Aminoglycoside Therapy Research Articles

Low Adherence to Recommended Guidelines for Open Fracture Antibiotic Prophylaxis.

Prompt administration of antibiotics is a critical component of open fracture treatment. Traditional antibiotic recommendations have been a first-generation cephalosporin for Gustilo Type-I and Type-II open fractures, with the addition of an aminoglycoside for Type-III fractures and penicillin for soil contamination. However, concerns over changing bacterial patterns and the side effects of aminoglycosides have led to interest in other regimens. The purpose of the present study was to describe the adherence to current prophylactic antibiotic guidelines. We evaluated the antibiotic-prescribing practices of 24 centers in the U.S. and Canada that were participating in 2 randomized controlled trials of skin-preparation solutions for open fractures. A total of 1,234 patients were evaluated. All patients received antibiotics on the day of admission. The most commonly prescribed antibiotic regimen was cefazolin monotherapy (53.6%). Among patients with Type-I and Type-II fractures, there was 61.1% compliance with cefazolin monotherapy. In contrast, only 17.2% of patients with Type-III fractures received the recommended cefazolin and aminoglycoside therapy, with an additional 6.7% receiving piperacillin/tazobactam. There is moderate adherence to the traditional antibiotic treatment guidelines for Gustilo Type-I and Type-II fractures and low adherence for Type-III fractures. Given the divergence between current practice patterns and prior recommendations, high-quality studies are needed to determine the most appropriate prophylactic protocol.

Improvement of a Rapid and Highly Sensitive Method for the Diagnosis of the Mitochondrial m.1555A>G Mutation Based on a Single-Stranded Tag Hybridization Chromatographic Printed-Array Strip.

Aims: Pathogenic variants in mitochondrial DNA are known to be associated with sensorineural hearing loss (SNHL) and aminoglycoside-induced HL. Among them, the m.1555A>G mutation is the most common. Thus, a rapid and easy companion diagnostic method for this mutation would be desirable to prevent HL caused by aminoglycoside therapy. In this study, we report an improved protocol for the single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) method for identifying the m.1555A>G mutation.Methods: To evaluate the accuracy of a novel diagnostic for the m.1555A>G mutation we analyzed 378 DNA samples with or without the m.1555A>G mutation, as determined by Invader assay, and calculated the sensitivity, specificity, and false negative and false positive ratios of this new method.Results: The newly developed protocol was robust; we, obtained the same results using multiple DNA concentrations, differing annealing temperatures, and different polymerase chain reaction thermal cyclers. The diagnostic sensitivity based on the STH-PAS method was 0.99, and the specificity was 1.00. The false negative and false positive ratios were 0 and 0.01, respectively.Conclusion: We improved the genotyping method for m.1555A>G mutations. This assays will be useful as a rapid companion diagnostic before aminoglycoside use.

Oral cysteamine as an adjunct treatment in cystic fibrosis pulmonary exacerbations: An exploratory randomized clinical trial

BackgroundEmerging data suggests a possible role for cysteamine as an adjunct treatment for pulmonary exacerbations of cystic fibrosis (CF) that continue to be a major clinical challenge. There are no studies investigating the use of cysteamine in pulmonary exacerbations of CF. This exploratory randomized clinical trial was conducted to answer the question: In future pivotal trials of cysteamine as an adjunct treatment in pulmonary exacerbations of CF, which candidate cysteamine dosing regimens should be tested and which are the most appropriate, clinically meaningful outcome measures to employ as endpoints?Methods and findingsMulticentre double-blind randomized clinical trial. Adults experiencing a pulmonary exacerbation of CF being treated with standard care that included aminoglycoside therapy were randomized equally to a concomitant 14-day course of placebo, or one of 5 dosing regimens of cysteamine. Outcomes were recorded on days 0, 7, 14 and 21 and included sputum bacterial load and the patient reported outcome measures (PROMs): Chronic Respiratory Infection Symptom Score (CRISS), the Cystic Fibrosis Questionnaire–Revised (CFQ-R); FEV1, blood leukocyte count, and inflammatory markers. Eighty nine participants in fifteen US and EU centres were randomized, 78 completed the 14-day treatment period. Cysteamine had no significant effect on sputum bacterial load, however technical difficulties limited interpretation. The most consistent findings were for cysteamine 450mg twice daily that had effects additional to that observed with placebo, with improved symptoms, CRISS additional 9.85 points (95% CI 0.02, 19.7) p = 0.05, reduced blood leukocyte count by 2.46x109 /l (95% CI 0.11, 4.80), p = 0.041 and reduced CRP by geometric mean 2.57 nmol/l (95% CI 0.15, 0.99), p = 0.049.ConclusionIn this exploratory study cysteamine appeared to be safe and well-tolerated. Future pivotal trials investigating the utility of cysteamine in pulmonary exacerbations of CF need to include the cysteamine 450mg doses and CRISS and blood leukocyte count as outcome measures.Clinical trial registrationNCT03000348; www.clinicaltrials.gov.

Rhizobium radiobacter bacteremia in a two-year-old patient with an acute lymphoblastic leukemia: a case report

Rhizobium radiobacter is a Gram-negative rod-shaped bacterium usually associated with diseases in plants. Infections due to R. radiobacter in humans are strongly related to the presence of foreign plastic materials, immunocompromised and chronically debilitated hosts with underlying conditions such as malignancies, human immunodeficiency virus as well as bone marrow transplant recipients. The aim of this paper was to present a rare blood infection with Rhizobium radiobacter in North Macedonia in a pediatric patient with underlying conditions. The treatment was successful with appropriate cephalosporin and aminoglycoside therapy without removing the central venous catheter

Infective Endocarditis Guidelines: The Challenges of Adherence-A Survey of Infectious Diseases Clinicians.

BackgroundGuidelines exist to aid clinicians in managing patients with infective endocarditis (IE), but the degree of adherence with guidelines by Infectious Disease (ID) physicians is largely unknown.MethodsAn electronic survey assessing adherence with selected IE guidelines was emailed to 1409 adult ID physician members of the Infectious Diseases Society of America’s Emerging Infections Network.ResultsFive hundred fifty-seven physicians who managed IE responded. Twenty percent indicated that ID was not consulted on every case of IE at their hospitals, and 13% did not recommend transthoracic echocardiography (TTE) for all IE cases. The duration of antimicrobial therapy was timed from the first day of negative blood cultures by 91% of respondents. Thirty-four percent of clinicians did not utilize an aminoglycoside for staphylococcal prosthetic valve IE (PVE). Double β-lactam therapy was “usually” or “almost always” employed by 83% of respondents for enterococcal IE. For patients with active IE who underwent valve replacement and manifested positive surgical cultures, 6 weeks of postoperative antibiotics was recommended by 86% of clinicians.ConclusionsThe finding that adherence was <90% with core guideline recommendations that all patients with suspected IE be seen by ID and that all patients undergo TTE is noteworthy. Aminoglycoside therapy of IE appears to be declining, with double β-lactam regimens emerging as the preferred treatment for enterococcal IE. The duration of postoperative antimicrobial therapy for patients undergoing valve replacement during acute IE is poorly defined and represents an area for which additional evidence is needed.

Prevalence of aminoglycoside therapy and other determinant factors that induce hearing loss in neonates

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Hearing loss is the most common disorder in neonates; it can be best managed if it is diagnosed at early stage of life. The global prevalence of permanent neonatal hearing loss mainly occurs in developing countries, which accounts 0.5 to 5.0 per 1000 live births. The objective of this study was to determine the prevalence of aminoglycoside therapy and other risk factors that induce hearing loss in neonates admitted at NICU at Cipto-Mangunkusumo General Hospital (CMGH).&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This was a case-control study conducted among 112 neonates at Cipto-Mangunkusumo General Hospital (CMGH). Data from neonatal hearing screening were retrospectively collected from hospital electronic medical records and medical files. Only patients treated at neonatal unit from November 2018 to October 2019 were recruited. &lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; Out of 112 neonates studied, the gestational age at birth (GA) and craniofacial anomalies were considered risk factors for hearing loss since they were statistically significant (p&amp;lt;0.05). The study showed no statistical significant association in gender, birth weight, mechanical ventilation, NICU stay period (&amp;gt;5 days), hyperbilirubinemia (&amp;gt;20 mg/dl), asphyxia, and aminoglycoside therapy (p&amp;gt;0.05).&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; The prevalence of hearing loss in neonates with lower gestational age less than 37 weeks and craniofacial anomalies are significant higher compare to neonates born full term. They are more associated with 3 and 6 times increased risk of hearing loss in neonates.&lt;/p&gt;

A study of effect of aminoglycoside therapy on auditory brainstem evoked responses in preterm and term neonates

Background: Aminoglycosides are widely used drugs in neonates with associated ototoxic side effects, that can be diagnosed with auditory brainstem evoked responses, which is the recommended screening technique in neonatal intensive care unit infants. This study was conducted to evaluate the effect of aminoglycoside therapy on auditory brainstem evoked responses in term and preterm neonates.Methods: A cross-sectional case control study. Two groups of 26 term and 22 preterm neonates who received aminoglycosides, with no other known risk factors for ototoxicity, were compared with suitable matched control group of 10 neonates in each. ABER was done after at least 5 days of aminoglycoside therapy and results were compared to suitable matched controls.Results: Mean latency of wave I in term neonates at 90 dB and 60 dB and mean interwave latencies of I-V waves in preterm neonates at 30 dB was higher in study group and statistically significant. No statistically significant difference in any of ABER parameters was observed in any group, at all other intensities.Conclusions: Wave I latency was prolonged in study group of term neonates at two intensities which indicates effect of aminoglycoside therapy on distal portion of acoustic nerve. But as there were no such findings at other intensities in term study group and in preterm study group and moreover no other ABER abnormalities were observed, it was concluded that the aminoglycoside therapy has low potential for ototoxicity. Authors support the ABER screening for early detection of hearing abnormalities, and recommend study on larger group of neonates and meta-analysis for final conclusion for evidence-based recommendations to use aminoglycosides in neonates, in view of audiometric and neurological abnormalities.

Short-course aminoglycosides as adjunctive empirical therapy in patients with Gram-negative bloodstream infection, a cohort study

ObjectiveShort-course aminoglycosides as adjunctive empirical therapy to β-lactams in patients with a clinical suspicion of sepsis are used to broaden antibiotic susceptibility coverage and to enhance bacterial killing. We quantified the impact of this approach on 30-day mortality in a subset of sepsis patients with a Gram-negative bloodstream infection. MethodsFrom a prospective cohort study conducted in seven hospitals in the Netherlands between June 2013 and November 2015, we selected all patients with Gram-negative bloodstream infection (GN-BSI). Short-course aminoglycoside therapy was defined as tobramycin, gentamicin or amikacin initiated within a 48-hour time window around blood-culture obtainment, and prescribed for a maximum of 2 days. The outcome of interest was 30-day all-cause mortality. Confounders were selected a priori for adjustment using a propensity score analysis with inverse probability weighting. ResultsA total of 626 individuals with GN-BSI who received β-lactams were included; 156 (24.9%) also received aminoglycosides for a median of 1 day. Patients receiving aminoglycosides more often had septic shock (31/156, 19.9% versus 34/470, 7.2%) and had an eight-fold lower risk of inappropriate treatment (3/156, 1.9% versus 69/470, 14.7%). Thirty-day mortality was 17.3% (27/156) and 13.6% (64/470) for patients receiving and not receiving aminoglycosides, respectively; yielding crude and adjusted odds ratios for 30-day mortality for patients treated with aminoglycosides of 1.33 (95% CI 0.80–2.15) and 1.57 (0.84–2.93), respectively. ConclusionsShort-course adjunctive aminoglycoside treatment as part of empirical therapy with β-lactam antibiotics in patients with GN-BSI did not result in improved outcomes, despite better antibiotic coverage of pathogens.

The Physiologic Role of Corticosteroids in Menière's Disease: An Update on Glucocorticoid-mediated Pathophysiology and Corticosteroid Inner Ear Distribution.

: There are multiple treatment options for Ménière's disease (MD), including dietary modifications, aminoglycoside therapy, and surgery. All have limitations, ranging from limited effectiveness to permanent hearing loss. Corticosteroids have long been used to manage MD due to their relative efficacy and tolerability, but the exact mechanism for disease alleviation is uncertain. Until recently, the precise distribution and role that glucocorticoid receptors play in inner ear diseases have remained largely uninvestigated. Several studies propose they influence mechanisms of fluid regulation through ion and water homeostasis. This review will provide an update on the basic science literature describing the activity of endogenous glucocorticoids and exogenous corticosteroids in the inner ear and the relevance to MD, as well as early clinical trial data pertaining to the application of novel technologies for more effective administration of corticosteroids for the treatment of MD.

Evaluation of the clinical practice of aminoglycoside use in paediatric patients in Kenya: findings and implications for lower-middle income countries.

ObjectivesTo evaluate the practice of aminoglycoside use/monitoring in Kenya and explore healthcare worker (HCW) perceptions of aminoglycoside monitoring to identify gaps and opportunities for future improvements, given the low therapeutic index of aminoglycosides.MethodsThis was a two-phase study whereby we reviewed patients’ medical records at Kenyatta National Hospital (October–December 2016) in Phase 1 and interviewed HCWs face to face in Phase 2. Outcome measures included describing and evaluating the practice of aminoglycoside use and monitoring and compliance to guidelines. Data were analysed using descriptive and inferential analysis.ResultsOverall, out of the 2318 patients admitted, 192 patients (8.3%) were prescribed an aminoglycoside, of which 102 (53.1%) had aminoglycoside doses that did not conform to national guidelines. Aminoglycoside-related adverse effects were suspected in 65 (33.9%) patients. Monitoring of aminoglycoside therapy was performed in only 17 (8.9%) patients, with no therapeutic drug monitoring (TDM), attributed mainly to knowledge and skill gaps and lack of resources. Out of the 28 recruited HCWs, 18 (64.3%) needed training in how to perform and interpret TDM results.ConclusionsThe practice of using and monitoring aminoglycosides was suboptimal, raising concerns around potential avoidable harm to patients. The identified gaps could form the basis for developing strategies to improve the future use of aminoglycosides, not only in Kenya but also in other countries with similar settings and resources.

Aminoglycocides as An Alternative Antibiotic Therapy Against Urinary Tract Infection in Children due to Extended-Spectrum Β-Lactamase (ESBL) Producing Escherichia Coli in Carbapenem Trends

Background: Extended-spectrum β-lactamase (ESBL) is an enzyme produced by certain Escherichia coli and Klebsiella pneumoniae. ESBL can induce theantibiotic resistance for betalactam antibiotics such as penicillin, cephalosporin, etc. Frequent utilization of carbapenem may induce the risk for carbapenem resistant against ESBLs producing microorganisms. This stud aimed to communicate Aminoglycocides as an alternative antibiotic therapy against urinary tract infection in children. Case Presentation: We present a case of 4 years child who was admitted to the state hospital of Madiun with main complaint of 10 days high fever accompanied by phimosis appearance. Laboratory results based on urine culture show the ESBL positive Escherichia coli. Results: We have used aminoglycoside for treating the patient. Clinical presentation in this patient start showing an improved clinical response and negative bacteriuria in the second urine test after the aminoglycoside therapy. Conclusion: Aminoglycosides such as gentamicin can be considered to be one of the best options for treating an ESBL infection beside carbapenem in order to reduce the carbapenem trend In clinical setting of the urinary tract infection caused by ESBL Eschericia coli. Keywords: Aminoglycosides, Carbapenem, Extended-spectrum β-lactamase, Gentamicin, urinary tract infection Correspondence: Muhammad Pradhika Mapindra. General Practitioner in State Hospital of Madiun, Easy Java. Email: mpradhika57@gmail.com. Indonesian Journal of Medicine (2020), 05(03): 200-205 https://doi.org/10.26911/theijmed.2020.05.03.04

Cefazolin Monotherapy Versus Cefazolin Plus Aminoglycosides for Antimicrobial Prophylaxis of Type III Open Fractures.

There are conflicting recommendations between organizations regarding aminoglycoside use for the prophylaxis of type III open fractures. To compare cefazolin monotherapy versus cefazolin plus aminoglycoside therapy for prophylaxis of type III open fractures in trauma patients. This was a multicenter, retrospective, cohort study conducted in 3 academic medical centers in the United States. Consecutive adult trauma patients with type III open fractures between January 2014 and September 2016 were included. Patients were divided into 2 groups: (1) cefazolin monotherapy versus (2) cefazolin plus aminoglycoside. The primary outcome measure was the occurrence of infection at the open fracture site. The secondary outcome measure was the occurrence of acute kidney injury. There were 134 patients included in the study cohort. Of these, 39 received cefazolin monotherapy and 95 received cefazolin plus aminoglycoside. Overall, the mean age was 39 ± 15 years, 105 (78%) were male, and the most common fracture location was tibia/fibula (n = 74, 56%). Infection at the open fracture site occurred in 6 of 39 patients (15%) in the cefazolin monotherapy group and 15 of 95 patients (16%) in the cefazolin plus aminoglycoside group (P = 1.000). Acute kidney injury occurred in 0 of 39 (0%) in the cefazolin monotherapy group and 1 of 95 (1%) in the cefazolin plus aminoglycoside group (P = 1.000). Cefazolin monotherapy may be appropriate for antimicrobial prophylaxis of type III open fractures in trauma patients.

Is computer-assisted aminoglycoside dosing managed by a pharmacist a safety tool of pharmacotherapy?

This pilot prospective study verified the hypothesis that use of computer-assisted therapeutic drug monitoring of aminoglycosides by pharmacists leads to better safety therapeutic outcomes and cost avoidance than only concentration measurement and dose adjustments based on a physician's experience. Two groups of patients were enrolled according to the technique of monitoring. Patients (Group 1, n=52) underwent monitoring by a pharmacist using pharmacokinetic software. In a control group (Group 2, n=11), plasma levels were measured but not interpreted by the pharmacist, only by physicians. No statistically significant differences were found between the groups in factors influenced by therapy. However, the results are not statistically significant but a comparison of the groups showed a clear trend towards safety and cost avoidance, thus supporting therapeutic drug monitoring. Safety limits were achieved in 76 % and 63 % of cases in Groups 1 and 2, respectively. More patients achieved both concentrations (peak and trough) with falling eGFR in Group 1. In present pilot study, the pharmacist improved the care of patients on aminoglycoside therapy. A larger study is needed to demonstrate statistically significantly improved safety and cost avoidance of aminoglycoside therapy monitoring by the pharmacist using pharmacokinetic software.

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.

1551. Systemic Tobramycin Absorption Resulting from Antibiotic-Impregnated Cement Spacers for the Treatment of Prosthetic Joint Infection

BackgroundAntibiotic-impregnated cement spacer (ACS) placement has been a cornerstone of two-stage surgical management of prosthetic hip and knee infection for decades. Utilized antibiotics have included aminoglycosides and vancomycin. Pharmacokinetic modeling studies have described peak systemic levels within the first 24–48 hours post-operatively, followed by rapid clearance. While this systemic exposure was previously felt insufficient to cause organ toxicity, a few studies have described antibiotic-induced nephrotoxicity.MethodsWe prospectively enrolled patients with prosthetic hip or knee infection, and subsequent ACS placement, containing vancomycin and tobramycin, from October 2017 to February 2019, at Allegheny General Hospital. Risk factors for post-operative nephrotoxicity, including patient comorbidities, receipt of potentially nephrotoxic medications, estimated creatinine clearance (CrCl), perioperative hypotension, total spacer tobramycin dosage, and post-operative day 1 (POD1) and 3 (POD3) serum tobramycin levels were recorded. Patients who had antibiotic cement spacer exchange, or had received systemic aminoglycoside therapy, were excluded.ResultsThirteen patients were enrolled, comprising 4 hip and 9 knee ACS, with respective median (interquartile range (IQR)) tobramycin cement dosages of 3.8 (2.86–4.58) and 4.8 (4.8–9.6) grams. Tobramycin levels were measured at a median 16.5 and 60.7 hours on POD1 and POD3, respectively. Three hip and six knee ACS had respective, detectable POD1 median serum tobramycin levels of 0.6 (0.38–1.20) and 0.8 (0–0.8) μg/mL; three knees, but no hip ACS had detectable POD3 serum tobramycin levels. Six of the nine patients with detectable POD1 serum tobramycin levels had a CrCl of less than or equal to 65 mL/minute (figure), while each patient with detectable POD3 levels had a CrCl of less than 45 mL/minute. No significant changes in baseline CrCl were identified. A relationship between tobramycin cement dosage and detectable serum tobramycin levels was not observed.ConclusionLow baseline CrCl, but not the total tobramycin dosage or other nephrotoxicity risk factors, may be the single most reliable predictor of detectable postoperative systemic tobramycin levels in patients who have received hip or knee ACS. Disclosures All authors: No reported disclosures.

Vitamin C in the Presence of Sub-Inhibitory Concentration of Aminoglycosides and Fluoroquinolones Alters Proteus mirabilis Biofilm Inhibitory Rate.

Vitamin C has antimicrobial activity and is often used as an oral supplement accompanying antibiotic treatment in urinary tract infections (UTI). Proteus mirabilis is the third common species responsible for UTIs that are mostly treated with fluoroquinolones or aminoglycosides. Treatment of the UTI caused by P. mirabilis is problematic due to the ability to form biofilm on the urinary catheters. The aim of the study was to evaluate the influence of ascorbic acid in combination with antibiotics on P. mirabilis abilities to form biofilm. The susceptibility of P. mirabilis reference strain ATCC® 29906™ and four clinical strains isolated from the urine samples of patients with urinary catheter were evaluated according to EUCAST recommendations. The influence of ascorbic acid (0.4 mg × mL−1) in combination with antibiotics on biofilm formation was evaluated spectrophotometrically. Aminoglycosides at sub-inhibitory concentrations more successfully limited biofilm formation by P. mirabilis strains without ascorbic acid addition. Inhibition rate differences at the lowest concentrations of gentamicin and amikacin were statistically significant (p ≤ 0.05). Ascorbic acid addition to the culture medium limited the inhibitory effect of fluoroquinolones, facilitating biofilm formation by P. mirabilis strains. The addition of ascorbic acid during aminoglycosides therapy may disturb treatment of urinary tract infections related to the presence of P. mirabilis biofilm.

P091 What's that you say? Hearing impairment in cystic fibrosis patients treated with aminoglycoside therapy - is conventional pure tone audiometry enough?

P091 What's that you say? Hearing impairment in cystic fibrosis patients treated with aminoglycoside therapy - is conventional pure tone audiometry enough?

Design, Multigram Synthesis, and in Vitro and in Vivo Evaluation of Propylamycin: A Semisynthetic 4,5-Deoxystreptamine Class Aminoglycoside for the Treatment of Drug-Resistant Enterobacteriaceae and Other Gram-Negative Pathogens.

Infectious diseases due to multidrug-resistant pathogens, particularly carbapenem-resistant Enterobacteriaceae (CREs), present a major and growing threat to human health and society, providing an urgent need for the development of improved potent antibiotics for their treatment. We describe the design and development of a new class of aminoglycoside antibiotics culminating in the discovery of propylamycin. Propylamycin is a 4'-deoxy-4'-alkyl paromomycin whose alkyl substituent conveys excellent activity against a broad spectrum of ESKAPE pathogens and other Gram-negative infections, including CREs, in the presence of numerous common resistance determinants, be they aminoglycoside modifying enzymes or rRNA methyl transferases. Importantly, propylamycin is demonstrated not to be susceptible to the action of the ArmA resistance determinant whose presence severely compromises the action of plazomicin and all other 4,6-disubstituted 2-deoxystreptamine aminoglycosides. The lack of susceptibility to ArmA, which is frequently encoded on the same plasmid as carbapenemase genes, ensures that propylamycin will not suffer from problems of cross-resistance when used in combination with carbapenems. Cell-free translation assays, quantitative ribosome footprinting, and X-ray crystallography support a model in which propylamycin functions by interference with bacterial protein synthesis. Cell-free translation assays with humanized bacterial ribosomes were used to optimize the selectivity of propylamycin, resulting in reduced ototoxicity in guinea pigs. In mouse thigh and septicemia models of Escherichia coli, propylamycin shows excellent efficacy, which is better than paromomycin. Overall, a simple novel deoxy alkyl modification of a readily available aminoglycoside antibiotic increases the inherent antibacterial activity, effectively combats multiple mechanisms of aminoglycoside resistance, and minimizes one of the major side effects of aminoglycoside therapy.

The renoprotective effect of concomitant fosfomycin in the treatment of pulmonary exacerbations in cystic fibrosis.

BackgroundFosfomycin, effective in Cystic Fibrosis (CF), competes with aminoglycosides at renal binding sites and may therefore afford a renoprotective effect when used in combination therapy. We explored this by using markers of acute renal tubular damage [N-acetyl-β-d-glucose-aminidase (NAG), alanine amino-peptidase (AAP) and β2-microglobulin].Methods Using a prospective randomized crossover trial design, at an acute pulmonary exacerbation, 18 adult CF patients received either 14 days of intravenous (IV) tobramycin or IV tobramycin and IV fosfomycin, both in combination with a second IV antibiotic (colomycin).Results Urinary NAG (P = 0.003) and AAP (P = 0.03) following treatment with concomitant fosfomycin were lower than those after treatment with tobramycin and colomycin alone. Fosfomycin attenuated the total 24-h urinary protein leak (P = 0.0001). The 14-day improvements in all surrogate markers of exacerbation resolution (FEV1% predicted, FVC, white cell count and C-reactive protein) were similar for both treatment regimens.Conclusion The addition of fosfomycin reduces acute renal injury caused by IV aminoglycoside therapy in CF pulmonary exacerbations.

Antibiotic Dosing in Chronic Kidney Disease and End-Stage Renal Disease: A Focus on Contemporary Challenges.

Infections are an important cause of morbidity and mortality among patients with chronic kidney disease. Therefore, appropriate antibiotic dosing is imperative to achieve positive patient outcomes while minimizing antibiotic dose-related toxicity. Accurately assessing renal function and determining the influence of renal replacement therapy on antibiotic clearance makes drug dosing in this patient population challenging. Furthermore, as technological advances in hemodialysis and peritoneal dialysis occur, research incorporating newer dialysis parameters to guide drug dosing may not be readily available. Currently, there are limited data to guide drug dosing in the setting of automated peritoneal dialysis, short daily hemodialysis, and nocturnal hemodialysis. Antibiotic-dosing recommendations should be carefully evaluated considering the accuracy of the renal function assessment, the similarity of the operating characteristics of the renal replacement therapy studied compared with those being used, and whether the dosing strategy takes advantage of the pharmacodynamic profile of the antibiotic under consideration. After implementing the antibiotic-dosing regimen, therapeutic drug monitoring should occur when possible along with careful monitoring for antibiotic efficacy and safety.