Multidrug-resistant Gram-negative Bacterial Research Articles

Detection of FOX-AmpC-β-lactamase gene and antibiogram of AmpC-beta-lactamase-producing pathogens isolated from chronic suppurative otitis media patients in Nigeria.

AmpC-producing Gram-negative bacterial (GNB) pathogens are distributed worldwide, especially in clinical settings. This study aimed to determine the antibiogram and the type of AmpC-β-lactamase gene harboured by GNB pathogens implicated in chronic suppurative otitis media (CSOM) cases. Ear swab samples (300) collected from patients with active CSOM were analysed using standard microbiological techniques. Phenotypic and molecular detection of AmpC β-lactamase production was done by cefoxitin/cloxacillin double-disk synergy test and PCR respectively. Antibiogram was determined by disk diffusion technique. Among the GNB pathogens isolated from CSOM patients, P. aeruginosa was the most predominant (36.3%); followed by K. pneumoniae (22.3%), and E. coli (13.7%). Patients with active CSOM showed increased bacteria isolation rate from bilateral ear discharges than unilateral ear discharges. E. coli and P. aeruginosa were more prevalent among patients with duration of discharge >2 weeks; recording 9.0% and 20.3% respectively. AmpC β-lactamase producers accounted for 14.0%; they were highly resistant (60%-100%) to cephalosporins, trimethoprim-sulfamethoxazole, ofloxacin, amoxicillin, and tetracycline, but very susceptible (70.4%-100%) to ciprofloxacin, imipenem, and amikacin. Multiple antibiotic resistance indices of isolates ranged from 0.7-0.8. FOX-AmpC-β-lactamase gene was detected in 3.9% of the isolates. The detection of AmpC β-lactamase-producing multidrug-resistant GNB pathogens harbouring FOX-AmpC-β-lactamase gene among patients with CSOM infections in our study is a serious public health problem which needs urgent intervention.

Local Use of Colistimethate Sodium as Antimicrobial Dressing Agent in Multidrug-resistant Gram-negative Bacteria-colonised Pressure Injuries in Spinal Cord Injury Patients: A Case Series

Abstract Despite advancements in dressing materials and techniques, the management of pressure injuries (PIs) remains a challenging problem for clinicians across the world. The failure to heal in PIs is multifactorial such as nutritional status of patients, bacterial load, site of ulcer, risk of contamination and presence of comorbidities. Multidrug-resistant (MDR) Gram-negative bacterial (GNB) infections are frequent occurrence in hospitalised patients with PI. The limited chemotherapeutic options available for treating MDR strains of GNB have forced the reintroduction of the cationic cyclic peptide, polymyxin E (colistin). We report a case series of seven patients of traumatic spinal cord injury with PIs and poor healing due to MDR GNB sensitive only to colistin. In view of the worsening condition of the PIs and financial constraints, it was decided to start colistin therapy locally by colistimethate sodium. All patients responded well to the treatment and got clinically better. In our study, we used the Pressure Ulcer Scale for Healing score, Functional Independence Measure and World Health Organization Quality of Life Brief Version score to measure the outcome. We found this novel dressing a very promising and cost-effective treatment option in achieving infection-free healing, especially against MDR strains of bacteria.

Efficacy and safety of intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of multidrug-resistant gram-negative bacterial pneumonia: A systematic review and meta-analysis

BackgroundPrevious studies have questioned the efficacy and safety of intravenous combined with aerosolised (IV + AS) polymyxin versus intravenous (IV) polymyxin alone in the treatment of patients with multidrug-resistant gram-negative bacterial (MDR-GNB) pneumonia. Therefore, we conducted a meta-analysis to evaluate the efficacy and safety of IV + AS polymyxin in the treatment of MDR-GNB pneumonia. MethodsWe identified all relevant studies by searching the PubMed, EMBASE and Cochrane library databases from their inception to May 31, 2022. All included studies were evaluated using the Newcastle Ottawa scale (NOS) checklist. The summary relative risk (RR) and 95% confidence interval (CI) were used to determine the outcome differences between the IV + AS and the IV groups. Subgroup analysis was performed based on population, polymyxin dose and kinds of polymyxin. ResultsA total of 16 studies were included in the meta-analysis. The IV + AS group had lower mortality (RR = 0.86, 95% CI: 0.77–0.97, P = 0.01) than the IV group. Subgroup analysis revealed that IV + AS polymyxin could reduce mortality only when used in low doses. Simultaneously, the IV + AS group outperformed the IV group in terms of clinical response rate, clinical cure rate, microbiological eradication and duration of mechanical ventilation. The duration of hospitalisation and the incidence of nephrotoxicity did not differ significantly between the two groups. ConclusionsIV + AS polymyxin is beneficial in the treatment of MDR-GNB pneumonia. It could lower patient mortality and improve clinical and microbial outcomes without increasing the risk of nephrotoxicity. However, retrospective analysis in the majority of studies and heterogeneity between studies implies that our findings must be interpreted carefully.

Colistin-Induced Acute Kidney Injury and the Effect on Survival in Patients with Multidrug-Resistant Gram-Negative Infections: Significance of Drug Doses Adjusted to Ideal Body Weight.

Background Colistin is a lifesaving treatment for multidrug-resistant Gram-negative bacterial (MDR-GNB) infections along with its well-known nephrotoxicity. The controversy of colistin-induced acute kidney injury (AKI) on mortality is noted. This study aimed to determine the risk factors and impact of AKI on the survival and significance of colistin dosage. Methods A retrospective cohort study was performed in adult patients who received intravenous colistin for MDR-GNB treatment between June 2015 and June 2017. Factors influencing colistin-induced AKI and survival were evaluated by Cox regression analysis. Cut-off levels of the colistin dose per ideal body weight (IBW) that significantly affected clinical outcomes were assessed with linearity trends and receiver operating characteristic analyses. Results AKI occurred in 68.5% of 412 enrolled patients with an incidence rate of 10.6 per 100 patients-days and a median time was 6 (3–13) days. Stages I–III of AKI were 38.3, 24.5, and 37.2%. Factors associated with colistin-induced AKI were advanced age, high serum bilirubin, AKI presented before colistin administration, increased daily colistin doses per IBW, and concomitant use of nephrotoxic drugs. Colistin-induced AKI was related to mortality (HR 1.74, 95% CI 1.06–2.86, p=0.028). In the non-AKI before colistin usage subgroup, the total dose and total dose/IBW were >1,500–2,000 mg and 30–35 mg/kg to benefit mortality reduction but were <2,500–3,000 mg and 45–50 mg/kg for risk reduction of AKI. A daily colistin dose/IBW >4.5 mg/kg/day also increased the risk of AKI. In the AKI developed before colistin subgroup, the cut-off values of total colistin dose >1250–1350 mg and total dose/IBW >23.5–24 mg/kg demonstrated significant risks of AKI. Conclusion The incidence of AKI after colistin administration was high and impacted mortality. Prevention and early correction of these related factors are mandatory. Careful use of colistin was also both beneficial in mortality and AKI reductions.

Risk factors and mortality associated with multi-drug-resistant Gram-negative bacterial infection in adult patients following abdominal surgery

Multi-drug-resistant (MDR) Gram-negative bacterial (GNB) infection remains a significant cause of morbidity and mortality among surgical patients. The objective of this study was to recognize the risk factors for MDR GNB infection in patients following abdominal surgery, and determine the predictors independently associated with death. From 2010 to 2017, a retrospective cohort study was conducted among patients with abdominal surgery admitted to the surgical intensive care unit (ICU). Patients with GNB infection were included for analyses. In total, 364 patients experienced GNB infection following abdominal surgery. Of these, 117 (32.1%) were MDR GNB infection. Of 133 MDR GNB isolates, the most common isolate was Escherichia coli (45.1%). Patients with MDR GNB infection had significantly longer ventilator-days and hospital stay, as well as higher 30-day and in-hospital mortality compared with non-MDR GNB patients. Multi-variable analysis showed that longer length of pre-ICU stay, surgical re-exploration, receipt of group 2 carbapenems (e.g. imipenem, meropenem and doripenem) and fluoroquinolones, and higher total bilirubin were independent risk factors for the acquisition of MDR GNB infection. Predictors for 30-day mortality among patients with MDR GNB infection were chronic kidney disease, receipt of group 2 carbapenems and inappropriate empirical antimicrobial therapy. This study provides important information about the risk factors for MDR GNB infection and 30-day mortality among patients following abdominal surgery.

Rational Use of Polymyxins Against Multi-Drug Resistant Gram-Negative Bacteria

The current strategy in treating multi-drug resistant gram-negative bacterial (MDR-GNB) infections is salvage therapy by using polymyxins. However, the beginning emergence of polymyxin resistance should enforce strict antimicrobial stewardship programs to preserve polymyxin efficacy. Knowledge of structural characteristics, pharmacodynamic, and pharmacokinetic profiles of polymyxins, as well as consideration of efficacy, safety, suitability, and cost, will help in the choice of the appropriate polymyxin for therapy. Polymyxin B is the recommended polymyxin for systemic use, while colistin is recommended for lower urinary tract infections, intraventricular, and intrathecal use. Either polymyxin can be used for hospital-acquired and ventilator-associated pneumonia. Combination therapy over monotherapy remains to be advantageous due to synergism and decreased resistance development. The choice of the second drug to be used should be based on full susceptibility, or if unavailable, a drug with the least minimum inhibitory concentration relative to the breakpoint set by the Clinical and Laboratory Standards Institute. Using the mnemonic ESCAPE can also guide physicians in their polymyxin prescription process: (1) Checking if the pathogen is Extensively resistant or multi-drug resistant; (2) checking the patient’s clinical status if compatible with Significant infection; (3) using Combination therapy; (4) ensuring Adequate dosing; (5) Proper preparation and administration of drug; and (6) keeping an Eye for response and adverse effects.

Predictors of in-hospital mortality in critically ill Geriatric patients

Objective: To determine the predictors of in-hospital mortality in critically ill older patients. Participants and Methods: A prospective cohort study including 305 critically ill older adults (age ≥60 years) who were admitted to High Dependency Units (HDUs) in a tertiary care university hospital from March 22, 2019 to January 4, 2020. Demographic, clinical and laboratory data of participants were collected thought a review of medical records and clinical observation at HDUs till either death or discharge alive. Statistical analysis included univariate analysis of selected potential predictors such as various comorbidities, C- reactive protein / Albumin ratio (CAR), Neutrophil-lymphocyte ratio (NLR), Red cell distribution width (RDW), Po2/Fio2 ratio (PFR), Simplified acute physiology score II (SAPS II), Charlson comorbidity index (CCI) and multidrug-resistant Gram-negative bacterial (MDR-GNB) infection to ascertain their association with mortality, followed by multivariable logistic regression to derive the final prediction model. The discriminative ability of the model was evaluated by using the receiver operating characteristic (ROC) curve. RESULTS: Overall mortality was 53.1%. Multivariate regression analysis revealed independent predictors of mortality including dementia in clinical history with an odds ratio (OR) of 4.86 (95% CI: 1.28-18.34), total protein with an OR of .53 (95% CI: .30-.95) and the use of mechanical ventilation (MV) and/or intravenous cardiovascular support with an OR of 148.34 (95% CI: 34.28-641.77), formulating a novel prognostic model with an area under the ROC curve of .93 (95% CI: .89-.96, P.000). CONCLUSION: History of dementia, total protein and the use of MV and/or intravenous cardiovascular support are predictors of mortality in critically ill geriatric patients. It provides a novel prognostic model which needs validation in other multicenter prospective studies.

Effectiveness and Adverse Effects of Intravenous Colistin In Neonates with Multi-Drug Resistant Gram-Negative Bacterial Infections

Background: The global burden of multi-drug resistant gram-negative bacterial (MDR-GNB) infections has been increasing. Neonates are at a particularly high-risk and there is limited treatment option. The use of colistin has been re-introduced for this population. However, data on its use in neonates is scarce. Objectives: To determine the effectiveness and adverse effects of intravenous colistin in neonates with multidrug-resistant gram-negative infections. Design: This is a retrospective cohort study of the clinical profile and outcome of neonates with MDR-GNB infections given colistin for a minimum of 3 days conducted from April 2015 to April 2019. Results: A total of 175 pediatric patients had MDR-GNB infections. 75 (43%) neonates met the inclusion criteri a and received intravenous colistin. Of the 75 patients with MDRGNB infections- that included sepsis, pneumonia, urinary tract infection and abscess, 37 (49.3%) were alive and 38 (50.7%) patients died. Nephrotoxicity was seen in 4% if patients and 2.6% patients had hypersensitivity reaction. MDROs isolated were Acinetobacter baumanii, Klebsiella pneumoniae and Pseudomonas aeruginosa. Conclusions: Intravenous colistin is 50% effective and is relatively safe to use in neonates.

2384. Multidrug-Resistant Gram-Negative Infections Treated With Ceftolozane–Tazobactam: Impact of Delayed Initiation

BackgroundDelayed appropriate antibiotic therapy for multidrug-resistant (MDR) Gram-negative bacterial (GNB) infections has been associated with increased mortality. Ceftolozane-tazobactam (C/T) is a novel antipseudomonal cephalosporin and β-lactamase inhibitor combination with excellent in vitro activity against MDR GNB, however its ability to improve patient outcomes may be attenuated if initiation is delayed or it is reserved for salvage therapy. We sought to determine the impact of delayed C/T initiation on 30-day mortality in patients with MDR GNB infections.MethodsThis was a multicenter, retrospective cohort study including adult patients treated with C/T (≥72 hours) for suspected or confirmed MDR GNB (resistant to ≥1 drug from ≥3 classes) infections between January 2015 and February 2018. Classification and regression tree (CART) analysis was used to determine the time point of C/T initiation from index culture or diagnosis most predictive of 30-day mortality. Clinical characteristics and outcomes were compared between patients receiving early or delayed C/T, defined by the CART time point. Multivariable logistic regression was conducted to determine the independent association between early C/T initiation and 30-day mortality.ResultsA total of 144 patients were included. The median (IQR) age was 61 (49, 71) years with a male (65%) and African American (53%) predominance. The most common source of infection was respiratory (64%) and MDR Pseudomonas aeruginosa was isolated from 92% of cultures. A breakpoint in time was identified of 119 hours where 30-day mortality was significantly increased (11.8% vs. 26.2%; P = 0.032). Absence of prior infection or colonization with MDR GNB was the only variable independently associated with delayed C/T (aOR 3.28, 95% CI 1.53, 7.01). After adjustment for confounding variables, delayed C/T was associated with a > 3-fold increase in 30-day mortality (aOR 3.22, 95% CI 1.11, 9.40).ConclusionThese data suggest that delaying C/T initiation by approximately 5 days substantially increases the risk of mortality in patients with MDR GNB infections, underscoring the importance of early appropriate therapy and the need for incorporation of C/T into automated susceptibility testing panels to support earlier initiation.Disclosures S. L. Davis, Achaogen: Scientific Advisor, Consulting fee. Allergan: Scientific Advisor, Consulting fee. Melinta: Scientific Advisor, Consulting fee. Nabriva: Scientific Advisor, Consulting fee. Zavante: Scientific Advisor, Consulting fee. M. J. Rybak, Allergan: Consultant, Grant Investigator and Speaker’s Bureau, Research grant and Research support. Achaogen: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Bayer: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Melinta: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Merck: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Theravance: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Sunovian: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. Zavante: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support. NIAID: Consultant, Grant Investigator and Speaker’s Bureau, Consulting fee, Research grant and Research support.

Multidrug-resistant and extensively drug-resistant Gram-negative prosthetic joint infections: Role of surgery and impact of colistin administration

Factors influencing treatment outcome of patients with Gram-negative bacterial (GNB) multidrug-resistant (MDR) and extensively drug-resistant (XDR) prosthetic joint infection (PJIs) were analysed. Data were collected (2000-2015) by 18 centres. Treatment success was analysed by surgery type for PJI, resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) using logistic regression and survival analyses. A total of 131 patients (mean age 73.0 years, 35.9% male, 58.8% with co-morbidities) with MDR (n = 108) or XDR (n = 23) GNB PJI were assessed. The most common pathogens were Escherichia coli (33.6%), Pseudomonas aeruginosa (25.2%), Klebsiella pneumoniae (21.4%) and Enterobacter cloacae (17.6%). Pseudomonas aeruginosa predominated in XDR cases. Isolates were carbapenem-resistant (n = 12), fluoroquinolone-resistant (n = 63) and ESBL-producers (n = 94). Treatment outcome was worse in XDR versus MDR cases (P = 0.018). Success rates did not differ for colistin versus non-colistin in XDR cases (P = 0.657), but colistin was less successful in MDR cases (P = 0.018). Debridement, antibiotics and implant retention (DAIR) (n = 67) was associated with higher failure rates versus non-DAIR (n = 64) (OR = 3.57, 95% CI 1.68-7.58; P < 0.001). Superiority of non-DAIR was confirmed by Kaplan-Meir analysis (HR = 0.36, 95% CI 0.20-0.67) and remained unchangeable by time of infection (early/late), antimicrobial resistance (MDR/XDR) and antimicrobials (colistin/non-colistin) (Breslow-Day, P = 0.737). DAIR is associated with higher failure rates even in early MDR/XDR GNB PJIs versus implant removal. Colistin should be preserved for XDR cases as it is detrimental in MDR infections.

Multi-drug resistant gram negative bacteria colonization and infection in burned children: Lessons learned from a 20-year experience

ObjectivesOur objective is to highlight the growing problem of multi-drug resistant gram negative bacterial (MDRGNB) species in burn units and demonstrate strategies for successful management. MethodsUsing a concurrent data collection, a 20-year experience with MDRGNB in a pediatric burn unit was reviewed. Results220 (6.5%) of 3,359 children admitted for management of acute burns or open wounds had MDRGNB recovered. The children had an average age of 8.8 ± 0.3 years and average burn size of 42.9 ± 22.8 percent. The incidence of MDRGNB increased over the 20 years of the study from 2.5% of admissions in the first decade to 8.6% in the second. 90% (198) were found colonized with MDRGNB on admission on transfer from other facilities. MDRGNB sepsis (blood recovery) occurred in 80 (36.4%), MDRGNB invasive wound infection in 46 (20.9%), MDRGNB pneumonia in 19 (8.6%), and MDRGNB UTI in 46 (20.9%) of the children. There were 14 (6.4%) fatalities, the cause of death being MDRGNB sepsis in all 14 children. However the large majority of the children 206 (93.6%) survived despite their MDRGNB infection. ConclusionsMDRGNB may be transferred into burn units during transfers of patients with complex wounds and can be the cause of life threatening infections. The number of children arriving with MDRGNB organisms has steadily increased over time. MDRGNB infected patients can be successfully managed with wound excision and closure supported by topical mafenide acetate and administration of the limited antibiotics to which the organisms are sensitive, particularly Colistin. Strict infection control practices will limit cross infection with these difficult organisms.

Infection with multidrug‐resistant gram‐negative bacteria in a pediatric oncology intensive care unit: risk factors and outcomes

ObjectiveThis study aimed at evaluating the predictors and outcomes associated with multidrug‐resistant gram‐negative bacterial (MDR‐GNB) infections in an oncology pediatric intensive care unit (PICU). MethodsData were collected relating to all episodes of GNB infection that occurred in a PICU between January of 2009 and December of 2012. GNB infections were divided into two groups for comparison: (1) infections attributed to MDR‐GNB and (2) infections attributed to non‐MDR‐GNB. Variables of interest included age, gender, presence of solid tumor or hematologic disease, cancer status, central venous catheter use, previous Pseudomonas aeruginosa infection, healthcare‐associated infection, neutropenia in the preceding 7 days, duration of neutropenia, length of hospital stay before ICU admission, length of ICU stay, and the use of any of the following in the previous 30 days: antimicrobial agents, corticosteroids, chemotherapy, or radiation therapy. Other variables included initial appropriate antimicrobial treatment, definitive inadequate antimicrobial treatment, duration of appropriate antibiotic use, time to initiate adequate antibiotic therapy, and the 7‐ and 30‐day mortality. ResultsMultivariate logistic regression analyses showed significant relationships between MDR‐GNB and hematologic diseases (odds ratio [OR] 5.262; 95% confidence interval [95% CI] 1.282–21.594; p=0.021) and healthcare‐associated infection (OR 18.360; 95% CI 1.778–189.560; p=0.015). There were significant differences between MDR‐GNB and non‐MDR‐GNB patients for the following variables: inadequate initial empirical antibiotic therapy, time to initiate adequate antibiotic treatment, and inappropriate antibiotic therapy. ConclusionsHematologic malignancy and healthcare‐associated infection were significantly associated with MDR‐GNB infection in this sample of pediatric oncology patients.

Infection with multidrug-resistant gram-negative bacteria in a pediatric oncology intensive care unit: risk factors and outcomes

ObjectiveThis study aimed at evaluating the predictors and outcomes associated with multidrug-resistant gram-negative bacterial (MDR-GNB) infections in an oncology pediatric intensive care unit (PICU). MethodsData were collected relating to all episodes of GNB infection that occurred in a PICU between January of 2009 and December of 2012. GNB infections were divided into two groups for comparison: (1) infections attributed to MDR-GNB and (2) infections attributed to non-MDR-GNB. Variables of interest included age, gender, presence of solid tumor or hematologic disease, cancer status, central venous catheter use, previous Pseudomonas aeruginosa infection, healthcare-associated infection, neutropenia in the preceding 7 days, duration of neutropenia, length of hospital stay before ICU admission, length of ICU stay, and the use of any of the following in the previous 30 days: antimicrobial agents, corticosteroids, chemotherapy, or radiation therapy. Other variables included initial appropriate antimicrobial treatment, definitive inadequate antimicrobial treatment, duration of appropriate antibiotic use, time to initiate adequate antibiotic therapy, and the 7- and 30-day mortality. ResultsMultivariate logistic regression analyses showed significant relationships between MDR-GNB and hematologic diseases (odds ratio [OR] 5.262; 95% confidence interval [95% CI] 1.282–21.594; p=0.021) and healthcare-associated infection (OR 18.360; 95% CI 1.778–189.560; p=0.015). There were significant differences between MDR-GNB and non-MDR-GNB patients for the following variables: inadequate initial empirical antibiotic therapy, time to initiate adequate antibiotic treatment, and inappropriate antibiotic therapy. ConclusionsHematologic malignancy and healthcare-associated infection were significantly associated with MDR-GNB infection in this sample of pediatric oncology patients.

Patient-level interventions to prevent the acquisition of resistant gram-negative bacteria in critically ill patients: a systematic review.

The rising incidence of multidrug-resistant Gram-negative bacterial (MDR-GNB) infections acquired in intensive care units has prompted a variety of patient-level infection control efforts. However, it is not known whether these measures are effective in reducing colonisation and infection. The purpose of this systematic review was to assess the efficacy of patient-level interventions for the prevention of colonisation with MDR-GNB and whether these interventions are associated with a reduction in the rate of infection due to MDR-GNB in the intensive care unit. Searches were conducted on PubMed, Cochrane, EMBASE and World of Science databases to identify comparative interventional studies on patient-level interventions implemented in the intensive care unit. Literature published in English, Spanish or French from January 1, 2000, until April 30, 2013, was searched. A total of 631 reports were found and we included and analysed 13 comparative studies that reported outcomes for an intervention compared with a control group. There were ten randomised and three observational interventional trials evaluating seven interventions. Overall, there was a reduction in colonisation (odds ratio [OR] 0.75; 95% confidence interval [CI] 0.66 to 0.85) and infection (OR 0.66; 95% CI 0.59 to 0.75) with MDR-GNB. This trend persisted after restricting pooled analysis to randomised controlled trials (pooled OR 0.66; 95% CI 0.57 to 0.76 and pooled OR 0.62; 95% CI 0.54 to 0.72, respectively). We identified a significant reduction in MDR-GNB colonisation and infection through the use of patient-level interventions. This effect was mostly accounted for by selective digestive decontamination. However, given the limitations of the analysed trials, adequately powered controlled studies are needed to further explore the effects of patient-level interventions on colonisation and infection with MDR-GNB.

Is Fosfomycin a Potential Treatment Alternative for Multidrug-Resistant Gram-Negative Prostatitis?

Multidrug-resistant gram-negative bacterial (MDR-GNB) infections of the prostate are an increasing problem worldwide, particularly complicating transrectal ultrasound (TRUS)-guided prostate biopsy. Fluoroquinolone-based regimens, once the mainstay of many protocols, are increasingly ineffective. Fosfomycin has reasonable in vitro and urinary activity (minimum inhibitory concentration breakpoint ≤64 µg/mL) against MDR-GNB, but its prostatic penetration has been uncertain, so it has not been widely recommended for the prophylaxis or treatment of MDR-GNB prostatitis. In a prospective study of healthy men undergoing a transurethral resection of the prostate for benign prostatic hyperplasia, we assessed serum, urine, and prostatic tissue (transition zone [TZ] and peripheral zone [PZ]) fosfomycin concentrations using liquid chromatography-tandem mass spectrometry, following a single 3-g oral fosfomycin dose within 17 hours of surgery. Among the 26 participants, mean plasma and urinary fosfomycin levels were 11.4 ± 7.6 µg/mL and 571 ± 418 µg/mL, 565 ± 149 minutes and 581 ± 150 minutes postdose, respectively. Mean overall prostate fosfomycin levels were 6.5 ± 4.9 µg/g (range, 0.7-22.1 µg/g), with therapeutic concentrations detectable up to 17 hours following the dose. The mean prostate to plasma ratio was 0.67 ± 0.57. Mean concentrations within the TZ vs PZ prostate regions varied significantly (TZ, 8.3 ± 6.6 vs PZ, 4.4 ± 4.1 µg/g; P = .001). Only 1 patient had a mean prostatic fosfomycin concentration of <1 µg/g, whereas the majority (70%) had concentrations ≥4 µg/g. Fosfomycin appears to achieve reasonable intraprostatic concentrations in uninflamed prostate following a single 3-g oral dose, such that it may be a potential option for prophylaxis pre-TRUS prostate biopsy and possibly for the treatment of MDR-GNB prostatitis. Formal clinical studies are now required.

Infected foot ulcers in male and female diabetic patients: a clinico-bioinformative study

BackgroundThe study aimed at (i) characterizing the mode of transmission of blaCTX-M and blaTEM-1 among extended-spectrum-β-lactamase (ESBL)-producing Escherichia coli strains isolated from infected diabetic foot ulcers, and (ii) identifying the risk factors for "sex-associated multidrug resistant Gram-negative bacterial (MDRGNB)-infection status" of the ulcers.MethodsSeventy-seven diabetic patients having clinically infected foot ulcers were studied in a consecutive series. The E. coli strains isolated from the ulcers were screened for blaCTX-M, blaTEM-1, armA, rmtA and rmtB during the 2-year study-period. PCR amplified blaCTX-M genes were cloned and sequenced. Enterobacterial repetitive intergenic consensus (ERIC)-PCR was used for the analysis of genetic relatedness of the ESBL-producers. Risk factors for "sex-associated MDRGNB-infection status" of ulcers were assessed. Modeling was performed using Swiss-Model-Server and verified by Procheck and verify3D programmes. Discovery Studio2.0 (Accelrys) was used to prepare Ramachandran plots. Z-scores were calculated using 'WHAT IF'-package. Docking of cefotaxime with modeled CTX-M-15 enzyme was performed using Hex5.1.ResultsAmong 51 E. coli isolates, 14 (27.5%) ESBL-producers were identified. Only 7 Class1 integrons, 2 blaCTX-M-15, and 1 blaTEM-1 were detected. Ceftazidime and cefotaxime resistance markers were present on the plasmidic DNA of both the blaCTX-M-15 positive strains and were transmissible through conjugation. The residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 were found to make important contacts with cefotaxime in the docked-complex. Multivariate analysis proved 'Glycemic control at discharge' as the single independent risk factor.ConclusionsMale diabetic patients with MDRGNB-infected foot ulcers have poor glycemic control and hence they might have higher mortality rates compared to their female counterparts. Plasmid-mediated conjugal transfer, albeit at a low frequency might be the possible mechanism of transfer of blaCTX-M-15 resistance marker in the present setting. Since the docking results proved that the amino acid residues Asn132, Glu166, Pro167, Val172, Lys234 and Thr235 of CTX-M-15 (enzyme) make important contacts with cefotaxime (drug) in the 'enzyme-drug complex', researchers are expected to duly utilize this information for designing more potent and versatile CTX-M-inhibitors.