Aminoglycoside Therapy Research Articles

Piplartine attenuates aminoglycoside-induced TRPV1 activity and protects from hearing loss in mice.

Hearing loss is a major health concern in our society, affecting more than 400 million people worldwide. Among the causes, aminoglycoside therapy can result in permanent hearing loss in 40% to 60% of patients receiving treatment, and despite these high numbers, no drug for preventing or treating this type of hearing loss has yet been approved by the US Food and Drug Administration. We have previously conducted high-throughput screenings of bioactive compounds, using zebrafish as our discovery platform, and identified piplartine as a potential therapeutic molecule. In the present study, we expanded this work and characterized piplartine's physicochemical and therapeutic properties. We showed that piplartine had a wide therapeutic window and neither induced nephrotoxicity in vivo in zebrafish nor interfered with aminoglycoside antibacterial activity. In addition, a fluorescence-based assay demonstrated that piplartine did not inhibit cytochrome C activity in microsomes. Coadministration of piplartine protected from kanamycin-induced hair cell loss in zebrafish and protected hearing function, outer hair cells, and presynaptic ribbons in a mouse model of kanamycin ototoxicity. Last, we investigated piplartine's mechanism of action by phospho-omics, immunoblotting, immunohistochemistry, and molecular dynamics experiments. We found an up-regulation of AKT1 signaling in the cochleas of mice cotreated with piplartine. Piplartine treatment normalized kanamycin-induced up-regulation of TRPV1 expression and modulated the gating properties of this receptor. Because aminoglycoside entrance to the inner ear is, in part, mediated by TRPV1, these results suggested that by regulating TRPV1 expression, piplartine blocked aminoglycoside's entrance, thereby preventing the long-term deleterious effects of aminoglycoside accumulation in the inner ear compartment.

Acute kidney injury in Staphylococcus aureus bacteraemia: a recurrent events analysis

ObjectivesTo estimate risk factors for acute kidney injury (AKI) and the effect of AKI on mortality in Staphylococcus aureus bacteraemia, while taking into account recurrent AKI episodes, competing risks, time-varying variables, and time-varying effects. MethodsWe performed an unplanned analysis using data from a multicentre cohort study of patients with Staphylococcus aureus bacteraemia (SAB). The primary outcome was cumulative incidence of AKI, according to Kidney Disease Improving Global Outcomes definitions. ResultsWe included 453 patients in this study of whom 194 (43%) patients experienced one or more AKI episodes. Age (hazard ratio (HR) 1.013, 95% CI 1.001–1.024), Charlson comorbidity index (HR 1.07, 95% CI 1.01–1.14), prior chronic kidney disease (HR 1.76, 95% CI 1.28–2.42), septic shock (HR 3.28, 95% CI 2.31–4.66), persistent bacteraemia (HR 1.53, 95% CI 1.08–2.17), and vancomycin therapy (HR 1.80, 95% CI 1.05–3.09) were independently associated with AKI, but flucloxacillin, cefazolin, rifampicin, and aminoglycoside therapy were not. After adjustment for confounders and immortal time bias, AKI was associated with an increased risk of 90-day mortality (HR 4.26, 95% CI 2.91–6.23). DiscussionThe incidence of AKI in SAB is high and a substantial proportion of patients develop recurrent episodes of AKI after recovery. AKI is specifically linked to the use of vancomycin and not to anti-staphylococcal penicillins. The clinical outcome of patients with SAB complicated by AKI is worse than previously estimated.

Exciting Bacteria to a Hypersensitive State for Enhanced Aminoglycoside Therapy by a Rationally Constructed AIE Luminogen.

The diminishing effectiveness of existing aminoglycoside antibiotics (AGs) compels scientists to seek new approaches to enhance the sensitivity of current AGs. Despite ongoing efforts, currently available approaches remain restricted. Herein, a novel strategy involving the rational construction of an aggregation-induced-emission luminogen (AIEgen) is introduced to significantly enhance Gram-positive bacteria's susceptibility to AGs. The application of this approach involves the simple addition of AIEgens to bacteria followed by a 5 min light irradiation. Under light exposure, AIEgens efficiently generate reactive oxygen species (ROS), elevating intrabacterial ROS levels to a nonlethal threshold. Post treatment, the bacteria swiftly enter a hypersensitive state, resulting in a 21.9-fold, 15.5-fold, or 7.2-fold increase in susceptibility to three AGs: kanamycin, gentamycin, and neomycin, respectively. Remarkably, this approach is specific to AGs, and the induced hypersensitivity displays unparalleled longevity and heritability. Further in vivo studies confirm a 7.0-fold enhanced bactericidal ability of AGs against Gram-positive bacteria through this novel approach. This research not only broadens the potential applications of AIEgens but also introduces a novel avenue to bolster the effectiveness of AGs in combating bacterial infections.

Priorities for hearing loss prevention and estimates of global cause-specific burdens of hearing loss: a systematic rapid review

Hearing loss affects approximately 1·6 billion individuals worldwide. Many cases are preventable. We aimed to estimate the annual number of new hearing loss cases that could be attributed to meningitis, otitis media, congenital rubella syndrome, cytomegalovirus, and ototoxic medications, specifically aminoglycosides, platinum-based chemotherapeutics, and antimalarials. We used a targeted and a rapid systematic literature review to calculate yearly global incidences of each cause of hearing loss. We estimated the prevalence of hearing loss for each presumed cause. For each cause, we calculated the global number of yearly hearing loss cases associated with the exposure by multiplying the estimated exposed population by the prevalence of hearing loss associated with the exposure, accounting for mortality when warranted. An estimated 257·3 million people per year are exposed to these preventable causes of hearing loss, leading to an estimated 33·8 million new cases of hearing loss worldwide per year. Most hearing loss cases were among those with exposure to ototoxic medications (19·6 million [range 12·6 million-27·9 million] from short-course aminoglycoside therapy and 12·3 million from antimalarials). We estimated that 818 000 cases of hearing loss were caused by otitis media, 346 000 by meningitis, 114 000 by cytomegalovirus, and 59 000 by congenital rubella syndrome. The global burden of preventable hearing loss is large. Hearing loss that is attributable to disease sequelae or ototoxic medications contributes substantially to the global burden of hearing loss. Prevention of these conditions should be a global health priority. The US National Institute on Deafness and Other Communication Disorders and the US National Institute on Aging.

P03 Amikacin drug levels and efficacy—a 3 month remissive study

Abstract Background The therapeutic drug monitoring (TDM) of toxic drugs is a routine practice in our 200-bed hospital. Amikacin is not often used except in MDR bacteria. TDM is based on trough and peak levels of aminoglycosides, although AUC TDM may be the way forward, as discussed in the conclusions. According to the literature, measurement of serum amikacin levels is indicated in cases when prolonged aminoglycoside therapy is expected or in patients with compromised renal function and is not recommended for aminoglycoside use for less than 5–7 days or for treatment of mild infections in patients with no risk factors for drug toxicity. Objectives This study delivers some controversy on not to recommend monitoring for aminoglycoside use for less than 5–7 days, or for treatment of mild infections in patients with no risk factors for drug toxicity. Methods A retrospective study was conducted in our hospital between May and June 2023. Five patients aged 62–82 years on amikacin therapy for 5 to 10 days were included, all with Klebsiella pneumoniae OXA-48 UTI. At least two peak and trough samples were collected, and data were submitted to the Precise PK© software for precision dosing. The software is designed to predict population-based levels and patient-based levels. Interpretation of these values by pharmacists delivers optimized/viable amikacin intervals and dose individualized recommendations. Results Results are shown in Table 1. Conclusions Serum amikacin monitoring should guide therapy to ensure adequate levels, especially in Gram-negative resistant bacterial infections. According to these results, with Gram-negative resistant bacteria, it is worth monitoring even the short treatments—as seen in Patient 3. AUC TDM instead of peak TDM might be the way forward— this obviates distribution phase underdosing and delivers more accurate correlation to efficacy after changing intervals.

Re-telling the story of aminoglycoside ototoxicity: tales from sub-Saharan Africa.

Aminoglycosides, such as Streptomycin, are cheap, potent antibiotics widely used Sub-Saharan Africa. However, aminoglycosides are the commonest cause of ototoxicity. The limited prospective epidemiological studies on aminoglycoside ototoxicity from Sub-Saharan Africa motivated this study to provide epidemiological information on Streptomycin-induced ototoxicity, identify risk factors and predictors of ototoxicity. A longitudinal study of 153 adults receiving Streptomycin-based anti-tuberculous drugs was done. All participants underwent extended frequency audiometry and had normal hearing thresholds at baseline. Hearing thresholds were assessed weekly for 2 months, then monthly for the subsequent 6 months. Ototoxicity was determined using the ASHA criteria. Descriptive statistics were used to analyze socio-demographic variables. Ototoxicity incidence rate was calculated, and Kaplan-Meier estimate used to determine cumulative probability of ototoxicity. Chi-square test was done to determine parameters associated with ototoxicity and Cox regression models were used to choose the predictors of ototoxicity. Age of participants was 41.43 ± 12.66 years, with a male-to-female ratio of 1:0.6. Ototoxicity was found in 34.6% of the participants, giving an incidence of 17.26 per 1,000-person-week. The mean onset time to ototoxicity was 28.0 ± 0.47 weeks. By 28th week, risk of developing ototoxicity for respondents below 40 years of age was 0.29, and for those above 40 years was 0.77. At the end of the follow-up period, the overall probability of developing ototoxicity in the study population was 0.74. A significant difference in onset of ototoxicity was found between the age groups: the longest onset was seen in <40 years, followed by 40-49 years, and shortest onset in ≥50 years. Hazard of ototoxicity was significantly higher in participants aged ≥50 years compared to participants aged ≤40 years (HR = 3.76, 95% CI = 1.84-7.65). The probability of ototoxicity at 40 g, 60 g and 80 g cumulative dose of Streptomycin was 0.08, 0.43 and 2.34, respectively. Age and cumulative dose were significant predictors of ototoxicity. The mean onset time to Streptomycin-induced ototoxicity was 28 weeks after commencement of therapy. Age and cumulative dose can reliably predict the onset of Streptomycin-induced ototoxicity. Medium to long term monitoring of hearing is advised for patients on aminoglycoside therapy.

2403. Outcomes in Infective Endocarditis due to Granulicatella species and Abiotrophia defectiva

Abstract Background Infective Endocarditis (IE) due to Granulicatella sp. and Abiotrophia defectiva (formerly known as nutritionally variant streptococci - NVS) remains a clinically important entity given difficulty in diagnosis, optimal management, and possible treatment failure outcomes. These microorganisms account for roughly 4-8% of all IE cases. To the best of our knowledge this study entails the largest single center registry in the US of Granulicatella sp. and A. defectiva IE looking at patient characteristics, survival and relapse outcomes and susceptibility data. Methods Retrospective chart review of 35 patients (13 A. defectiva, 20 Granulicatella sp. and 2 labelled as NVS) with IE admitted to our facility from January 1st, 2008, to January 1st, 2023. Results Patient characteristics including valves affected, presenting symptoms and complications can be seen in Table 1. Seven patients (20% - 5 for A. defectiva and 2 for Granulicatella sp.) had failed medical management at outside facilities prior to admission at our center. Valve replacement or repair was performed on 31 (88.6%) patients. Molecular testing was performed on 28 (80%) isolates of which all had positive identification. Susceptibilities were obtained in 22 (63%) isolates as summarized in Table 2 below. All isolates were found to be vancomycin-susceptible, and varying degrees of susceptibilities to ceftriaxone and penicillin depending on the species. Vancomycin therapy was used in 11 (31.4%) patients, ceftriaxone in 19 (54.3%) patients (combination of vancomycin and ceftriaxone in 3 patients), and penicillin in 8 (22.9%) patients. Adjuvant aminoglycoside therapy was used in only 2 (5.7%) patients (one combination with ampicillin and one with vancomycin). Average length of IV antibiotic therapy was 6 weeks post-surgery, and 5 patients were treated with an oral tail after IV antibiotics. Survival curves since hospitalization are demonstrated in Figure 1. There were no treatment failures or relapses of IE due to these organisms. Conclusion The majority of patients presented with constitutional symptoms, heart failure and embolic events. Five-year survival exceeded 80% and there were no relapses in this series. Most importantly, outcomes were excellent without the use of aminoglycosides contrary to guideline recommendations. Disclosures All Authors: No reported disclosures

Hearing assessment and treatment outcome in ENT tuberculosis at a tertiary hospital in India

AimAn attempt has been made to observe the response of anti-Koch’s treatment and the effect of anti-Koch’s treatment on hearing in ENT tuberculosis patients by pure tone audiometry.Material and methodsA prospective observational study was carried out at the Government Medical College Hospital. A total of 200 cases diagnosed with tuberculosis in the head and neck regions were included in the study. Sputum/pus of patients were sent for cartridge-based nucleic acid amplification test (CBNAAT). Hearing assessment was done with PTA1 at the start of the treatment, PTA2 after the intensive phase (IP) at 2 months for newly diagnosed patients and at 3 months for previously treated patients, and PTA3 at the end of the AKT treatment given as per guidelines.ResultsAmong 200 ENT tuberculosis patients, 176 patients were cured with a new case regimen, and one patient was a defaulter. Among 19 patients who were previously treated cases (CAT II regimen), two patients had treatment failure, and the other 17 patients were cured. Four patients diagnosed to have multidrug-resistant tuberculosis (MDR-TB) on the initial drug susceptibility testing (DST) were given 24 months’ treatment according to the recent guidelines of MDR-TB treatment regimen, and the patients were cured. In the present study of 200 patients, in the first PTA, 192 patients had normal hearing; in the second PTA, 106 patients had normal hearing; and in the third PTA, 35 patients had normal hearing. 21.7% of cases who were on aminoglycoside therapy developed significant sensorineural hearing loss in high frequency.ConclusionAnti-Koch’s treatment (AKT) has proven effective in ENT tuberculosis. All patients taking anti-Koch’s treatment should be regularly monitored for hearing loss, adherence to treatment, drug-resistant variants, and local recurrences.

Early and Long-Term Ototoxicity Noted in Children Due to Platinum Compounds: Prevalence and Risk Factors.

Platinum compounds are a group of fundamental chemotherapeutics used in the treatment of solid tumors, but they are burdened by side effects, such as ototoxicity. The objective of this study was to evaluate the incidence of ototoxicity caused by platinum compounds and the risk factors affecting its appearance/progression. Data from 53 patients who received platinum compounds and who had been off therapy for at least 5 years were analyzed. We collected data relating to audiometry conducted annually from the end of treatment and for at least 5 subsequent years, as well as information concerning the oncological history and comorbidities. At the end of the treatment, 17 patients (32.08%) presented ototoxicity, according to the Boston SIOP Ototoxicity Scale; the risk factors included a higher serum creatinine value at diagnosis, having undergone cranial radiotherapy, and needing magnesium supplementation. After 5 years from the end of the treatment, the number of patients with exhibiting ototoxicity was 31 (58.5%); the factors that influenced the onset/progression of the damage were having undergone radiotherapy (HR 1.23; p < 0.01) and having received therapy with aminoglycosides (HR 1.27; p < 0.01). Ototoxicity caused by platinum compounds can occur even after the conclusion of the treatments, and the factors affecting its progression are radiotherapy and the aminoglycosides therapy.

39: INCIDENCE OF DETECTABLE DRUG LEVELS WITH INHALED AMINOGLYCOSIDE THERAPY IN CRITICALLY ILL ADULTS

Introduction: Advantages of aminoglycosides administered via inhalation include achievement of high concentrations in the lung parenchyma, optimization of concentration-dependent bactericidal killing, and minimization of dose-dependent systemic toxicity. Systemic accumulation of inhaled antibiotic therapy has been reported, though is poorly understood. The objective of this study is to characterize the incidence of a detectable drug level (DDL) in critically ill patients that received inhaled aminoglycoside therapy. Methods: This retrospective, single-center study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during intensive care unit (ICU) hospitalization between January 1, 2009, and July 1, 2020. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn as a trough. Drug levels were considered detectable for tobramycin ≥ 0.5 mcg/mL or amikacin ≥ 1.5 mcg/mL. Results: A total of 93 drug levels in 54 critically ill patients were included in the study. Median age was 44.5 years; median BMI was 20; 43 (79.6%) patients were lung transplant recipients and 20 (37%) patients had cystic fibrosis. A DDL was observed for 39 (41.9%) levels: 29 (31.2%) tobramycin and 10 (10.7%) amikacin. The median DDL was 3.7 mcg/mL (IQR 1.98-4.53) for amikacin and 0.9 mcg/mL for tobramycin (IQR 0.7 -1.6). Therapy was modified in 30 (76.9%) DDLs: frequency reduction in 18 (60%), therapy discontinuation in 6 (20%), dose and frequency reduction in 4 (13.3%), and dose reduction in 2 (6.7%). Conclusions: For critically ill adults receiving inhaled aminoglycoside therapy, approximately 40% of drug levels evaluated were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy. Future trials with protocolized therapeutic drug monitoring and clinical outcomes and safety endpoints associated with dose adjustments are needed for patients receiving inhaled aminoglycoside therapy.

Incidence and associated risk factors for systemic drug levels with inhaled aminoglycoside therapy.

To characterize the incidence of and risk factors for a detectable drug level (DDL) in patients that received inhaled aminoglycoside therapy. This retrospective, single-centre study included adult patients who received at least one dose of an inhaled aminoglycoside with a drug level during inpatient hospitalization. Patients were excluded if they received an aminoglycoside intravenously within 7 days or if the drug level was not drawn within 4 h of the next dose. A repeated measures logistic regression model evaluated the association between potential risk factors and a DDL. Among 286 drug levels, 88 (30.8%) drug levels were detectable. In multivariable analysis, cystic fibrosis (CF) (OR: 3.03; 95% CI: 1.10-8.35), chronic kidney disease (CKD) (OR: 4.25; 95% CI: 1.84-9.83), lung transplant recipient (OR: 3.08; 95% CI: 1.09-8.73), mechanical ventilation (OR: 2.99; 95% CI: 1.25-7.15) and tobramycin (OR: 5.26; 95% CI: 2.35-11.78) were associated with higher odds of a DDL. Among those with a DDL, inhaled aminoglycoside type and drug level concentration were not associated with acute kidney injury (P = 0.161). Among 286 drug levels identified among inpatients receiving inhaled aminoglycoside therapy, 88 (30.8%) unique drug levels were detectable. Based on the results of this study, periodic trough concentrations should be considered for patients receiving inhaled aminoglycoside therapy with CF, CKD, lung transplantation, mechanical ventilation or tobramycin.

Aminoglycoside Therapy for Tuberculosis: Evidence for Ototoxicity among Tuberculosis Patients in Ghana.

Background: Hearing impairment (HI) is a major problem in Ghana; however, the few attempts at shedding light on its causes appear to overlook the adverse effects of some medications—a gap that this study sought to fill. Aminoglycoside therapy for tuberculosis (TB) treatment is one of these medications. Aim: The aim of this study was to establish the potential of aminoglycoside as a cause of hearing impairment among patients on anti-TB treatment. Method: This was a case–control study, involving patients receiving treatment for TB with aminoglycoside at the chest clinic of the Tema General Hospital and a control group of age- and gender-matched healthy volunteers. A structured questionnaire was administered to obtain the demographic data and case history of the participants. The hearing sensitivity of the participants was assessed using conventional pure tone audiometry and transient evoked otoacoustic emission tests. Results: A hearing loss prevalence of 20% (12/60) was found among patients receiving treatment for TB, with the intensity of impairment ranging from mild to severe. Hearing thresholds of patients receiving anti-TB medications were significantly elevated (p < 0.05) in comparison to the thresholds of the control group, especially at the high frequencies. Conclusion: This study shows that aminoglycoside therapy for tuberculosis may contribute to hearing impairment among tuberculosis patients in Ghana. Audiological management of these patients should therefore be an essential part of their therapeutic treatment plan.

Gemella morbillorum an underappreciated cause of endocarditis: Case report and review of 37 cases

Background: Gemella morbillorum is a part of the human oral flora and associated with endocarditis. Gemella morbillorum is difficult to identify and is associated with but an underappreciated cause of endocarditis; Review of 37 such cases showed susceptibility data is generally anecdotal. Mortality was associated with the recommended combination (beta-lactam plus aminoglycoside) therapy. Methods: Search of internet databases. Results: We review data on 37 cases. Native valve involvement occurred in 43%, and 57% had predisposing cardiac conditions; the median age was 53 years and most were male (68%). Death occurred in 5 patients (5/37, 13.5%) who were treated with combination therapy of gentamicin plus penicillin/ampicillin. Conclusion: G. morbillorum is a not infrequent cause of endocarditis. There was no correlation with susceptibility of the isolates and mortality. Optimal therapy remains to be defined.

Synergistic Antibacterial Effects of Meropenem in Combination with Aminoglycosides against Carbapenem-Resistant Escherichia coli Harboring blaNDM-1 and blaNDM-5.

Infections due to carbapenem-resistant Escherichia coli (CREC) are problematic due to limitation in treatment options. Combination therapies of existing antimicrobial agents have become a reliable strategy to control these infections. In this study, the synergistic effects of meropenem in combination with aminoglycosides were assessed by checkerboard and time-kill assays. Of the 35 isolates, 19 isolates (54.3%) were resistant to carbapenems (imipenem and meropenem) with the MIC ranges from 16 to 128 µg/mL. These isolates were resistant to almost all antibiotic classes. Molecular characteristics revealed co-harboring of carbapenemase (blaNDM-1, blaNDM-5 and blaOXA-48) and extended-spectrum β-lactamases (ESBL) genes (blaCTX-M, blaSHV and blaTEM). The checkerboard assay displayed synergistic effects of meropenem and several aminoglycosides against most CREC isolates. Time-kill assays further demonstrated strong synergistic effects of meropenem in combination with either amikacin, gentamicin, kanamycin, streptomycin, and tobramycin. The results suggested that meropenem in combination with aminoglycoside therapy might be an efficient optional treatment for infections cause by CREC.

Outcomes of Resectional Thoracic Surgery for the Treatment of Pulmonary Nontuberculous Mycobacterial Disease in 105 Patients in the United States

Outcomes of Resectional Thoracic Surgery for the Treatment of Pulmonary Nontuberculous Mycobacterial Disease in 105 Patients in the United States

Use of Doxycycline in a Renal Impaired Patient with Enteroccocal Sepsis

Aim: This report highlights the use of doxycycline therapy other than the more standard regimen that includes an aminoglycoside in the management of enterococcal infection in patients with renal impairment without causing further damages to the kidney due to aminoglycoside therapy.&#x0D; Presentation of Case: A case of enteroccocal septicemia in a 29-year-old woman who was admitted on account of acute kidney injury secondary to pregnancy induced hypertension in the setting of pre-eclampsia. She was referred from another centre where she had emergency caesarean section done on account of severe pre-eclampsia at 36 weeks gestational age. Blood culture yielded Enterococcus species. When other antibiotic regimen failed, she was started on doxycycline. Patient had good clinical response and was discharged 7 days after commencement of doxycycline.&#x0D; Discussion: Enteroccoci have emerged as important agent of human disease largely because of their resistance to antimicrobial agents. They are important nosocomial pathogens capable of causing serious and potentially life-threatening infections, including sepsis. The incidence of enteroccocal infections, mainly hospital-acquired, has increased over the past 2 decades and isolates with novel mechanism of resistance to antimicrobial agents are more and more frequent. Furthermore, they have great capacity for transmitting these resistances to other species and even to other genera.&#x0D; Conclusion: Doxycycline is a safe and effective alternative antibiotic for the treatment of enterococcal sepsis in patients with impaired renal status.

Bolus Versus Prolonged Infusion of Broad-Spectrum Beta-Lactams for Patients with Hematologic Malignancies and High Risk Febrile Neutropenia - a Single Center Prospective Unblinded Randomized Trial

▪Background: Neutropenic fever is a life-threatening condition which is common in patients with hematologic malignancies, and prompt initiation of appropriate antibiotics is of great importance.Empirical treatment includes monotherapy with a beta-lactam containing anti-pseudomonal activity. Theoretically, time-dependent antibiotics are most active when administered as a continuous infusion, but evidence is lacking in cases of febrile neutropenia. This study examines the optimal dosing regimen (bolus infusion vs. prolonged 4 hour-infusion) for high risk patients undergoing hematopoietic cell transplantation or patients with acute leukemia and febrile neutropenia.Methods: This was a single center, prospective, unblinded randomized study, of 123 hospitalized hematologic patients enrolled between July 2015 and March 2017. The primary outcome was a successful response to treatment, defined as the combination of- defervescence at 96 hours after initiation of broad spectrum beta-lactams (pipracillin/tazobactam or ceftazidime) or before, sterile cultures after 72-96 hours, and no requirement of additional aminoglycoside therapy after 48 hours. Secondary outcomes included breakthrough fever or additional infection after 5 days from initiation of treatment, death within 30 days of study enrollment, duration of hospitalization, duration of neutropenia, occurrence of renal failure (doubling of serum creatinine levels) within 5 days, and requirement for noradrenaline due to hypotension. Patients were randomized using a computerized random number program and allocation was concealed by sequentially numbered sealed and opaque envelopes. All patients signed informed consent and the study was approved by the Tel Aviv Medical Center Institutional Review Board.Results: 123 patients were randomized to bolus infusion (n=63) and prolonged infusion (n=60). Febrile neutropenia occurred in 87% of the patients, and these patients were eligible for the intention-to-treat analysis (ITT). 73% of the patients were given at least one dose of antibiotic according to the allocation arm and were eligible for the per-protocol analysis, Figure. The patients' baseline characteristics were well-balanced between the 2 groups, Table 1. In the ITT analysis (Table 2), there was a higher success rate in patients allocated to the prolonged infusion arm, compared to those allocated to the bolus infusion arm (76% vs. 55%, p= .03). This was also true for the subgroups of patients with microbiologically documented infections (MDI) - (55.6% vs. 7.7%, p=.013) and blood stream infections, (BSI) - (67% vs. 8.3%, p=.009). Similarly, in the per-protocol analysis, the success rate was higher in patients allocated to the prolonged infusion arm who had MDI (62.5% vs. 12.5%, p=.039) or BSI (80% vs. 14.3%, p=.023). There was no difference in the secondary endpoint outcomes between the 2 groups. 30-day death rate was similarly low in both groups. Prolonged beta-lactam infusion was associated with significantly higher treatment success in a logistic regression model that included either BSI (odds ratio of 2.4, 95% CI 0.97-6.1, p=.058) or MDI (OR 2.8, 95% CI 1.1-7.4, p=.032) .Conclusions: This is the first randomized study showing superior treatment outcomes in patients with high-risk febrile neutropenia treated with prolonged versus bolus beta-lactam infusion. Optimization of beta-lactam dosing is a widely available and cost-effective strategy to improve treatment outcomes in patients with high risk febrile neutropenia. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Appropriateness of empirical antibiotic therapy and added value of adjunctive gentamicin in patients with septic shock: a prospective cohort study in the ICU

Objectives To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection. Methods Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal. Results Of 203 septic shock patients, with abdominal (n = 143), urogenital (n = 27) or unknown (n = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal (p = .223). A fungal infection was present in 22 patients (11%). Conclusion Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Effect of Gentamicin on Urinary Calcium Creatinine Ratio and Serum Calcium in Neonates

Introduction: Gentamicin was associated with an apparent increase in the number of neonates with symptoms of hypocalcemia, including seizures. Aim of the study: This study aimed to assess the effect of gentamicin on calcium /creatinine ratio in urine and serum calcium in neonates. Methods: This case-control study included 100 children, divided into two groups. Group I: Fifty neonates received gentamicin. Group II: Fifty neonates did not receive antibiotics at all (control group), Serum calcium and urinary calcium/creatinine ratio, were done at 1st day of admission, and at day 3 and 6 of aminoglycosides therapy. Results: On admission, serum calcium showed a non-significant difference between both groups, P-value was 0.453. On the 3rd day, serum calcium was significantly lower in cases compared to controls with P-value was Conclusion: Gentamicin was associated with decreased serum calcium and increased urinary calcium excretion on 3rd day and 6th day of treatment, so cautious and proper monitoring of serum calcium is mandatory in neonates treated with gentamycin.

Electrolyte and Acid-Base Disorders Triggered by Aminoglycoside or Colistin Therapy: A Systematic Review.

Aminoglycoside or colistin therapy may alter the renal tubular function without decreasing the glomerular filtration rate. This association has never been extensively investigated. We conducted a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations. Databases searched included United States National Library of Medicine, Excerpta Medica, and Web of Science. For the final analysis, we evaluated 46 reports, published after 1960, describing 82 cases. A total of 286 electrolyte and acid-base disorders were reported. Hypomagnesemia, hypokalemia, and hypocalcemia were reported in more than three quarter of cases. Further disorders were, in decreasing order of frequency, metabolic alkalosis, hyponatremia, hypophosphatemia, hypouricemia, hypernatremia, and metabolic acidosis. Six electrolyte and acid-base disorders were reported in seven cases, five in 12 cases, four in 16 cases, three in 31 cases, two in 11 cases, and one in five cases. Laboratory features consistent with a loop of Henle/distal tubular dysfunction were noted in 56 (68%), with a proximal tubular dysfunction in three (3.7%), and with a mixed dysfunction in five (6.1%) cases. The laboratory abnormality was unclassified in the remaining 18 (22%) cases. Treatment with aminoglycosides or colistin may trigger a proximal tubular or, more frequently, a loop of Henle/distal tubular dysfunction.