Sulopenem for the Treatment of Complicated Urinary Tract Infections Including Pyelonephritis: A Phase 3, Randomized Trial.

BACKGROUND: Sulopenem is a thiopenem antibiotic being developed for the treatment of multidrug-resistant infections. The availability of both intravenous (IV) and oral formulations will facilitate earlier hospital discharge. METHODS: Hospitalized adults with pyuria, bacteriuria, and signs and symptoms of complicated urinary tract infection (cUTI) were randomized to 5 days of IV sulopenem followed by oral sulopenem etzadroxil/probenecid or 5 days of IV ertapenem followed by oral ciprofloxacin or amoxicillin-clavulanate, depending on uropathogen susceptibility. The primary end point was overall combined clinical and microbiologic response at the test-of-cure visit (day 21). RESULTS: Of 1392 treated patients, 444 and 440 treated with sulopenem and ertapenem, respectively, had a positive baseline urine culture and were eligible for the primary efficacy analyses. Extended-spectrum ß-lactamase-producing organisms were identified in 26.6% of patients and fluoroquinolone-nonsusceptible pathogens in 38.6%. For the primary end point, noninferiority of sulopenem to the comparator regimen was not demonstrated, 67.8% vs 73.9% (difference, -6.1%; 95% confidence interval, -12.0 to -.1%). The difference was driven by a lower rate of asymptomatic bacteriuria in the subgroup of ertapenem-treated patients who stepped down to ciprofloxacin. No substantial difference in overall response was observed at any other time point. Both IV and oral formulations of sulopenem were well-tolerated and compared favorably to the comparator. CONCLUSIONS: Sulopenem followed by oral sulopenem-etzadroxil/probenecid was not noninferior to ertapenem followed by oral step-down therapy for the treatment of cUTIs, driven by a lower rate of asymptomatic bacteriuria in those who received ciprofloxacin. Both formulations of sulopenem were well-tolerated. CLINICAL TRIAL REGISTRATION: NCT03357614.

Model for Evaluating Antimicrobial Therapy To Prevent Life-Threatening Bacterial Infections following Exposure to a Medically Significant Radiation Dose.

More evidence is needed to support recommendations for medical management of acute radiation syndrome (ARS) and associated infections resulting from a radiological/nuclear event. While current guidelines recommend the administration of antibiotics to chemotherapy patients with febrile neutropenia, the clinical benefit is unclear for acute radiation injury patients. A well-characterized nonhuman primate (NHP) model of hematopoietic ARS was developed that incorporates supportive care postirradiation. This model evaluated the efficacy of myeloid growth factors within 24 to 48 h after total body irradiation (TBI). However, in this model, NHPs continued to develop life-threatening bacterial infections, even when granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor was administered in combination with antibiotic monotherapy. In this study, we evaluated the efficacy of combination antibiotic therapies administered to NHPs following 7.4-Gy TBI to understand the occurrence of bacterial infection in NHPs with hematopoietic ARS. We compared enrofloxacin-linezolid, enrofloxacin-cefepime, and enrofloxacin-ertapenem to enrofloxacin monotherapy. The primary endpoint was 60-day postirradiation mortality, with secondary endpoints of overall survival time, incidence of bacterial infection, and bacteriologic culture with antimicrobial susceptibility testing. We observed that enrofloxacin-ertapenem significantly increased survival compared to enrofloxacin monotherapy. Bacteria isolated from nonsurviving macaques with systemic bacterial infections exhibited uniform resistance to enrofloxacin and variable resistance to beta-lactam antibiotics, linezolid, gentamicin, and azithromycin. Multidrug antibiotic resistance was observed in Enterococcus spp. and Escherichia coli. We conclude that antibiotic combination therapies appear to be more effective than monotherapy alone but acknowledge that more work is needed to identify an optimal antimicrobial therapy.

Sulopenem: An Intravenous and Oral Penem for the Treatment of Urinary Tract Infections Due to Multidrug-Resistant Bacteria.

Sulopenem (formerly known as CP-70,429, and CP-65,207 when a component of a racemic mixture with its R isomer) is an intravenous and oral penem that possesses in vitro activity against fluoroquinolone-resistant, extended spectrum ß-lactamases (ESBL)-producing, multidrug-resistant (MDR) Enterobacterales. Sulopenem is being developed to treat patients with uncomplicated and complicated urinary tract infections (UTIs) as well as intra-abdominal infections. This review will focus mainly on its use in UTIs. The chemical structure of sulopenem shares properties of penicillins, cephalosporins, and carbapenems. Sulopenem is available as an oral prodrug formulation, sulopenem etzadroxil, which is hydrolyzed by intestinal esterases, resulting in active sulopenem. In early studies, the S isomer of CP-65,207, later developed as sulopenem, demonstrated greater absorption, higher drug concentrations in the urine, and increased stability against the renal enzyme dehydropeptidase-1 compared with the R isomer, which set the stage for its further development as a UTI antimicrobial. Sulopenem is active against both Gram-negative and Gram-positive microorganisms. Sulopenem's ß-lactam ring alkylates the serine residues of penicillin-binding protein (PBP), which inhibits peptidoglycan cross-linking. Due to its ionization and low molecular weight, sulopenem passes through outer membrane proteins to reach PBPs of Gram-negative bacteria. While sulopenem activity is unaffected by many ß-lactamases, resistance arises from alterations in PBPs (e.g., methicillin-resistant Staphylococcus aureus [MRSA]), expression of carbapenemases (e.g., carbapenemase-producing Enterobacterales and in Stenotrophomonas maltophilia), reduction in the expression of outer membrane proteins (e.g., some Klebsiella spp.), and the presence of efflux pumps (e.g., MexAB-OprM in Pseudomonas aeruginosa), or a combination of these mechanisms. In vitro studies have reported that sulopenem demonstrates greater activity than meropenem and ertapenem against Enterococcus faecalis, Listeria monocytogenes, methicillin-susceptible S. aureus (MSSA), and Staphylococcus epidermidis, as well as similar activity to carbapenems against Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus pyogenes. With some exceptions, sulopenem activity against Gram-negative aerobes was less than ertapenem and meropenem but greater than imipenem. Sulopenem activity against Escherichia coli carrying ESBL, CTX-M, or Amp-C enzymes, or demonstrating MDR phenotypes, as well as against ESBL-producing Klebsiella pneumoniae, was nearly identical to ertapenem and meropenem and greater than imipenem. Sulopenem exhibited identical or slightly greater activity than imipenem against many Gram-positive and Gram-negative anaerobes, including Bacteroides fragilis. The pharmacokinetics of intravenous sulopenem appear similar to carbapenems such as imipenem-cilastatin, meropenem, and doripenem. In healthy subjects, reported volumes of distribution (Vd) ranged from 15.8 to 27.6 L, total drug clearances (CLT) of 18.9-24.9 L/h, protein binding of approximately 10%, and elimination half-lives (t½) of 0.88-1.03 h. The estimated renal clearance (CLR) of sulopenem is 8.0-10.6 L/h, with 35.5% ± 6.7% of a 1000 mg dose recovered unchanged in the urine. An ester prodrug, sulopenem etzadroxil, has been developed for oral administration. Initial investigations reported a variable oral bioavailability of 20-34% under fasted conditions, however subsequent work showed that bioavailability is significantly improved by administering sulopenem with food to increase its oral absorption or with probenecid to reduce its renal tubular secretion. Food consumption increases the area under the curve (AUC) of oral sulopenem (500 mg twice daily) by 23.6% when administered alone and 62% when administered with 500 mg of probenecid. Like carbapenems, sulopenem demonstrates bactericidal activity that is associated with the percentage of time that free concentrations exceed the MIC (%f T > MIC). In animal models, bacteriostasis was associated with %f T > MICs ranging from 8.6 to 17%, whereas 2-log10 kill was seen at values ranging from 12 to 28%. No pharmacodynamic targets have been documented for suppression of resistance. Sulopenem concentrations in urine are variable, ranging from 21.8 to 420.0 mg/L (median 84.4 mg/L) in fasted subjects and 28.8 to 609.0 mg/L (median 87.3 mg/L) in those who were fed. Sulopenem has been compared with carbapenems and cephalosporins in guinea pig and murine systemic and lung infection animal models. Studied pathogens included Acinetobacter calcoaceticus, B. fragilis, Citrobacter freundii, Enterobacter cloacae, E. coli, K. pneumoniae, Proteus vulgaris, and Serratia marcescens. These studies reported that overall, sulopenem was non-inferior to carbapenems but appeared to be superior to cephalosporins. A phase III clinical trial (SURE-1) reported that sulopenem was not non-inferior to ciprofloxacin in women infected with fluoroquinolone-susceptible pathogens, due to a higher rate of asymptomatic bacteriuria in sulopenem-treated patients at the test-of-cure visit. However, the researchers reported superiority of sulopenem etzadroxil/probenecid over ciprofloxacin for the treatment of uncomplicated UTIs in women infected with fluoroquinolone/non-susceptible pathogens, and non-inferiority in all patients with a positive urine culture. A phase III clinical trial (SURE-2) compared intravenous sulopenem followed by oral sulopenem etzadroxil/probenecid with ertapenem in the treatment of complicated UTIs. No difference in overall success was noted at the end of therapy. However, intravenous sulopenem followed by oral sulopenem etzadroxil was not non-inferior to ertapenem followed by oral stepdown therapy in overall success at test-of-cure due to a higher rate of asymptomatic bacteriuria in the sulopenem arm. After a meeting with the US FDA, Iterum stated that they are currently evaluating the optimal design for an additional phase III uncomplicated UTI study to be conducted prior to the potential resubmission of the New Drug Application (NDA). It is unclear at this time whether Iterum intends to apply for EMA or Japanese regulatory approval. The safety and tolerability of sulopenem has been reported in various phase I pharmacokinetic studies and phase III clinical trials. Sulopenem (intravenous and oral) appears to be well tolerated in healthy subjects, with and without the coadministration of probenecid, with few serious drug-related treatment-emergent adverse events (TEAEs) reported to date. Reported TEAEs affecting ≥1% of patients were (from most to least common) diarrhea, nausea, headache, vomiting and dizziness. Discontinuation rates were low and were not different than comparator agents. Sulopenem administered orally and/or intravenously represents a potentially well tolerated and effective option for treating uncomplicated and complicated UTIs, especially in patients with documented or highly suspected antimicrobial pathogens to commonly used agents (e.g. fluoroquinolone-resistant E. coli), and in patients with documented microbiological or clinical failure or patients who demonstrate intolerance/adverse effects to first-line agents. This agent will likely be used orally in the outpatient setting, and intravenously followed by oral stepdown in the hospital setting. Sulopenem also allows for oral stepdown therapy in the hospital setting from intravenous non-sulopenem therapy. More clinical data are required to fully assess the clinical efficacy and safety of sulopenem, especially in patients with complicated UTIs caused by resistant pathogens such as ESBL-producing, Amp-C, MDR E. coli. Antimicrobial stewardship programs will need to create guidelines for when this oral and intravenous penem should be used.

Retrospective assessment of antimicrobial stewardship initiative in outpatient use of ertapenem for uncomplicated extended spectrum beta lactamase Enterobacteriaceae urinary tract infections.

BACKGROUND: Urinary tract infections (UTI) are often over-diagnosed and over-treated, which can induce and select for resistant pathogens. After observing wide-spread outpatient use of ertapenem, a broad-spectrum antibiotic, a structured antimicrobial stewardship initiative (ASI) to improve appropriate antimicrobial prescribing was undertaken. ASI objectives were to achieve a goal of reducing ertapenem utilization for extended spectrum beta lactamase Enterobacteriaceae (ESBL-EB) UTI by 10% and evaluate the clinical outcomes associated with the ASI. METHODS: A pre-to-post cohort study was conducted at a single-center integrated healthcare system between November 1, 2014 and February 26, 2017. An intensive, 90-day, pharmacist-driven, structured ASI was implemented between November 1, 2015 and January 29, 2016. Female patients aged ≥18 years who were treated for an uncomplicated, ESBL-EB urinary tract infection (UTI) were included. Primary outcome was clinical resolution defined as cure, persistence, relapse and recurrence. Secondary outcome measured was monthly ertapenem use expressed as number of days of therapy (DOT)/1000 adjusted patient days (APD). Segmented regression analysis for interrupted time series was performed to estimate ASI intervention effect. RESULTS: A total of 184 patients were included in the study. Ertapenem utilization decreased from 0.0145 DOT/1000 APD in Nov. 2014 to 0.0078 DOT/1000 APD Feb. 2017(p < 0.01). The mean ertapenem DOT declined 19% overall from the pre vs. post intervention periods (32 vs 26, p < 0.01). Frequency of recurrent UTIs between treatments did not significantly differ and no adverse effects were reported in patients treated with aminoglycosides. CONCLUSIONS: A structured ASI for uncomplicated ESBL-EB UTI was associated with a clinically meaningful decrease in ertapenem utilization and once-daily, 5-day aminoglycoside treatment was well-tolerated.

Effect of Oral Moxifloxacin vs Intravenous Ertapenem Plus Oral Levofloxacin for Treatment of Uncomplicated Acute Appendicitis: The APPAC II Randomized Clinical Trial.

Importance: Antibiotics are an effective and safe alternative to appendectomy for managing uncomplicated acute appendicitis, but the optimal antibiotic regimen is not known. Objective: To compare oral antibiotics with combined intravenous followed by oral antibiotics in the management of computed tomography-confirmed uncomplicated acute appendicitis. Design, Setting, and Participants: The Appendicitis Acuta (APPAC) II multicenter, open-label, noninferiority randomized clinical trial was conducted from April 2017 until November 2018 in 9 Finnish hospitals. A total of 599 patients aged 18 to 60 years with computed tomography-confirmed uncomplicated acute appendicitis were enrolled in the trial. The last date of follow-up was November 29, 2019. Interventions: Patients randomized to receive oral monotherapy (n = 295) received oral moxifloxacin (400 mg/d) for 7 days. Patients randomized to receive intravenous antibiotics followed by oral antibiotics (n = 288) received intravenous ertapenem (1 g/d) for 2 days followed by oral levofloxacin (500 mg/d) and metronidazole (500 mg 3 times/d) for 5 days. Main Outcomes and Measures: The primary end point was treatment success (≥65%) for both groups, defined as discharge from hospital without surgery and no recurrent appendicitis during 1-year follow-up, and to determine whether oral antibiotics alone were noninferior to intravenous and oral antibiotics, with a margin of 6% for difference. Results: Among 599 patients who were randomized (mean [SD] age, 36 [12] years; 263 [44%] women), 581 (99.7%) were available for the 1-year follow-up. The treatment success rate at 1 year was 70.2% (1-sided 95% CI, 65.8% to ∞) for patients treated with oral antibiotics and 73.8% (1-sided 95% CI, 69.5% to ∞) for patients treated with intravenous followed by oral antibiotics. The difference was -3.6% ([1-sided 95% CI, -9.7% to ∞]; P = .26 for noninferiority), with the confidence limit exceeding the noninferiority margin. Conclusion and Relevance: Among adults with uncomplicated acute appendicitis, treatment with 7 days of oral moxifloxacin compared with 2 days of intravenous ertapenem followed by 5 days of levofloxacin and metronidazole resulted in treatment success rates greater than 65% in both groups, but failed to demonstrate noninferiority for treatment success of oral antibiotics compared with intravenous followed by oral antibiotics. Trial Registration: ClinicalTrials.gov Identifier: NCT03236961; EudraCT Identifier: 2015-003633-10.

[The 473rd case: renal failure, abdominal pain, and mental abnormality].

A 43-year-old male presented with elevated serum creatinine for 4 years and developed abdominal pain for 3 days. He started peritoneal dialysis 2 months ago. Dialysis-related peritonitis was ruled out and acute gastroenteritis was diagnosed. The patient was administrated with ertapenem 500 mg/d. An acute mental abnormality developed 3 days later. After excluded organic encephalopathy, ertapenem was discontinued for the suspicion of antibiotic-related encephalopathy. The frequency of peritoneal dialysis was increased to accelerate the clearance of antibiotics. However, the metal abnormality became even more severe. Then a diagnosis of Wernick-Korsakoff syndrome was considered. After the administration of high dose vitamin B(1), the mental disorder dramatically relieved. Vitamin B(1) 30 mg/d is maintained during peritoneal dialysis and the mental disorder does not relapse.

Carbapenem stewardship with ertapenem and antimicrobial resistance-a scoping review

Abstract Consumption of carbapenem has increased due to extended-spectrum beta-lactamase-producing bacteria spreading. Ertapenem has been suggested as a not carbapenem-resistance inducer. We performed a scoping review of carbapenem-sparing stewardship with ertapenem and its impact on the antibiotic resistance of Gram-negative bacilli. We searched PubMed for studies that used ertapenem as a strategy to reduce resistance to carbapenems and included epidemiologic studies with this strategy to evaluate susceptibility patterns to cephalosporins, quinolones, and carbapenems in Gram-negative-bacilli. The search period included only studies in English, up to February 2018. From 1294 articles, 12 studies were included, mostly from the Americas. Enterobacteriaceae resistance to quinolones and cephalosporins was evaluated in 6 studies and carbapenem resistance in 4 studies. Group 2 carbapenem (imipenem/meropenem/doripenem) resistance on A. baumannii was evaluated in 6 studies. All studies evaluated P. aeruginosa resistance to Group 2 carbapenem. Resistance profiles of Enterobacteriaceae and P. aeruginosa to Group 2 carbapenems were not associated with ertapenem consumption. The resistance rate of A. baumannii to Group 2 carbapenems after ertapenem introduction was not clear due to a lack of studies without bias. In summary, ertapenem as a strategy to spare use of Group 2 carbapenems may be an option to stewardship programs without increasing resistance of Enterobacteriaceae and P. aeruginosa. More studies are needed to evaluate the influence of ertapenem on A. baumannii.

Eravacycline: a new treatment option for complicated intra-abdominal infections in the age of multidrug resistance.

Aim: Recently approved for use in complicated intra-abdominal infection, eravacycline is a novel fluorocycline with broad spectrum of activity against resistant Gram-negative pathogens. This manuscript is a pooled analysis of two Phase III trials. Clinical efficacy: Clinical cure rates were 86.8% for eravacycline versus 87.6% for ertapenem, and 90.8% for eravacycline versus 91.2% for meropenem in the Intent to Treat (micro-ITT) populations, and 87.0% for eravacycline versus 88.8% ertapenem, and 92.4 versus 91.6% for meropenem in the Modified Intent to Treat (MITT) populations. Safety: Eravacycline is well tolerated, with lower rates of nausea, vomiting and diarrhea than other tetracyclines. Conclusion: Eravacycline is an effective new option for use in complicated intra-abdominal infections, and in particular, for the treatment of extended-spectrum ß-lactamase- and carbapenem-resistant Enterobacteriaceae-expressing organisms.

Carbapenem-Containing Combination Antibiotic Therapy against Carbapenem-Resistant Uropathogenic Enterobacteriaceae.

The increasing global prevalence of carbapenem-resistant Enterobacteriaceae (CRE) combined with the decline in effective therapies is a public health care crisis. After respiratory tract infections, urinary tract infections and associated urosepsis are the second most affected by CRE pathogens. By using checkerboard analysis, we tested eight different antibiotics in combination with carbapenems in CAMHB (cation-adjusted Müller-Hinton broth) and artificial urine against seven CRE strains and three susceptible strains. To further determine whether these combinations are also effective in a dynamic model, we have performed growth curves analyses in a dynamic bladder model with three uropathogenic CRE strains. In this model, we simulated the urinary pharmacokinetic after application of 1,000 mg intravenous (i.v.) ertapenem alone or in combination with 500 mg i.v. levofloxacin, 1,000 mg oral rifampin, or 3,000 mg oral fosfomycin. Bacterial growth was measured for 48 h, simulating voiding of the bladder every 3 h. According to the median fractional inhibitory concentration indices (ΣFICIs), the values we found were additive to synergistic results across all tested CRE strains for combinations of carbapenems with colistin sulfate, levofloxacin, fosfomycin, rifampin, and tigecycline in CAMHB and artificial urine. In the dynamic bladder model, all three CRE strains tested showed regrowth after treatment with ertapenem up to 48 h. Regrowth could be prevented by combination with levofloxacin, fosfomycin, or rifampin. Carbapenem-containing combination therapy with fosfomycin or rifampin could be an option for better treatment of urinary tract infections (UTIs) caused by CRE strains. This should be further investigated in clinical studies.

Pharmacokinetic-Pharmacodynamic Evaluation of Ertapenem for Patients with Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia.

Ertapenem provides activity against many pathogens commonly associated with hospital-acquired and ventilator-associated bacterial pneumoniae (HABP and VABP, respectively), including methicillin-susceptible Staphylococcus aureus and numerous Gram-negative pathogens with one major gap in coverage, Pseudomonas aeruginosa Pharmacokinetic-pharmacodynamic (PK-PD) target attainment analyses were conducted to evaluate ertapenem against the most prevalent Enterobacteriaceae causing HABP/VABP. The objective of these analyses was to provide dose selection support for and demonstrate the appropriateness of ertapenem to empirically treat patients with HABP/VABP when administered with murepavadin, a novel targeted antimicrobial exhibiting a highly specific spectrum of activity against P. aeruginosa A previously developed population pharmacokinetic model, a total-drug epithelial lining fluid (ELF) to free-drug serum penetration ratio, contemporary in vitro surveillance data for ertapenem against Enterobacteriaceae, and percentage of the dosing interval for which drug concentrations exceed the MIC value (%T>MIC) targets associated with efficacy were used to conduct Monte Carlo simulations for five ertapenem regimens administered over short or prolonged durations of infusion. Overall total-drug ELF percent probabilities of PK-PD target attainment based on a %T>MIC target of 35% among simulated patients with HABP/VABP arising from Enterobacteriaceae based on pathogen prevalence data for nosocomial pneumonia ranged from 89.1 to 92.7% for all five ertapenem regimens evaluated. Total-drug ELF percent probabilities of PK-PD target attainment ranged from 99.8 to 100%, 97.9 to 100%, 10.6 to 74.1%, and 0 to 1.50% at MIC values of 0.06, 0.12, 1, and 4 µg/ml, respectively (MIC90 values for Escherichia coli, Serratia marcescens, Enterobacter species, and Klebsiella pneumoniae, respectively). Results of these analyses provide support for the evaluation of ertapenem in combination with murepavadin for the treatment of patients with HABP/VABP.

In Vitro Effectiveness of Meropenem and Cefmetazole Combination Treatment Against KPC-2-Producing Enterobacteriaceae.

Purpose: Optimal treatment regimens are yet to be established for carbapenemase-producing Enterobacteriaceae (CPE). We assessed the in vitro efficacy of meropenem (MEM) and cefmetazole (CMZ) combination treatment against blaKPC-2-positive Enterobacteriaceae, in comparison with that of double-carbapenem therapy using ertapenem (ERT). Materials and Methods: We performed checkerboard assay for 10 blaKPC-2-positive clinical isolates and Klebsiella pneumoniae BAA-1705 (possessing blaKPC-2), with synergistic effect being defined by a fractional inhibitory concentration index of ≤0.5. Subsequently, we conducted time-kill assays using K. pneumoniae BAA-1705 with an initial inoculum of 104-107 colony forming unit (CFU)/mL. Bactericidal effect was defined as the reduction of initial bacterial count by ≥103 CFU/mL in 24 hr. Finally, we applied scanning electron microscopy to observe morphological changes induced by the combination of MEM and CMZ. Results: Checkerboard assays revealed a synergistic effect in 7 out of 11 blaKPC-2 -positive Enterobacteriaceae when the MEM and CMZ combination was used, and no effect when the MEM and ERT combination was used. The minimum inhibitory concentration of MEM decreased 4-8-fold when combined with CMZ. Time-kill assays with an initial inoculum of 5 × 105 CFU/mL revealed regrowth under the combination of MEM and ERT (0.25 × minimum inhibitory concentration [MIC] each), whereas the combination of 0.25 × MIC each of MEM and CMZ exhibited bactericidal effect. Scanning electron microscopy results demonstrated that the combination of 0.5 × MIC MEM and 0.5 × MIC CMZ facilitated bacterial cell lysis compared with each antibiotic alone. Conclusion: The combination therapy using MEM and CMZ potentially has bactericidal effect against KPC-producing Enterobacteriaceae.

Detection in the United Kingdom of the Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate resistance to azithromycin, October to December 2018.

We describe detection in the United Kingdom (UK) of the drug-resistant Neisseria gonorrhoeae FC428 clone, with ceftriaxone resistance and intermediate azithromycin resistance. Two female patients developed infection following contact with UK-resident men from the same sexual network linked to travel to Ibiza, Spain. One case failed treatment with ceftriaxone, and azithromycin and gentamicin, before successful treatment with ertapenem. Both isolates had indistinguishable whole-genome sequences. Urgent action is essential to contain this drug-resistant strain.

Role of Double-Carbapenem Regimen in the Treatment of Infections due to Carbapenemase Producing Carbapenem-Resistant Enterobacteriaceae: A Single-Center, Observational Study.

PURPOSE: (i) To compare infections caused by carbapenem-susceptible (CS) and carbapenemase producing carbapenem-resistant Enterobacteriaceae (CP-CRE); (ii) to evaluate the clinical effectiveness of the double-carbapenem (DC) regimen in comparison with the best available treatment (BAT) in infections caused by CP-CRE; and (iii) to determine the exact minimal inhibitory concentrations (MICs) of meropenem/ertapenem (MEM/ETP) and the degree of in vitro ETP+MEM synergism in subjects receiving the DC. METHODOLOGY: Over a 3-year period (2014-2017), patients with infections due to Enterobacteriaceae were included in a single-center, retrospective, observational study. According to the susceptibility to carbapenems, subjects were divided into CSE and CP-CRE groups. CP-CRE group was further divided into subjects receiving the DC regimen and those treated with other regimens (BAT group). Clinical characteristics and the presence of 5th-day response and 60-day outcome were evaluated for DC and BAT groups. The determination of MEM and ETP actual MICs and the MEM+ETP synergistic activity were performed on strains obtained from subjects receiving the DC regimen. RESULTS: A total of 128 patients were included in the study: 55/128 (43%) with infections due to CP-CRE and 73/128 (57%) with infections due to CSE. Among CP-CRE (n=55), 21 subjects (39%) were treated with the DC regimen whereas 34 (61%) received BAT. No differences in terms of severity of infection, presence/absence of concomitant bacteremia, type of infection, and resolution of infection were found; in contrast, DC group tended to have a higher rate of sepsis or septic shock at the onset of infection and a higher rate of 5th-day response. MICs 50/90 were 256/512 and 256/256 µg/mL for MEM and ETP, respectively. Overall, complete in vitro synergism was found in 6/20 strains (30%). CONCLUSION: The DC regimen is a valid and effective therapeutic option in patients with infections due to KPC producing CRE, including those with bacteremic infection and more severe clinical conditions. The clinical effectiveness is maintained even in the presence of extremely high MEM MICs.

Pharmacokinetics of 2,000 Milligram Ertapenem in Tuberculosis Patients.

Ertapenem is a carbapenem antibiotic with activity against Mycobacterium tuberculosis Dose simulations in a hollow-fiber infection model showed that 2,000 mg once daily is an appropriate dose to be tested in clinical studies. Before using this dose in a phase II study, the aim of this prospective pharmacokinetic study was to confirm the pharmacokinetics of 2,000 mg once daily in tuberculosis (TB) patients. Twelve TB patients received a single intravenous dose of 2,000 mg ertapenem as a 30-min infusion. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 8, 12, and 24 h postadministration. Drug concentrations were measured using a validated liquid chromatography-tandem mass spectrometry assay. A large interindividual variation in the pharmacokinetics of ertapenem was observed. The median (interquartile range) area under the plasma concentration-time curve to infinity (AUC0-∞) was 2,032 (1,751 to 2,346) mg · h/liter, the intercompartmental clearance (CL12) was 1.941 (0.979 to 2.817) liters/h, and the volume of distribution in the central compartment (V1) was 1.514 (1.064 to 2.210) liters. A more than dose-proportional increase in AUC was observed compared to results reported for 1,000 mg ertapenem in multidrug-resistant TB patients. Based on a MIC of 1.0 mg/liter, 11 out of 12 patients would have reached the target value of unbound drug exceeding the MIC over 40% of the time (f40% T>MIC). In conclusion, this study shows that 2,000 mg ertapenem once daily in TB patients reached the expected f40% T>MIC for most of the patients, and exploration in a phase 2 study can be advocated.

Multiplex Immunochromatographic Detection of OXA-48, KPC, and NDM Carbapenemases: Impact of Inoculum, Antibiotics, and Agar.

For the rapid detection of carbapenemase-producing Enterobacteriaceae (CPE), immunochromatographic lateral flow tests (ICT) have recently been developed. The aim of this study was to assess the new multiplex ICT Resist-3 O.K.N. and to investigate if it can be performed directly from susceptibility testing plates. Additionally, the impact of the inoculum and carbapenem disks on sensitivity and specificity was evaluated. The new ICT was challenged using 63 carbapenem-resistant Enterobacteriaceae (CRE) isolates, including 51 carbapenemase producers. It was assessed under five different conditions directly from Mueller-Hinton agar (MHA): 1 µl or 10 µl of inoculum harvested in the absence of antibiotic pressure or 1 µl taken from the inhibition zone of either an ertapenem, imipenem, or meropenem disk. The sensitivity of the ICT was 100% for OXA-48-like and KPC carbapenemases and 94.4% for the NDM carbapenemase with the 1-µl inoculum. When harvested adjacent to a carbapenem disk, the sensitivity increased to 100%. Additionally, with zinc-supplemented MHA, both the sensitivity increased and the NDM band became visible faster (mean time, 8 ± 3.9 min for MHA compared to 1.9 ± 1.5 min for MHA plus zinc; P = 0.0016). The specificity of the ICT was 100%. The Resist-3 O.K.N. ICT is a sensitive and rapid test for the detection of three highly prevalent carbapenemases. However, false-negative results for NDM can occur. We recommend an inoculum of 1 µl that is harvested adjacent to an ertapenem or meropenem disk and the use of agars with sufficient zinc content to achieve the best performance.

Impact of broad-spectrum antimicrobial treatment on the ecology of intestinal flora.

BACKGROUND: Suppression of intestinal flora by broad-spectrum antimicrobial agents facilitated risk of colonization or infection with resistant pathogen. We aimed to investigate the changes in bowel carriage of target resistant microorganisms (TRO) among patients treated with three different classes of Pseudomonas-sparing broad-spectrum antimicrobial agents (ertapenem, moxifloxacin and flomoxef) with anaerobic coverage. Risk factors for developing colonization of TRO were also analyzed. METHODS: We prospectively enrolled the adult hospitalized patients (>20 years old) who were indicated for at least 7-day course with either of ertapenem, moxifloxacin or flomoxef. Rectal swabs were performed for the patients who received at least 1-day course of study antibiotics during the treatment duration. The TROs included Pseudomonas aeruginosa, Enterobacteriaceae, and Acinetobacter baumannii. MacConkey agars with study antibiotics were used to isolate the TROs and evaluate the antimicrobial resistance. RESULTS: The mean age of our study population was 61.6 years, and 58.8% were males. The rates of rectal colonization for Pseudomonas aeruginosa was similar among the study medications (ertapenem 13.2%, flomoxef 20%, moxifloxacin 14.3%, p = 0.809). Compared with ertapenem, flomoxef (odds ratio [OR], 4.30; 95% confidence interval [95% CI], 1.28-14.48, p = 0.019) and moxifloxacin (OR, 6.95; 95% CI, 1.36-35.52, p = 0.019) had higher risk for colonization of ertapenem-resistant Escherichia coli colonization. CONCLUSION: The patients who received treatment of ertapenem may have a lower risk of rectal colonization for ertapenem resistant Escherichia coli than those who received flomoxef or moxifloxacin. The rate of Pseudomonas colonization did not differ between the three study Pseudomonas-sparing agents.

Copper Ions and Coordination Complexes as Novel Carbapenem Adjuvants.

Carbapenem-resistant Enterobacteriaceae are urgent threats to global human health. These organisms produce ß-lactamases with carbapenemase activity, such as the metallo-ß-lactamase NDM-1, which is notable due to its association with mobile genetic elements and the lack of a clinically useful inhibitor. Here we examined the ability of copper to inhibit the activity of NDM-1 and explored the potential of a copper coordination complex as a mechanism to efficiently deliver copper as an adjuvant in clinical therapeutics. An NDM-positive Escherichia coli isolate, MS6192, was cultured from the urine of a patient with a urinary tract infection. MS6192 was resistant to antibiotics from multiple classes, including diverse ß-lactams (penicillins, cephalosporins, and carbapenems), aminoglycosides, and fluoroquinolones. In the presence of copper (range, 0 to 2 mM), however, the susceptibility of MS6192 to the carbapenems ertapenem and meropenem increased markedly. In standard checkerboard assays, copper decreased the MICs of ertapenem and meropenem against MS6192 in a dose-dependent manner, suggesting a synergistic mode of action. To examine the inhibitory effect of copper in the absence of other ß-lactamases, the blaNDM-1 gene from MS6192 was cloned and expressed in a recombinant E. coli K-12 strain. Analysis of cell extracts prepared from this strain revealed that copper directly inhibited NDM-1 activity, which was confirmed using purified recombinant NDM-1. Finally, delivery of copper at a low concentration of 10 µM by using the FDA-approved coordination complex copper-pyrithione sensitized MS6192 to ertapenem and meropenem in a synergistic manner. Overall, this work demonstrates the potential use of copper coordination complexes as novel carbapenemase adjuvants.

Double carbapenem as a rescue strategy for the treatment of severe carbapenemase-producing Klebsiella pneumoniae infections: a two-center, matched case-control study.

BACKGROUND: Recent reports have suggested the efficacy of a double carbapenem (DC) combination, including ertapenem, for the treatment of carbapenem-resistant Klebsiella pneumoniae (CR-Kp) infections. We aimed to evaluate the clinical impact of such a regimen in critically ill patients. METHODS: This case-control (1:2), observational, two-center study involved critically ill adults with a microbiologically documented CR-Kp invasive infection treated with the DC regimen matched with those receiving a standard treatment (ST) (i.e., colistin, tigecycline, or gentamicin). RESULTS: The primary end point was 28-day mortality. Secondary outcomes were clinical cure, microbiological eradication, duration of mechanical ventilation and of vasopressors, and 90-day mortality. Forty-eight patients treated with DC were matched with 96 controls. Occurrence of septic shock at infection and high procalcitonin levels were significantly more frequent in patients receiving DC treatment (p < 0.01). The 28-day mortality was significantly higher in patients receiving ST compared with the DC group (47.9% vs 29.2%, p = 0.04). Similarly, clinical cure and microbiological eradication were significantly higher when DC was used in patients infected with CR-Kp strains resistant to colistin (13/20 (65%) vs 10/32 (31.3%), p = 0.03 and 11/19 (57.9%) vs 7/27 (25.9%), p = 0.04, respectively). In the logistic regression and multivariate Cox-regression models, the DC regimen was associated with a reduction in 28-day mortality (OR 0.33, 95% CI 0.13-0.87 and OR 0.43, 95% CI 0.23-0.79, respectively). CONCLUSIONS: Improved 28-day mortality was associated with the DC regimen compared with ST for severe CR-Kp infections. A randomized trial is needed to confirm these observational results. TRIAL REGISTRATION: ClinicalTrials.gov NCT03094494 . Registered 28 March 2017.

Patterns of antimicrobial resistance in intensive care unit patients: a study in Vietnam.

BACKGROUND: Antimicrobial resistance has emerged as a major concern in developing countries. The present study sought to define the pattern of antimicrobial resistance in ICU patients with ventilator-associated pneumonia. METHODS: Between November 2014 and September 2015, we enrolled 220 patients (average age ~ 71 yr) who were admitted to ICU in a major tertiary hospital in Ho Chi Minh City, Vietnam. Data concerning demographic characteristics and clinical history were collected from each patient. The Bauer-Kirby disk diffusion method was used to detect the antimicrobial susceptibility. RESULTS: Antimicrobial resistance was commonly found in ceftriaxone (88%), ceftazidime (80%), ciprofloxacin (77%), cefepime (75%), levofloxacin (72%). Overall, the rate of antimicrobial resistance to any drug was 93% (n = 153/164), with the majority (87%) being resistant to at least 2 drugs. The three commonly isolated microorganisms were Acinetobacter (n = 75), Klebsiella (n = 39), and Pseudomonas aeruginosa (n = 29). Acinetobacter baumannii were virtually resistant to ceftazidime, ceftriaxone, piperacilin, imipenem, meropenem, ertapenem, ciprofloxacin and levofloxacin. High rates (>70%) of ceftriaxone and ceftazidime-resistant Klebsiella were also observed. CONCLUSION: These data indicated that critically ill patients on ventilator in Vietnam were at disturbingly high risk of antimicrobial resistance. The data also imply that these Acinetobacter, Klebsiella, and Pseudomonas aeruginosa and multidrug resistance pose serious therapeutic problems in ICU patients. A concerted and systematic effort is required to rapidly identify high risk patients and to reduce the burden of antimicrobial resistance in developing countries.