervous system, and behaviour/neurological phenotypes. Beside these physiological pathways, aminoglycosides affected genes known to be involved in certain diseases such as neuronitis, breast cancer, prostatitis, endotheliitis, pancreatitis, leukaemia, hepatitis, prostate cancer, lung cancer, adenocarcinoma and hepatocellular carcinoma. Conclusion: Aminoglycosides have numerous off-target effects on human genomes by affecting the expression of genes involved in major cellular phenotypes and clinical conditions that may explain the clinically documented side-effects of prolonged use of such drugs. Confirming these observations using in vitro and in vivo models, such as cell lines and animal models, is recommended.

Designer Aminoglycosides That Selectively Inhibit Cytoplasmic Rather than Mitochondrial Ribosomes Show Decreased Ototoxicity: A STRATEGY FOR THE TREATMENT OF GENETIC DISEASES

There is compelling evidence that aminoglycoside (AG) antibiotics can induce the mammalian ribosome to suppress disease-causing nonsense mutations and partially restore the expression of functional proteins. However, prolonged AG treatment can cause detrimental side effects in patients, including most prominently, ototoxicity. Recent mechanistic discussions have considered the relative contributions of mitochondrial and cytoplasmic protein synthesis inhibition to AG-induced ototoxicity. We show that AGs inhibit mitochondrial protein synthesis in mammalian cells and perturb cell respiration, leading to a time- and dose-dependent increase in superoxide overproduction and accumulation of free ferrous iron in mitochondria caused by oxidative damage of mitochondrial aconitase, ultimately leading to cell apoptosis via the Fenton reaction. These deleterious effects increase with the increased potency of AG to inhibit the mitochondrial rather than cytoplasmic protein synthesis, which in turn correlates with their ototoxic potential in both murine cochlear explants and the guinea pig in vivo. The deleterious effects of AGs were alleviated in synthetic derivatives specially designed for the treatment of genetic diseases caused by nonsense mutations and possessing low affinity toward mitochondrial ribosomes. This work highlights the benefit of a mechanism-based drug redesign strategy that can maximize the translational value of "readthrough therapy" while mitigating drug-induced side effects. This approach holds promise for patients suffering from genetic diseases caused by nonsense mutations.

Identification of genes involved in low aminoglycoside-induced SOS response inVibrio cholerae: a role for transcription stalling and Mfd helicase

Sub-inhibitory concentrations (sub-MIC) of antibiotics play a very important role in selection and development of resistances. Unlike Escherichia coli, Vibrio cholerae induces its SOS response in presence of sub-MIC aminoglycosides. A role for oxidized guanine residues was observed, but the mechanisms of this induction remained unclear. To select for V. cholerae mutants that do not induce low aminoglycoside-mediated SOS induction, we developed a genetic screen that renders induction of SOS lethal. We identified genes involved in this pathway using two strategies, inactivation by transposition and gene overexpression. Interestingly, we obtained mutants inactivated for the expression of proteins known to destabilize the RNA polymerase complex. Reconstruction of the corresponding mutants confirmed their specific involvement in induction of SOS by low aminoglycoside concentrations. We propose that DNA lesions formed on aminoglycoside treatment are repaired through the formation of single-stranded DNA intermediates, inducing SOS. Inactivation of functions that dislodge RNA polymerase leads to prolonged stalling on these lesions, which hampers SOS induction and repair and reduces viability under antibiotic stress. The importance of these mechanisms is illustrated by a reduction of aminoglycoside sub-MIC. Our results point to a central role for transcription blocking at DNA lesions in SOS induction, so far underestimated.

Mitochondrial Peroxiredoxin 3 Regulates Sensory Cell Survival in the Cochlea

This study delineates the role of peroxiredoxin 3 (Prx3) in hair cell death induced by several etiologies of acquired hearing loss (noise trauma, aminoglycoside treatment, age). In vivo, Prx3 transiently increased in mouse cochlear hair cells after traumatic noise exposure, kanamycin treatment, or with progressing age before any cell loss occurred; when Prx3 declined, hair cell loss began. Maintenance of high Prx3 levels via treatment with the radical scavenger 2,3-dihydroxybenzoate prevented kanamycin-induced hair cell death. Conversely, reducing Prx3 levels with Prx3 siRNA increased the severity of noise-induced trauma. In mouse organ of Corti explants, reactive oxygen species and levels of Prx3 mRNA and protein increased concomitantly at early times of drug challenge. When Prx3 levels declined after prolonged treatment, hair cells began to die. The radical scavenger p-phenylenediamine maintained Prx3 levels and attenuated gentamicin-induced hair cell death. Our results suggest that Prx3 is up-regulated in response to oxidative stress and that maintenance of Prx3 levels in hair cells is a critical factor in their susceptibility to acquired hearing loss.

Extracellular DNA Shields against Aminoglycosides in Pseudomonas aeruginosa Biofilms

Within recent years, it has been established that extracellular DNA is a key constituent of the matrix of microbial biofilms. In addition, it has recently been demonstrated that DNA binds positively charged antimicrobials such as aminoglycosides and antimicrobial peptides. In the present study, we provide evidence that extracellular DNA shields against aminoglycosides in Pseudomonas aeruginosa biofilms. We show that exogenously supplemented DNA integrates into P. aeruginosa biofilms and increases their tolerance toward aminoglycosides. We provide evidence that biofilms formed by a DNA release-deficient P. aeruginosa quorum-sensing mutant are more susceptible to aminoglycoside treatment than wild-type biofilms but become rescued from the detrimental action of aminoglycosides upon supplementation with exogenous DNA. Furthermore, we demonstrate that exposure to lysed polymorphonuclear leukocytes, which are thought to be a source of extracellular DNA at sites of infections, increases the tolerance of P. aeruginosa biofilms toward aminoglycosides. Although biofilm-associated aminoglycoside tolerance recently has been linked to extracellular DNA-mediated activation of the pmr genes, we demonstrate that the aminoglycoside tolerance mediated by the presence of extracellular DNA is not caused by activation of the pmr genes in our P. aeruginosa biofilms but rather by a protective shield effect of the extracellular DNA.

CPC-139 Therapeutic Drug Monitoring For Glycopeptides and Aminoglycosides: Actual Situation and Perspectives in a French University Hospital

BackgroundOptimising glycopeptide and aminoglycoside treatment with Therapeutic Drug Monitoring is recommended. Under-dosing can lead to resistance and ineffective treatment while over-dosing is associated with toxicity.Purpose To evaluate current practise by...

GRP-062 Evaluation of Gentamicin Therapy For Elderly Hospitalised Patients

BackgroundNew guidelines for the use of aminoglycosides were published by French National Health Authority in March 2011 [1]. They recommended 3–5 mg/kg/d for 48–72 h. Before, aminoglycosides doses were reduced...

Hyperammonemic Encephalopathy Associated with Portal Vein Thrombosis in a Thoroughbred Foal

Hyperammonemic Encephalopathy Associated with Portal Vein Thrombosis in a Thoroughbred Foal

Rational use of aminoglycosides—Review and recommendations by the Swedish Reference Group for Antibiotics (SRGA)

The Swedish Reference Group for Antibiotics (SRGA) has carried out a risk-benefit analysis of aminoglycoside treatment based on clinical efficacy, antibacterial spectrum, and synergistic effect with beta-lactam antibiotics, endotoxin release, toxicity, and side effects. In addition, SRGA has considered optimal dosage schedules and advice on serum concentration monitoring, with respect to variability in volume of drug distribution and renal clearance. SRGA recommends that aminoglycoside therapy should be considered in the following situations: (1) progressive severe sepsis and septic shock, in combination with broad-spectrum beta-lactam antibiotics, (2) sepsis without shock, in combination with broad-spectrum beta-lactam antibiotics if the infection is suspected to be caused by multi-resistant Gram-negative pathogens, (3) pyelonephritis, in combination with a beta-lactam or quinolone until culture and susceptibility results are obtained, or as monotherapy if a serious allergy to beta-lactam or quinolone antibiotics exists, (4) serious infections caused by multi-resistant Gram-negative bacteria when other alternatives are lacking, and (5) endocarditis caused by difficult-to-treat pathogens when monotherapy with beta-lactam antibiotics is not sufficient. Amikacin is generally more active against extended-spectrum beta-lactamase (ESBL)-producing and quinolone-resistant Escherichia coli than other aminoglycosides, making it a better option in cases of suspected infection caused by multidrug-resistant Enterobacteriaceae. Based on their resistance data, local drug committees should decide on the choice of first-line aminoglycoside. Unfortunately, aminoglycoside use is rarely followed up with audiometry, and in Sweden we currently have no systematic surveillance of adverse events after aminoglycoside treatment. We recommend routine assessment of adverse effects, including hearing loss and impairment of renal function, if possible at the start and after treatment with aminoglycosides, and that these data should be included in hospital patient safety surveillance and national quality registries.

Tularemia in Central Anatolia

Tularemia is a bacterial zoonosis with diverse clinical manifestations depending on bacterial subspecies and the route of the infection. We collected data prospectively of cases diagnosed and treated for tularemia in our institution during the epidemics from December 2009 to August 2011. Specific antibodies were screened by a microagglutination test. Throat swab and lymph node aspirate cultures were obtained and polymerase chain reaction (PCR) was performed on these specimens. Lymph nodes were characterized on the basis of ultrasound reports. A total of 139 patients were confirmed with tularemia. The age range of the patients was 6-83 years (mean: 43) and 84 (60.4 %) of them were females. Patients had clinical presentations compatible with oropharyngeal (74 %), glandular (15.8 %), and oculoglandular (5.0 %) tularemia. Ultrasonography (US) was performed in 108 patients. Antibiotics (aminoglycosides, quinolones, and doxycycline) were used in 138 patients. Fine-needle aspiration (FNA) or surgical drainage of fluctuant lymph nodes were performed in 51 (39 %) patients. Therapeutic failure was observed in 43 (30.9 %) patients. Elevation of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were observed to be significantly higher in patients with therapeutic failures (p = 0.003 and 0.004, respectively). The success rate was significantly higher in patients with early treatment (p = 0.004). No difference was found between the effectiveness of aminoglycoside or quinolone treatments. The increase in the short and long axes, and the characteristics of lymph nodes detected on US were significantly associated with treatment failures (p < 0.001). Intranodal necrosis was found in 45 patients. The treatment success rate was 40 % in patients with intranodal necrosis. To the best of our knowledge, this is the first study defining the US findings of patients with tularemia and its association with treatment success. Ciprofloxacin is an effective and convenient choice in epidemics of tularemia and early treatment is still the cornerstone of successful therapies.