Non-aminoglycoside Antibiotics Research Articles

Mortality risks associated with empirical antibiotic activity in Escherichia coli bacteraemia: an analysis of electronic health records.

BackgroundReported bacteraemia outcomes following inactive empirical antibiotics (based on in vitro testing) are conflicting, potentially reflecting heterogeneity in causative species, MIC breakpoints defining resistance/susceptibility, and times to rescue therapy.MethodsWe investigated adult inpatients with Escherichia coli bacteraemia at Oxford University Hospitals, UK, from 4 February 2014 to 30 June 2021 who were receiving empirical amoxicillin/clavulanate with/without other antibiotics. We used Cox regression to analyse 30 day all-cause mortality by in vitro amoxicillin/clavulanate susceptibility (activity) using the EUCAST resistance breakpoint (>8/2 mg/L), categorical MIC, and a higher resistance breakpoint (>32/2 mg/L), adjusting for other antibiotic activity and confounders including comorbidities, vital signs and blood tests.ResultsA total of 1720 E. coli bacteraemias (1626 patients) were treated with empirical amoxicillin/clavulanate. Thirty-day mortality was 193/1400 (14%) for any active baseline therapy and 52/320 (16%) for inactive baseline therapy (P = 0.17). With EUCAST breakpoints, there was no evidence that mortality differed for inactive versus active amoxicillin/clavulanate [adjusted HR (aHR) = 1.27 (95% CI 0.83–1.93); P = 0.28], nor of an association with active aminoglycoside (P = 0.93) or other active antibiotics (P = 0.18). Considering categorical amoxicillin/clavulanate MIC, MICs > 32/2 mg/L were associated with mortality [aHR = 1.85 versus MIC = 2/2 mg/L (95% CI 0.99–3.73); P = 0.054]. A higher resistance breakpoint (>32/2 mg/L) was independently associated with higher mortality [aHR = 1.82 (95% CI 1.07–3.10); P = 0.027], as were MICs > 32/2 mg/L with active empirical aminoglycosides [aHR = 2.34 (95% CI 1.40–3.89); P = 0.001], but not MICs > 32/2 mg/L with active non-aminoglycoside antibiotic(s) [aHR = 0.87 (95% CI 0.40–1.89); P = 0.72].ConclusionsWe found no evidence that EUCAST-defined amoxicillin/clavulanate resistance was associated with increased mortality, but a higher resistance breakpoint (MIC > 32/2 mg/L) was. Additional active baseline non-aminoglycoside antibiotics attenuated amoxicillin/clavulanate resistance-associated mortality, but aminoglycosides did not. Granular phenotyping and comparison with clinical outcomes may improve AMR breakpoints.

Ototoxicity of Non-aminoglycoside Antibiotics

It is well-known that aminoglycoside antibiotics can cause significant hearing loss and vestibular deficits that have been described in animal studies and in clinical reports. The purpose of this review is to summarize relevant preclinical and clinical publications that discuss the ototoxicity of non-aminoglycoside antibiotics. The major classes of antibiotics other than aminoglycosides that have been associated with hearing loss in animal studies and in patients are discussed in this report. These antibiotics include: capreomycin, a polypeptide antibiotic that has been used to treat patients with drug-resistant tuberculosis, particularly in developing nations; the macrolides, including erythromycin, azithromycin and clarithromycin; and vancomycin. These antibiotics have been associated with ototoxicity, particularly in neonates. It is critical to be aware of the ototoxic potential of these antibiotics since so much attention has been given to the ototoxicity of aminoglycoside antibiotics in the literature.

Effectiveness and safety of an institutional aminoglycoside-based regimen as empirical treatment of patients with pyelonephritis.

To determine clinical outcomes associated with aminoglycosides versus other antimicrobial agents as empirical treatment of hospitalized patients with pyelonephritis. An institutional programme promoting aminoglycosides as empirical treatment of pyelonephritis was implemented in 2016. We reviewed the hospital records of patients with pyelonephritis from January 2017 to April 2019. The primary outcome was death within 30 days of index culture. Initial treatment with aminoglycoside-based regimens was compared with non-aminoglycoside antibiotics. Propensity score matching was performed to adjust for between-group differences in baseline covariates. The study cohort included 2026 patients, 715 treated with aminoglycosides and 1311 treated with non-aminoglycoside drugs (ceftriaxone, n = 774; piperacillin/tazobactam, n = 179; carbapenems, n = 161; and fluoroquinolones, n = 133); 589 patients (29%) had bloodstream infections. Treatment with aminoglycosides was associated with a higher likelihood of in vitro activity against clinical isolates (OR = 2.0; P < 0.001). Death at 30 days occurred in 55 (7.6%) versus 145 (11%) patients treated with aminoglycosides and non-aminoglycoside drugs, respectively (adjusted HR = 0.78; P = 0.013). Aminoglycosides were either superior or similar to comparator drugs in all patient subgroups, stratified according to age, glomerular filtration rate, bacteraemia, haemodynamic shock and infection with third-generation cephalosporin-resistant Enterobacteriaceae. The incidence of acute kidney injury was similar for aminoglycosides and comparators (2.5% versus 2.9%, respectively; P = 0.6). Within the context of an institutional programme, initial empirical treatment of pyelonephritis with aminoglycosides was associated with higher rates of in vitro activity and lower overall mortality compared with non-aminoglycoside drugs, without excess nephrotoxicity.

DNase I induced DNA degradation is inhibited by neomycin.

Preparations of antimicrobials from biotechnological sources containing nucleic acids may serve as vector for the dissemination of resistance genes. An essential prerequisite for the acquisition of a new resistance phenotype in a transformational scenario is the availability of physically intact DNA molecules capable of transforming competent microorganisms. DNA is thought to be an easy target for catabolic processes when present in the natural habitat of bacteria (e.g. gastrointestinal tract, soil) due to the overall presence of nucleolytic enzymes. Aminoglycoside antibiotics are known to display a strong affinity to nucleic acids rendering these compounds to be primary candidates for exerting DNA protective functions in the gastrointestinal tract when applied orally during antibiotic chemotherapy. Using a DNase I protection assay it could be demonstrated that neomycin B at a concentration of 2 mM completely inhibited degradation of plasmid DNA in vitro. No inhibition of degradation was observed with streptomycin and kanamycin and the non-aminoglycoside antibiotics oxytetracycline and ampicillin under identical assay conditions. Thus, neomycin preparations may be able to promote structural integrity of contaminating DNA-fragments in DNase-rich environments.

The effect of aminoglycoside-induced adaptive resistance on the antibacterial activity of other antibiotics against Pseudomonas aeruginosa in vitro.

The effect of gentamicin-induced adaptive resistance on the antibacterial activity of six non-aminoglycoside antibiotics was studied. Adaptive resistance was induced in Pseudomonas aeruginosa in a dynamic in-vitro model of infection. The bactericidal effect of ceftazidime, imipenem, aztreonam, ciprofloxacin, and piperacillin was not altered in the presence of adaptive resistance but the effect of rifampicin was increased.

Effects of Aminoglycoside Antibiotics on Cholinergic Autonomic Nervous Transmission

The effects of eight aminoglycoside antibiotics, gentamicin, neomycin B, ribostamycin, dibekacin B, kanamycin A, streptomycin, tobramycin and amikacin, and two non-aminoglycoside antibiotics, tetracycline and ampicillin, on cholinergic autonomic nervous transmission were studied using isolated guinea-pig ileum preparation. The aminoglycoside antibiotics blocked the transmurally elicited twitches of the ileum in a concentration-dependent manner. The blocking effect of aminoglycosides was biphasic, i.e., an initial reduction followed by a spontaneous partial recovery. Dibekacin was the most potent parasympathetic inhibitor, followed by neomycin B, tetracycline, gentamicin, streptomycin, kanamycin A, tobramycin, ribostamycin, and amikacin. Ampicillin had no blocking effect. The tested antibiotics did not affect acetylcholine (ACh)-induced contraction of the ileum, except for high concentrations of neomycin B, gentamicin, and streptomycin. The three antibiotics shifted the dose-response curves for ACh to the right without affecting the maximal contraction. Naloxon, yohimbine, hexamethonium and choline chloride failed to eliminate the blocking effect of the antibiotics on twitches of the ileum induced by transmural stimulation. However, increase of the extracellular Ca ion concentration virtually abolished the blockade. Dibekacin blocked the evoked but not the spontaneous release of ACh and shifted the dose-response curve of CaCl2-dependent transmurally elicited contractions of the ileum to the right. These results suggest that the site for the block of aminoglycosides is mainly the cholinergic nerve terminal, where they reduce the available Ca ions required for the release of ACh.

784 EFFECTS OF CONCURRENT ANTIBIOTICS ON PAIN MEDICATION REQUIREMENTS

In vitro human brain studies have indicated that aminoglycoside antibiotics may inhibit degradation of enkephalins. This study was designed to determine if requirements for pain medications in hospitalized children vary in relation to concurrent antibiotics. No published information exists concerning possible variations in amounts of pain medications required when children are concurrently receiving antibiotics. Charts of 420 children consecutively admitted to Minneapolis Children's Medical Center for surgical procedures were reviewed. Children were included in the study if they were between 2 and 17 years; were not on antibiotics or pain medications; had no prior training in self regulation techniques; and hospitalization totaled 3 days or more. Data analyzed included age, sex, diagnosis, procedures, frequency and amount of pain medications; time, frequency and amount of antibiotics; and total days of hospitalization. The study included 284 children. Of these, 118 received no antibiotics; 59 received aminoglycoside antibiotics; and 107 received non-aminoglycoside antibiotics only. Children on aminoglycoside antibiotics required significantly less narcotics on day 1 but an amount equal to non-aminoglycoside antibiotics on days 2 and 3. Children receiving aminoglycoside antibiotics received more doses of all pain medications than did other children; no differences were found when compared for prophylactic or therapeutic indications. Of 12 children who required no pain medications over the first 3 days of hospitalization, 7 were on aminoglycoside antibiotics and 5 were on other antibiotics.

Enzyme-linked immunosorbent assay for the detection of fermentation metabolites: aminoglycoside antibiotics.

A heterogeneous microplate enzyme immunoassay with a sensitivity of 10 pg/ml (1 pg/assay) toward gentamicin has been developed for the detection of aminoglycoside antibiotics in fermentation broths. Purified gentamicin antibody was coated onto the surface of the wells of microtiter plates and incubated with gentamicin-alkaline phosphatase conjugate. The amount of enzyme bound to the antibody was quantified by measuring the change in absorbance at 410 nm after the addition of the substrate, p-nitrophenylphosphate. Competitive assays performed by incubating the antibody and enzyme conjugate with various aminoglycosides showed that the antibody probe cross-reacted with all aminoglycosides tested, except neomycins B and C. No cross-reaction was detected with non-aminoglycoside antibiotics. Complex fermentation broths did not interfere with this assay. Cultures known to produce aminoglycosides were detected at levels well below the concentrations required for antimicrobial activity. This technique is useful in the identification, quantification and screening of fermentation metabolites.

Effects of Antibiotic-Diuretic Interactions in the Guinea Pig Model of Ototoxicity

The guinea pig model has been useful for estimating quantitatively the ototoxic effects of many different drugs. Our model utilizes measures of the Preyer pinna reflex, the alternating current cochlear potential and sensory hair-cell morphology to access drug effects. The principle pathophysiologic lesion of aminoglycoside-induced permanent ototoxicity appears to be sensory hair-cell loss in the organ of Corti. Aminoglycoside antibiotics were found to interact with loop-inhibiting diuretics, and the augmented ototoxic effects were attributed to hair-cell destruction. The interaction is specific for loop-inhibiting diuretics but not for the aminoglycosides since nonaminoglycoside antibiotics, such as viomycin and polymixin B, interacted similarly. Noninteractive antibiotics include amphotericin B and vancomycin. The absence of ototoxic effects with vancomycin is of interest in view of its broadening clinical utility.

Effects of Antibiotic-Diuretic Interactions in the Guinea Pig Model of Ototoxicity

The guinea pig model has been useful for estimating quantitatively the ototoxic effects of many different drugs. Our model utilizes measures of the Preyer pinna reflex, the alternating current cochlear potential, and sensory hair-cell morphology to access drug effects. The principle pathophysiologic lesion of aminoglycoside-induced permanent ototoxicity appears to be sensory hair-cell loss in the organ of Corti. Aminoglycoside antibiotics were found to interact with loop-inhibiting diuretics, and the augmented ototoxic effects were attributed to hair-cell destruction. The interaction is specific for loop-inhibiting diuretics but not for the aminoglycosides since nonaminoglycoside antibiotics, such as viomycin and polymixin B, interacted similarly. Noninteractive antibiotics include amphotericin B and vancomycin. The absence of ototoxic effects with vancomycin is of interest in view of its broadening clinical utility.

Nephrotoxicity of netilmicin in combination with non-aminoglycoside antibiotics

To assess the possibility that non-aminoglycoside antibiotics may adversely affect the nephrotoxicity of the new semisynthetic aminoglycoside netilmicin, we gave ampicillin, carbenicillin, methicillin, cefamandole, and clindamycin, either singly or in combination with netilmicin, at two dose concentrations in rats. Results were compared as to the effect of netilmicin given singly and to saline-injected and noninjected controls. Antibiotic combinations resulted in no greater nephrotoxicity than did netilmicin alone. Netilmicin concentrations in renal tissue were high, and these levels were not consistently affected by the other drugs. The data suggest that in rats the nephrotoxicity of netilmicin is not affected adversely by the presence of non-aminoglycoside antibiotics.

Simple method for elimination of aminoglycosides from serum to permit bioassay of other antimicrobial agents.

Cellulose phosphate powder can be added to serum to selectively bind aminoglycosides by ionic interaction without binding or inactivation of the penicillins, the cephalosporins, clindamycin, vancomycin, chloramphenicol, or trimethoprim. This simple, rapid technique permits the measurement of non-aminoglycoside antibiotics in the presence of aminoglycosides.

Isolation and characterization of mutants of Escherichia coli K12 resistant to the new aminoglycoside antibiotic, amikacin.

Spontaneous mutants of Escherichia coli K12 that are resistant to the new aminoglycoside antibiotic, amikacin, were isolated. These mutants have simultaneously acquired cross-resistance to kanamycin, gentamicin and neomycin but not to streptomycin or spectinomycin. Sensitivity of the mutant strains to the non-aminoglycoside antibiotics, ampicillin, tetracycline and polymyxin, was unaffected. The mutation responsible for amikacin resistance was mapped by PI transduction and found to be tightly linked to strA, distal with respect to spcA and aroE.