Efficacies of omadacycline + amikacin + imipenem and an all-oral regimen omadacycline + clofazimine + linezolid in a mouse model of M. abscessus lung disease.

Treatment outcomes for Mycobacteroides abscessus (Mab, also known as Mycobacterium abscessus) disease are still unsatisfactory, mainly due to issues with drug toxicity, tolerability, and efficacy. Treating Mab disease is challenging due to its high baseline antibiotic resistance, initial requirement for intravenous therapy, and poor medication tolerance. Omadacycline, a new tetracycline, is active against Mab. Since any new antibiotic effective against Mab is expected to be used in combination with other antibiotics, we evaluated the efficacy of two triple-drug combinations comprising omadacycline, omadacycline + amikacin + imipenem, and omadacycline + clofazimine + linezolid against two contemporary Mab clinical isolates in a mouse model of Mab lung disease. Antibiotic administration was initiated 1-week post-infection and was given daily, with Mab burden in the lungs at treatment completion serving as the endpoint. Omadacycline alone moderately reduced Mab levels and maintained better health in mice compared to untreated ones, which typically suffered from the infection. The omadacycline + clofazimine + linezolid combination showed immediate bactericidal activity and enhanced efficacy over 6 weeks, particularly against the more resistant strain (M9507). However, the clofazimine + linezolid combination lacked early bactericidal activity. When combined with amikacin and imipenem, omadacycline did not improve the regimen's effectiveness over 4 weeks of treatment. Our study showed that omadacycline + clofazimine + linezolid exhibited significant bactericidal activity over an extended treatment duration. However, adding omadacycline to amikacin and imipenem did not improve regimen effectiveness against the evaluated clinical isolates within 4 weeks. Further research in Mab disease patients is needed to determine the most effective omadacycline-containing regimen.IMPORTANCEMycobacteroides abscessus is a common environmental bacterium that causes infections in people with compromised lung function, including those with bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and weakened immune systems, especially among older individuals. Treating M. abscessus disease is challenging due to the limited effectiveness and toxicity of current antibiotics, which often require prolonged use. Omadacycline, a new antibiotic, shows promise against M. abscessus. Using a mouse model that mimics M. abscessus disease in humans, we studied the effectiveness of including omadacycline with recommended antibiotics. Adding omadacycline to clofazimine and linezolid significantly improved treatment outcomes, rapidly clearing the bacteria from the lungs and maintaining effectiveness throughout. This oral combination is convenient for patients. However, adding omadacycline to amikacin and imipenem did not improve treatment effectiveness within 4 weeks. Further study with M. abscessus patients is necessary to optimize omadacycline-based treatment strategies for this disease.

Imipenem/relebactam pharmacokinetics in critically ill patients supported on extracorporeal membrane oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is a life-saving modality but has the potential to alter the pharmacokinetics (PK) of antimicrobials. Imipenem/cilastatin/relebactam is an antibiotic with utility in treating certain multi-drug resistant Gram-negative infections. Herein, we describe the population pharmacokinetics of imipenem and relebactam in critically ill patients supported on ECMO. METHODS: Patients with infection supported on ECMO received 4-6 doses of imipenem/cilastatin/relebactam per current prescribing information based on estimated creatinine clearance. Blood samples were collected following the final dose of the antibiotic. Concentrations were determined via LC-MS/MS. Population PK models were fit with and without covariates using Pmetrics. Monte Carlo simulations of 1000 patients assessed joint PTA of fAUC0-24/MIC ≥ 8 for relebactam, and ≥40% fT > MIC for imipenem for each approved dosing regimen. RESULTS: Seven patients supported on ECMO were included in PK analyses. A two-compartment model with creatinine clearance as a covariate on clearance for both imipenem and relebactam fitted the data best. The mean ±â€Šstandard deviation parameters were: CL0, 15.21 ±â€Š6.52 L/h; Vc, 10.13 ±â€Š2.26 L; K12, 2.45 ±â€Š1.16 h-1 and K21, 1.76 ±â€Š0.49 h-1 for imipenem, and 6.95 ±â€Š1.34 L/h, 9.81 ±â€Š2.69 L, 2.43 ±â€Š1.13 h-1 and 1.52 ±â€Š0.67 h-1 for relebactam. Simulating each approved dose of imipenem/cilastatin/relebactam according to creatinine clearance yielded PTAs of ≥90% up to an MIC of 2 mg/L. CONCLUSIONS: Imipenem/cilastatin/relebactam dosed according to package insert in patients supported on ECMO is predicted to achieve exposures sufficient to treat susceptible Gram-negative isolates, including Pseudomonas aeruginosa.

Relationship of imipenem therapeutic drug monitoring to clinical outcomes in critically ill patients: a retrospective cohort study.

The primary objective of this study was to evaluate the predictors associated with target concentration (non-)attainment of imipenem in critically ill patients. The secondary objective was to explore the correlation between achieving imipenem target concentrations and clinical outcomes of therapy. A retrospective cohort study was conducted in critically ill patients treated with imipenem. Clinical data were extracted from the patients' electronic medical records. The pharmacokinetic/pharmacodynamic target was defined as free imipenem concentrations above the minimum inhibitory concentration (MIC) of the pathogen at 100% (100%fT>MIC) of the dosing interval. Factors associated with the non-attainment of target concentrations were evaluated using binomial logistic regression. Kaplan-Meier analysis was used to investigate the correlation between (non-)attainment targets and 30-day mortality. A total of 406 patients were included, and 55.4% achieved the target of 100%fT>MIC. Regression analysis identified an initial daily dose of imipenem ≤ 2 g/day, augmented renal clearance, age ≤ 60 years, recent surgery, and absence of positive microbiology culture as risk factors for target non-attainment. Achieving the 100%fT>MIC target was significantly associated with clinical efficacy but not with 30-day mortality. Selective application of therapeutic drug monitoring in the early stages of imipenem treatment for critically ill patients can improve clinical outcomes. Further research should explore the potential benefits of TDM-guided dosing strategies for imipenem in critical care settings.

Effectiveness and antimicrobial susceptibility profiles during primary antimicrobial prophylaxis for pediatric acute myeloid leukemia.

Limited data are available on antimicrobials exposure and microbiology evolution in pediatric acute myeloid leukemia (AML) patients underwent antimicrobials prophylaxis. To assess the effectiveness of antimicrobials prophylaxis, antibiotic susceptibilities of bacteria, and exposure of antimicrobials during intensive chemotherapy for AML patients, 90 consecutive de novo AML patients aged 0-18 years between January 1, 1997 and March 31, 2018 were enrolled. Vancomycin, ciprofloxacin and voriconazole prophylaxis was administered from January 1, 2010. During the preprophylaxis period, January 1997 to December 2009, 62 patients experienced a total of 87 episodes of bloodstream infection (BSI) and 17 episodes of invasive fungal infection (IFI) among 502 courses of chemotherapy. In contrast, 16 episodes of BSI occurred and no IFIs were reported to occur in 28 patients who received 247 courses of chemotherapy in the prophylaxis period. Patients who received antimicrobial prophylaxis had a significant reduction of BSI, IFI, and febrile neutropenia in comparison with patients without prophylaxis. Exposure to amikacin, carbapenem, amphotericin B was reduced in the prophylaxis period. Imipenem susceptibility of Enterobacter cloacae as well as vancomycin susceptibility of Enterococcus species were reduced in the prophylaxis period. At the time of the last follow up, patients with prophylaxis had a better subsequent 5-year overall survival rate than those without prophylaxis. Prophylactic antimicrobials administration in children with AML who undergo chemotherapy can significantly reduce the rates of life-threatening infection, exposure to antimicrobials, and might result in a better outcome.

Radiographic severity and treatment outcome of Mycobacterium abscessus complex pulmonary disease.

INTRODUCTION: The lack of reliable predictors for the treatment response complicates decisions to initiate treatment in patients with Mycobacterium abscessus complex pulmonary disease (MABC-PD). We aimed to investigate whether baseline radiographic disease severity is associated with treatment outcome in MABC-PD. METHOD: We retrospectively analyzed 101 patients with MABC-PD (54 with M. abscessus-PD and 47 with M. massiliense-PD) treated in a tertiary referral hospital between January 2006 and December 2019. Using chest computed tomography images, baseline radiographic disease severity was quantitatively scored according to five categories of radiographic lesions (bronchiectasis, bronchiolitis, cavities, nodules, and consolidation). RESULTS: Treatment success was achieved in 53.7% of patients with M. abscessus-PD and 85.1% of patients with M. massiliense-PD. Higher overall scores for baseline radiographic disease severity were associated with treatment failure in patients with M. massiliense-PD (aOR 1.35, 95% CI 1.02-1.79 for each 1-point increase in severity score), as well as in patients with M. abscessus-PD (aOR 1.15, 95% CI 1.00-1.33). This was particularly prominent in patients with overall severity score of ≥14 (aOR 31.16, 95% CI 1.12-868.95 for M. massiliense-PD and aOR 3.55, 95% CI 1.01-12.45 for M. abscessus-PD). Among variable radiographic abnormalities, the score for cavitary lesion severity was associated with treatment failure in patients with M. abscessus-PD (aOR 1.26, 95% CI 1.01-1.56), but not in patients with M. massiliense-PD. CONCLUSIONS: Given the association between baseline radiographic disease severity and treatment outcome, initiating treatment should be actively considered before significant progression of radiographic lesions in patients with MABC-PD.

NONMEM population pharmacokinetics and Monte Carlo dosing simulations of imipenem in critically ill patients with life-threatening severe infections during support with or without extracorporeal membrane oxygenation in an intensive care unit.

STUDY OBJECTIVES: The objectives of this study were (i) to determine the population pharmacokinetic (PK) of imipenem in critically ill patients with life-threatening severe infections, (ii) to investigate the impact of extracorporeal membrane oxygenation (ECMO) on the population PK of imipenem during support with ECMO compared to those without ECMO support, and (iii) to assess the probability of target attainment (PTA) for finding the optimal dosage regimens of imipenem in critically ill patients with life-threatening severe infections. DESIGN: Open-label, PK study. SETTING: Academic tertiary care medical center. PATIENTS: Fifty critically ill patients with or without ECMO by pooling data from previously published studiesand unpublished data from 14 patients. INTERVENTION AND MEASUREMENTS: The population PK of imipenem was determined using NONMEM and a Monte Carlo simulation was performed to determine the PTAs of achieving 40% and 75% exposure times during which the plasma drug concentrations remained above the MIC. MAIN RESULTS: The values of volume of distribution and total clearance were 30.5 L and 13.3 L/h, respectively. The ECMO circuit did not show a significant influence on the PK parameters of imipenem. For pathogens with a MIC of 4 mg/L, the PTA target of 75% fT>MIC in patients with normal renal function was achieved when the imipenem was administered by a 4-h infusion of 1 g q6h. CONCLUSION: The ECMO circuit had little effect on enhancing the PK changes of imipenem that had already occurred in these patients. A high dosage of imipenem may be required for achieving the PK/pharmacodynamic targets against less susceptible pathogens, however, the dosage regimens in patients with renal impairment may not need to be as high as those required in patients with normal renal function. ClinicalTrials.gov: NCT03858387.

Conjugation of imipenem to silver nanoparticles for enhancement of its antibacterial activity against multi-drugresistant isolates of Pseudomonas aeruginosa.

Due to the broad-spectrum of antibiotic resistance, herein we investigated the possibility of using imipenemconjugated silver nanoparticles (IMP-AgNPs) against multidrug-resistant isolates of Pseudomonas aeruginosa. For this purpose, 200 clinical isolates were tested against different antibiotics to determine the antimicrobial susceptibility. To identify blaVIM and blaIMP resistance genes, PCR was used. The synthesized AgNPs and conjugants were characterized using UV-vis spectroscopy, XRD, SEM, TEM, DLS, and FTIR. The stability, drug release kinetics, cytotoxicity, hemolytic and apoptotic effects of NPs were also investigated. MIC of the imipenem, AgNPs, and conjugants were evaluated versus P. aeruginosa isolates. Finally, the effects of the IMP-AgNPs to heal burn wounds in rats was evaluated. According to the results, about 68% of isolates showed resistance to imipenem (MIC ≥ 64 µg/ml to ≥ 512 µg/ml). Analytical results verified the synthesis of AgNPs and IMP-AgNPs. A Dose-dependent decrease happened in terms of the MIC values of IMP-AgNPs were also affected by the existence of resistant genes. Low cytotoxic was observed regarding AgNPs which lead to apoptosis. The histopathological results showed a considerable epithelization in treated groups with IMPAgNPs. Accordingly, IMP-AgNPs can be considered as a powerful antibacterial agent to treat the infections caused by multidrug-resistant P. aeruginosa.

Pioderma gangrenoso ampollar como forma de presentación de leucemia mieloide agudo: informe de un caso / Acute myeloid leukemia presented in the form of bullous pyoderma gangrenosum: a case report

El pioderma gangrenoso ampollar es una variedad infrecuente de pioderma gangrenoso, que se asocia en el 50-70% de los casos con trastornos oncohematológicos. Se comunica el caso de una paciente de 59 años, que consultó por fiebre y ampollas purpúricas de rápida progresión, con compromiso cutáneo mucoso. Con sospecha de una enfermedad neutrofílica, ampollar, o infección por gérmenes oportunistas, se realizó biopsia de piel para estudio histopatológico, inmunofluorescencia directa y cultivo. Los cultivos y la inmunofluorescencia directa fueron negativos, y la anatomía patológica reveló un denso infiltrado inflamatorio con predominio neutrofílico en dermis. Ante el diagnóstico de pioderma gangrenoso ampollar, se realizó una punción-aspiración de médula ósea cuyo resultado fue compatible con leucemia mieloide aguda. Se instauró tratamiento con corticosteroides sistémicos, a pesar de lo cual la paciente evolucionó desfavorablemente y falleció a los 15 días de su ingreso hospitalario. Este caso ilustra la asociación de esta enfermedad cutánea con trastornos oncohematológicos y el mal pronóstico que esto implica a corto plazo. (AU)

Bullous pyoderma gangrenosum is an infrequent type of pyoderma gangrenosum, associated with onco hematological diseases in 50-70% of cases. We present the case of a 59-year-old patient with fever and mucocutaneous hemorrhagic bullous of rapid progression. A biopsy for histopathology, direct immunofluorescence (DIF) and skin culture was made, considering the possibility of neutrophilic dermatoses, bullous dermatosis or an opportunistic infection. The results of both the culture and the DIF were negative. The histopathological examination of the specimen revealed a dense dermal polymorphic infiltrate composed primarily of neutrophils. Considering bullous pyoderma gangrenosum as a potential diagnosis, a bone-marrow biopsy was performed. This study revealed an acute myeloid leukemia. Although systemic corticosteroid therapy was begun, the patient presented an unfavorable evolution that led to her death 15 days after her admission at the hospital. This case shows the association between bullous pyoderma gangrenosum and onco hematological diseases. In addition, it highlights the poor prognosis related to these diseases in the short term. (AU)

Maternal antibiotic administration during a critical developmental window has enduring neurobehavioural effects in offspring mice.

Rates of perinatal maternal antibiotic use have increased in recent years linked to prophylactic antibiotic use following Caesarean section delivery. This antibiotic use is necessary and beneficial in the short-term; however, long-term consequences on brain and behaviour have not been studied in detail. Here, we endeavoured to determine whether maternal administration of antibiotics during a critical window of development in early life has lasting effects on brain and behaviour in offspring mice. To this end we studied two different antibiotic preparations (single administration of Phenoxymethylpenicillin at 31 mg/kg/day; and a cocktail consisting of, ampicillin 1 mg/mL; vancomycin 0.5 mg/mL; metronidazole 1 mg/mL; ciprofloxacin 0.2 mg/mL and imipenem 0.25 mg/mL). It was observed that early life exposure to maternal antibiotics led to persistent alterations in anxiety, sociability and cognitive behaviours. These effects in general were greater in animals treated with the broad-spectrum antibiotic cocktail compared to a single antibiotic with the exception of deficits in social recognition which were more robustly observed in Penicillin V exposed animals. Given the prevalence of maternal antibiotic use, our findings have potentially significant translational relevance, particularly considering the implications on infant health during this critical period and into later life.

Ceftazidime-avibactam, meropenen-vaborbactam, and imipenem-relebactam in combination with aztreonam against multidrug-resistant, metallo-ß-lactamase-producing Klebsiella pneumoniae.

The spread of multidrug-resistant (MDR), metallo-ß-lactamase (MBL)-producing Klebsiella pneumoniae represents a major therapeutic challenge. The newly introduced ß-lactam-ß-lactamase inhibitors (BLBLIs), ceftazidime/avibactam (CAZ/AVI), meropenem/vaborbactam (M/V), and imipenem/relebactam (I/R) are inactive against MBLs. The aim of this study was to evaluate the in vitro efficacy of aztreonam (ATM) in combination with CAZ/AVI, M/V, and I/R against 40 MDR, MBL-producing, and serine-ß-lactamases co-producing Klebsiella pneumoniae using the Etest method. Synergy was defined as a fractional inhibitory concentration index ≤0.5. All isolates were resistant to ATM, CAZ/AVI, and I/R and 38/40 (95%) were resistant to M/V. Synergy was observed in 97.5% in the combinations CAZ/AVI-ATM, and I/R-ATM and in 72.5% in the combination M/V-ATM. Further clinical studies are required to confirm the efficacy of these antimicrobial combinations.

Imipenem/Cilastatin/Relebactam: A Review in Gram-Negative Bacterial Infections.

Imipenem/cilastatin/relebactam (Recarbrio™) is an intravenously administered combination of the carbapenem imipenem, the renal dehydropeptidase-I inhibitor cilastatin, and the novel ß-lactamase inhibitor relebactam. Relebactam is a potent inhibitor of class A and class C ß-lactamases, conferring imipenem activity against many imipenem-nonsusceptible strains. Imipenem/cilastatin/relebactam is approved in the USA and EU for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in adults and other gram-negative infections, including complicated urinary tract infections (cUTIs) [including pyelonephritis] and complicated intra-abdominal infections (cIAIs), in adults with limited or no alternative treatment options. In pivotal phase II and III trials, imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam in patients with HABP/VABP and to imipenem/cilastatin in patients with cUTIs and cIAIs. It was also effective in imipenem-nonsusceptible infections. Imipenem/cilastatin/relebactam was generally well tolerated, with a safety profile consistent with that of imipenem/cilastatin. Available evidence indicates that imipenem/cilastatin/relebactam is an effective and generally well tolerated option for gram-negative infections in adults, including critically ill and/or high-risk patients, and a potential therapy for infections caused by carbapenem-resistant pathogens.

Outcomes of Inhaled Amikacin-Containing Multidrug Regimens for Mycobacterium abscessus Pulmonary Disease.

BACKGROUND: Mycobacterium abscessus pulmonary disease (M abscessus-PD) is challenging to treat because of its resistance to antibiotics. RESEARCH QUESTION: What are the outcomes of treatment-naive patients with M abscessus-PD treated with inhaled amikacin-containing multidrug regimens? STUDY DESIGN AND METHODS: We identified 82 treatment-naive patients with M abscessus-PD from a prospective observational cohort treated with regimens containing inhaled amikacin with or without clofazimine between March 2015 and June 2018 (ClinicalTrials.gov identifier: NCT00970801). During the initial phase, all patients received IV amikacin, imipenem (or cefoxitin), and oral azithromycin. Oral clofazimine was added in cases of (1) M abscessus subspecies abscessus (here M abscessus) or (2) M abscessus subspecies massiliense (here M massiliense) with cavitary lesions. During the continuation phase, amikacin was changed from an injectional to inhalational form. RESULTS: Of 82 patients, 46 (56%) had M massiliense-PD and 36 (44%) had M abscessus-PD. Among 59 patients with nodular bronchiectatic disease (72%), 23 of 59 had a concurrent cavitary lesion. The remaining 23 patients (28%) had fibrocavitary disease. Twelve months after treatment initiation, cure was achieved in 53 patients (65%): 42 of 46 patients (91%) with M massiliense-PD and 11 of 36 patients (31%) with M abscessus-PD (P < .001). Symptomatic and radiologic improvements were observed in 72 patients (88%) and 64 patients (78%), respectively, with significantly greater improvement in patients with M massiliense-PD (symptom improvement, 96% vs 78% [P = .047]; improvement on CT scanning, 93% vs 61% [P = .002]). INTERPRETATION: Inhaled amikacin with or without clofazimine in the regimen provides favorable treatment outcomes in M massiliense-PD. However, more effective treatments are needed for M abscessus-PD.

Minimum inhibitory concentrations and resistance for selected antimicrobial agents (including imipenem, linezolid and tigecycline) of bacteria obtained from eye infections.

Objective: To determine bacteria obtained from eye infections, both resistance and minimal inhibitory concentration (MIC) to gatifloxacin, moxifloxacin, tigecycline, linezolid and imipenem, in vitro. Methods: A cross-sectional descriptive study was undergone with 50 samples from 50 eyes of patients diagnosed with keratitis or endophthalmitis, who came to a consultation at the Fundación Oftalmológica de Santander (Floridablanca, Colombia) from August to November 2014. The MICs of the isolated microorganisms were established through Etest® strips (BioMérieux SA, Marcy-l'Etoile - France). Results: Of the 50 samples in total, 17 different bacteria species or groups were isolated. The main isolate for gram-positives was Methicillin Resistant Coagulase-Negative Staphylococcus (17 samples), and for gram-negatives was Pseudomonas aeruginosa (6 samples). The susceptibility percentages sorted from highest to lowest for gram-positive isolates (n=38) were: imipenem 90.3%, linezolid 87.9%, tigecycline 78.1%, gatifloxacin 68.8% and moxifloxacin 68.8%. For gram-negative isolates (n=12), they were: imipenem 72.7%, gatifloxacin 70%, moxifloxacin 66.7% (no reference cut-off points were found for Pseudomonas aeruginosa), tigecycline 22.2%, and linezolid 0% (as expected according to its inhibition spectrum). Conclusions: Although fourth generation fluoroquinolones are currently the preferred initial empirical monotherapy in our practice, given the increasing bacterial resistance, in cases in which gram-positive bacteria were isolated in the initial staining imipenem, linezolid or tigecycline could be used as an alternative. On the other hand, for cases of gram-negative bacteria, no antimicrobial susceptibility exceeded 80%, so using two antimicrobials looking for a synergy between them could be a better option. Abbreviations: S = Susceptibility, IS = Intermediate susceptibility, R = Resistance.

Pharmacokinetics and Monte Carlo Dosing Simulations of Imipenem in Critically Ill Patients with Life-Threatening Severe Infections During Support with Extracorporeal Membrane Oxygenation.

BACKGROUND: Extracorporeal membrane oxygenation (ECMO), a cardiopulmonary bypass device, has been found to increase the profound pathophysiological changes associated with life-threatening severe infections in patients with multiple comorbidities, which results in alterations of pharmacokinetic patterns for antibiotics. OBJECTIVES: The aims of this study were (1) to determine the pharmacokinetics of imipenem and (2) to assess the probability of target attainment (PTA) for imipenem in critically ill patients with life-threatening severe infections during support with ECMO. METHODS: The pharmacokinetic studies were carried out following administration of 0.5 g of imipenem every 6 h on the 4th dose of drug administration in 10 patients and a Monte Carlo simulation was performed to determine the PTA of achieving 40% exposure time during which the plasma drug concentrations remained above minimum inhibitory concentration (T > MIC) and 80% T > MIC. RESULTS: The median values of volume of distribution and total clearance (CL) of imipenem in these patients were 13.98 L and 9.78 L/h, respectively. A high PTA (≥ 90%) for a target of 80% with a MIC of 4 µg/mL in patients with CLCR 60-120 mL/min and flow rate of ECMO circuit 3-5.5 L/min was observed when imipenem was administered by a 4-h infusion of 1 g every 6 h. CONCLUSIONS: A high dosage regimen such as 1 g every 6 h of imipenem may be required to achieve pharmacodynamic targets against less susceptible pathogens in this patient population. CLINICALTRIAL. GOV IDENTIFIER: NCT03776305, date of registration: 11 December 2018.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.

Choosing the therapy for neurological infection with rapidly growing mycobacteria.

The management of neurological infections due to non-tubercular mycobacteria is extremely challenging because of scarce literature, issues with penetration, lack of easily available susceptibility platforms and adverse effects associated with long term therapy. We report a case of a young girl with neurological infection due to rapidly growing mycobacteria to discuss the factors that should be considered while choosing the therapy for such rare and persistent infections.

Ambulatory management of pre- and extensively drug resistant tuberculosis patients with imipenem delivered through port-a-cath: A mixed methods study on treatment outcomes and challenges.

BACKGROUND: Imipenem, an intravenous antibiotic is recommended for use in drug resistant tuberculosis (DR-TB) when an effective regimen with combination of other second line drugs is not possible. Though the treatment success rates with carbapenems are promising, the twice daily injection of Imipenem usually requires patients to be hospitalized. The Médecins Sans Frontières independent clinic in Mumbai, India implemented ambulatory and home based management of patients receiving Imipenem through the use of port-a-cath. OBJECTIVE: We aimed to describe the adverse events and treatment outcomes of ambulatory pre- and XDR-TB patients initiated on imipenem through port-a-cath between January 2015 and June 2018 and to explore the challenges with this regimen as perceived by healthcare providers and patients. METHODS: A convergent mixed methods study with quantitative (longitudinal descriptive study using the routine data) and qualitative (descriptive study) part conducted concurrently. For the quantitative component, all XDR-TB and pre-XDR-TB initiated on imipenem containing regimen during January 2015-June 2018 were included. For qualitative component, interviews were carried out including patients who initiated on imipenem (n = 5) and healthcare providers (n = 7) involved in providing treatment. Treatment outcomes, culture conversion and adverse events during treatment were described. Thematic analysis was carried out for qualitative component. RESULTS: Of the 70 patients included, the mean age was 28.1 (standard deviation: 11.2) years and 36 (51.4%) were females. Fifty one (72.9%) had XDR-TB. All patients were resistant to fluoroquinilone, levofloxacin. Vomiting was reported by 55 (78.6%) patients and at least one episode of QTC prolongation (more than 500 msec by Fredrecia method) was detected in 25 (35.7%). Port-a-cath block and infection was seen in 11 (15.7%) and 20 (28.6%) patients respectively. Favourable outcomes were seen in 43 (61.4%) patients. Mortality was seen in 22 (31.4%) patients, 2 (2.9%) were lost-to-follow-up and 3 (4.3%) were declared as treatment failure. The overarching theme of the qualitative analysis was: Challenges in delivering Imipenem via port-a-cath device in ambulatory care. Major challenges identified were difficulties in adhering to drug dose timelines, vomiting, restricted mobility due to port-a-cath, paucity of infection control and space constraints at patients' home for optimal care. CONCLUSION: Administration of imipenem was feasible through port-a-cath. Though outcomes with ambulatory based imipenem containing regimens were promising, there were several challenges in providing care. The feasibility of infusion at day care facilities needs to explored to overcome challenges in infusion at patients home.

First report of Tsukamurella endocarditis in an immunocompromised patient receiving chemotherapy.

Tsukamurella spp. are gram-positive rods that can be isolated from the environment in soil and moist areas. In rare instances, they are known to cause infections in immunocompromised hosts. We present the first reported case of Tsukamurella endocarditis in an immunocompromised patient who was successfully treated with a 6-week course of imipenem and trimethoprim-sulfamethoxazole.

Comparable Effect of Two-Step Versus Extended Infusions on the Pharmacokinetics of Imipenem in Patients with Sepsis and Septic Shock.

INTRODUCTION: The present study aimed to compare the pharmacokinetic/pharmacodynamic (PK/PD) parameters of imipenem administered by two-step (50% delivered in a 30-min bolus, 50% for the following 90 min) or extended (administered continuously for 2 h) infusion. METHODS: Patients with sepsis and septic shock were prospectively enrolled and randomized into four groups. Subjects in the two-step or extended groups were given two doses of imipenem (0.5 g q6h and 1.0 g q8h). The plasma imipenem concentrations were measured at given time points after the fifth dose. The PK/PD target was defined as the achievement of a fractional time above the minimal inhibitory concentration (MIC) of > 40%. RESULTS: Thirty-five patients were eventually enrolled. No significant difference was observed in the percentage of patients achieving 40% T > MIC between the different infusion modes with the same dosage, although the two-step groups exhibited a significantly shorter Tmax compared with the extended groups (0.5 g q6h: 1.5 ± 0.8 vs. 2.0 ± 0.0 h; 1.0 g q8h: 1.0 ± 0.6 vs. 2.0 ± 0.0 h; both, p < 0.05). All four groups achieved 40% T > MIC when MIC was 0.5-4.0 µg/ml, but only regimens with a higher dose (1.0 g q8h) achieved target when MIC was 8 µg/ml. CONCLUSION: The two-step and extended regimens of imipenem are comparable to the PK/PD target in the treatment of sepsis and septic shock. A higher dose (1.0 g q8h) should be considered for target achievement at an MIC of > 8 µg/ml. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT02616354.