Beneficial herb-drug interaction of rhein in Jinhongtang and Imipenem/Cilastatin mediated by organic anion transporters.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinhongtang as a traditional Chinese medicine (TCM) formula, has been widely used as a clinical adjuvant in the treatment of acute abdominal diseases and sepsis. Clinical benefits of the concurrent use of Jinhongtang and antibiotics have been observed, however, the mechanism has not been fully understood. AIM OF THE STUDY: The present study aimed to explore the effect of Jinhongtang on the antibacterial activity of Imipenem/Cilastatin and to clarify the underlying mechanism of herb-drug interaction (HDI). MATERIALS AND METHODS: A mouse model of sepsis induced by Staphylococcus aureus (S. aureus) was used to evaluate the pharmacodynamic interaction in vivo. In vitro antibacterial activity of Imipenem/Cilastatin was studied by determining minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). Pharmacokinetic interaction was investigated by pharmacokinetic studies in rats and uptake assays using OAT1/3-HEK293 cells. The main constituents ingested into blood of rats were qualitatively identified by UHPLC-Q-TOF-MS. RESULTS: Mice treated by Imipenem/Cilastatin and Jinhongtang exhibited higher survival rate, lower bacteria load and less inflammation in blood and lung tissues, compared with those treated by Imipenem/Cilastatin alone after injection of S. aureus. However, MIC and MBC of Imipenem/Cilastatin against S. aureus in vitro were not significantly changed in the presence of Jinhongtang. On the contrary, Jinhongtang increased the plasma concentration of Imipenem and decreased its urinary excretion in rats. CLr of Imipenem was reduced by 58.5%, while its half-life (t1/2) was prolonged for approximate 1.2 times after coadministered Jinhongtang. Furthermore, the extracts of Jinhongtang, single herb in the prescription, and main absorbable constituents inhibited cellular uptake of probe substrates and Imipenem by OAT1/3-HEK293 cells to different extents. Among them, rhein exhibited the strongest inhibition capacity with IC50 values of 0.08 ± 0.01 µM (OAT1) and 2.86 ± 0.28 µM (OAT3). Moreover, coadministration of rhein also significantly enhanced the antibacterial activity of Imipenem/Cilastatin in sepsis mice. CONCLUSION: Concomitant administration of Jinhongtang enhanced antibacterial activity of Imipenem/Cilastatin in sepsis mice induced by S. aureus through reducing renal elimination of Imipenem via inhibition of OATs. Our investigation provided the insight of Jinhongtang as an effective supplement to enhance the antibacterial activity of Imipenem/Cilastatin and can be useful for future clinical studies.

Simultaneous and divergent evolution of resistance to cephalosporin/ß-lactamase inhibitor combinations and imipenem/relebactam following ceftazidime/avibactam treatment of MDR Pseudomonas aeruginosa infections.

OBJECTIVES: To describe and characterize the emergence of resistance to ceftolozane/tazobactam, ceftazidime/avibactam and imipenem/relebactam in a patient receiving ceftazidime/avibactam treatment for an MDR Pseudomonas aeruginosa CNS infection. METHODS: One baseline (PA1) and two post-exposure (PA2 and PA3) isolates obtained before and during treatment of a nosocomial P. aeruginosa meningoventriculitis were evaluated. MICs were determined by broth microdilution. Mutational changes were investigated through WGS. The impact on ß-lactam resistance of mutations in blaPDC and mexR was determined through cloning experiments and complementation assays. RESULTS: Isolate PA1 showed baseline resistance mutations in DacB (I354A) and OprD (N142fs) conferring resistance to conventional antipseudomonals but susceptibility to ceftazidime/avibactam, ceftolozane/tazobactam and imipenem/relebactam. Post-exposure isolates showed two divergent ceftazidime/avibactam-resistant phenotypes associated with distinctive mutations affecting the intrinsic P PDC ß-lactamase (S254Ins) (PA2: ceftolozane/tazobactam and ceftazidime/avibactam-resistant) or MexAB-OprM negative regulator MexR in combination with modification of PBP3 (PA3: ceftazidime/avibactam and imipenem/relebactam-relebactam-resistant). Cloning experiments demonstrated the role of PDC modification in resistance to ceftolozane/tazobactam and ceftazidime/avibactam. Complementation with a functional copy of the mexR gene in isolate PA3 restored imipenem/relebactam susceptibility. CONCLUSIONS: We demonstrated how P. aeruginosa may simultaneously develop resistance and compromise the activity of new ß-lactam/ß-lactamase inhibitor combinations when exposed to ceftazidime/avibactam through selection of mutations leading to PDC modification and up-regulation of MexAB-OprM-mediated efflux.

Management of antibacterial therapy of infectious and inflammatory diseases of the urinary tract in children and regional peculiarities during the COVID-19 pandemic.

Urinary tract infections (UTIs) remain an urgent issue in clinical pediatrics. Empirical selection of antibacterial therapy becomes more complicated, and antibacterial drug indication is not always clinically substantiated. This study aimed to compare the antibacterial susceptibility pattern of the main group of urinary tract infectious agents from 2009-2016 with intermediate results from 2020-2021, during the COVID-19 pandemic, among children in the Chernivtsi region. Urine samples were collected from 3089 children (0-17 years old) treated at the health care institutions in the Chernivtsi region (2009-2016). The clinical-laboratory examination of 177 children (0-17 years old) was carried out from 2020 to 2021. The children received specialized medical care at the Department of Nephrology. Preliminary data of regional monitoring (2020-2021) are not considerably different from the previous regional susceptibility of antibiotics: to penicillin (p<0.01), ІІ-ІІІ generation cephalosporin (p<0.01); an increased resistance to levofloxacin (χ2=4,338; p<0.01), tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01) and imipenem - χ2=5,594; p<0.01). The data obtained did not explain an increased resistance to fluoroquinolones completely (ofloxacin, pefloxacin, ciprofloxacin), except for levofloxacin (χ2=4,338; p<0.01). A reliable difference of susceptibility of tetracycline group was registered (tetracycline - χ2=7,277; p<0.01; doxycycline - χ2=5,309; p<0.01). Furthermore, there was a regional increase in some UTI-pathogen strains resistant to carbapenems (imipenem - χ2=5,594; p<0.01). The use of antibiotics from the group of penicillins and II-III generation cephalosporins as the starting antibacterial therapy for STIs during the COVID-19 pandemic should be justified. A regional increase (2020-2021) of some uropathogenic strains resistant to carbapenems administered to treat severe bacterial infections requires their exclusively designated purpose in everyday pediatric practical work.

Impact of Ceftazidime-Avibactam Treatment in the Emergence of Novel KPC Variants in the ST307-Klebsiella pneumoniae High-Risk Clone and Consequences for Their Routine Detection.

The emergence of Klebsiella pneumoniae isolates carrying novel blaKPC variants conferring ceftazidime-avibactam (CAZ/AVI) resistance is being increasingly reported. We evaluated the accuracy of phenotypic methods commonly used in routine clinical laboratories in the detection of novel K. pneumoniae carbapenemase (KPC) enzymes. Additionally, we characterized by whole-genome sequencing (WGS) the KPC-ST307-K. pneumoniae isolates recovered in our hospital before and after CAZ/AVI therapy. Rectal colonization or infection by carbapenem-resistant KPC-3 K. pneumoniae isolates (imipenem MIC, 16 mg/L; meropenem MIC, 8 to >16 mg/L) and CAZ/AVI-susceptible isolates (CAZ/AVI MIC, 1 to 2 mg/L) were first detected in three intensive care unit (ICU) patients admitted between March 2020 and July 2020. KPC K. pneumoniae isolates with increased CAZ/AVI MICs (8 to 32 mg/L) and carbapenem susceptibility (imipenem and meropenem MIC, <1 mg/L) were recovered within 6 to 24 days after CAZ/AVI treatment. WGS confirmed that all KPC K. pneumoniae isolates belonged to the sequence type 307 (ST307) high-risk clone and carried identical antimicrobial resistance genes and virulence factors. The presence of the novel blaKPC-46, blaKPC-66, and blaKPC-92 genes was confirmed in the K. pneumoniae isolates with increased CAZ/AVI MICs and restored carbapenem activity. KPC production was confirmed by immunochromatography, the eazyplex Superbug CRE system, and the Xpert Carba-R assay in all KPC K. pneumoniae isolates, but not in any isolate using chromogenic agar plates for carbapenemase producers (ChromID-CARBA), the KPC/MBL/OXA-48 Confirm kit, and the ß-CARBA test. Nevertheless, all grew in chromogenic agar plates for extended-spectrum ß-lactamase (ESBL) producers (ChromID-ESBL). We report the failure of the most common phenotypic methods used for the detection of novel KPC carbapenemases but not of rapid molecular or immunochromatography assays, thus highlighting their relevance in microbiology laboratories.

Evolution of Imipenem-Relebactam Resistance Following Treatment of Multidrug-Resistant Pseudomonas aeruginosa Pneumonia.

We report the emergence of imipenem-relebactam nonsusceptible Pseudomonas aeruginosa in 5 patients treated for nosocomial pneumonia for 10-28 days. Genome sequence analysis identified treatment-emergent mutations in MexAB-OprM and/or MexEF-OprN efflux operons that arose independently in each patient across distinct P. aeruginosa sequence types. Testing with efflux-inhibitor PAßN restored imipenem-relebactam susceptibility.

Comparative activity of newer ß-lactam/ß-lactamase inhibitor combinations against Pseudomonas aeruginosa from patients hospitalized with pneumonia in European medical centers in 2020.

Pseudomonas aeruginosa isolates were consecutively collected from patients with pneumonia in 29 medical centers in 2020 and susceptibility tested by broth microdilution method. Ceftazidime-avibactam (95.5% susceptible), imipenem-relebactam (94.3% susceptible), and ceftolozane-tazobactam (93.3% susceptible) were the most active compounds after colistin (99.5% susceptible). Susceptibility rates for the ß-lactam/ß-lactamase inhibitor combinations (BL/BLIs) varied against isolates resistant to piperacillin-tazobactam, meropenem, imipenem, and/or ceftazidime. Ceftazidime-avibactam was the most active BL/BLI against resistant subsets from Western Europe, whereas imipenem-relebactam was slightly more active than other BL/BLIs against resistant subsets from Eastern Europe. Susceptibility rates were markedly lower in Eastern Europe than Western Europe.

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.

Novel Multifunctional Silver Nanocomposite Serves as a Resistance-Reversal Agent to Synergistically Combat Carbapenem-Resistant Acinetobacter baumannii.

In the face of the abundant production of various types of carbapenemases, the antibacterial efficiency of imipenem, seen as "the last line of defense", is weakening. Following, the incidence of carbapenem-resistant Acinetobacter baumannii (CRAB), which can generate antibiotic-resistant biofilms, is increasing. Based on the superior antimicrobial activity of silver nanoparticles against multifarious bacterial strains compared with common antibiotics, we constructed the IPM@AgNPs-PEG-NOTA nanocomposite (silver nanoparticles were coated with SH-PEG-NOTA as well as loaded by imipenem) whose core was a silver nanoparticle to address the current challenge, and IPM@AgNPs-PEG-NOTA was able to function as a novel smart pH-sensitive nanodrug system. Synergistic bactericidal effects of silver nanoparticles and imipenem as well as drug-resistance reversal via protection of the ß-ring of carbapenem due to AgNPs-PEG-NOTA were observed; thus, this nanocomposite confers multiple advantages for efficient antibacterial activity. Additionally, IPM@AgNPs-PEG-NOTA not only offers immune regulation and accelerates tissue repair to improve therapeutic efficacy in vivo but also can prevent the interaction of pathogens and hosts. Compared with free imipenem or silver nanoparticles, this platform significantly enhanced antibacterial efficiency while increasing reactive oxygen species (ROS) production and membrane damage, as well as affecting cell wall formation and metabolic pathways. According to the results of crystal violet staining, LIVE/DEAD backlight bacterial viability staining, and real-time quantitative polymerase chain reaction (RT-qPCR), this silver nanocomposite downregulated the levels of ompA expression to prevent formation of biofilms. In summary, this research demonstrated that the IPM@AgNPs-PEG-NOTA nanocomposite is a promising antibacterial agent of security, pH sensitivity, and high efficiency in reversing resistance and synergistically combatting carbapenem-resistant A. baumannii. In the future, various embellishments and selected loads for silver nanoparticles will be the focus of research in the domains of medicine and nanotechnology.

An overview of cilastatin + imipenem + relebactam as a therapeutic option for hospital-acquired and ventilator-associated bacterial pneumonia: evidence to date.

Introduction: Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are prevalent nosocomial infections with a worrisomely increasing prevalence of multidrug-resistant causative organisms, including those with resistance to carbapenems. The addition of relebactam, a ß-lactamase inhibitor, to imipenem treatment restores the antimicrobial activity against the most of multidrug-resistant Gram-negative bacteria, including some carrying ß-lactamase enzyme-type carbapenemases.Areas covered: The aim of this article is to summarize the current evidence regarding imipenem/relebactam for the treatment of HAP/VAP. The authors discuss its chemistry, pharmacokinetics/pharmacodynamics, microbiology, tolerance and clinical efficacy. The results of clinical trials have demonstrated an efficacy of imipenem/relebactam similar to that of its comparator for the treatment of patients with HAP/VAP. Different studies have also shown its good safety profile, which is better than that of the combination of other ß-lactams with other antibiotics.Expert opinion: This drug should be incorporated as a new therapeutic option for the treatment of patients with HAP/VAP, especially as an alternative treatment in patients with confirmed infections caused by multidrug-resistant Gram-negatives.

Molecular characterization and antibiotic resistance of Acinetobacter baumannii in cerebrospinal fluid and blood.

The increasing prevalence of carbapenem-resistant Acinetobacter baumannii (CRAB) caused nosocomial infections generate significant comorbidity and can cause death among patients. Current treatment options are limited. These infections pose great difficulties for infection control and clinical treatment. To identify the antimicrobial resistance, carbapenemases and genetic relatedness of Acinetobacter baumannii isolates from cerebrospinal fluid (CSF) and blood, a total of 50 nonrepetitive CSF isolates and 44 blood isolates were collected. The resistance phenotypes were determined, and polymerase chain reaction (PCR) was performed to examine the mechanisms of carbapenem resistance. Finally, multilocus sequence typing (MLST) was conducted to determine the genetic relatedness of these isolates. It was observed that 88 of the 94 collected isolates were resistant to imipenem or meropenem. Among them, the blaOXA-23 gene was the most prevalent carbapenemase gene, with an observed detection rate of 91.5% (86/94), followed by the blaOXA-24 gene with a 2.1% detection rate (2/94). Among all carbapenem-resistant Acinetobacter baumannii (CRAB) observations, isolates with the blaOXA-23 gene were resistant to both imipenem and meropenem. Interestingly, isolates positive for the blaOXA-24 gene but negative for the blaOXA-23 gene showed an imipenem-sensitive but meropenem-resistant phenotype. The MLST analysis identified 21 different sequence types (STs), with ST195, ST540 and ST208 most frequently detected (25.5%, 12.8% and 11.7%, respectively). 80 of the 94 isolates (85.1%) were clustered into CC92 which showed a carbapenem resistance phenotype (except AB13). Five novel STs were detected, and most of them belong to CRAB. In conclusion, these findings provide additional observations and epidemiological data of CSF and blood A. baumannii strains, which may improve future infection-control measures and aid in potential clinical treatments in hospitals and other clinical settings.

Extensively drug-resistant Alcaligenes faecalis infection.

BACKGROUND: Alcaligenes faecalis is usually causes opportunistic infections in humans. Alcaligenes faecalis infection is often difficult to treat due to its increased resistance to several antibiotics. The results from a clinical study of patients with Alcaligenes faecalis infection may help improve patients' clinical care. METHODS: We conducted a retrospective analysis of all patients presenting with Alcaligenes faecalis infection from January 2014 to December 2019. The medical records of all patients were reviewed for demographic information, clinical symptoms and signs, comorbidities, use of intravenous antibiotics within the past three months, bacterial culture, antibiotics sensitivity test, and clinical outcomes. RESULTS: Sixty-one cases of Alcaligenes faecalis infection were seen during the study period, including 25 cases of cystitis, nine cases of diabetic foot infection, eight cases of pneumonia, seven cases of acute pyelonephritis, three cases of bacteremia, and nine cases of infection at specific sites. Thirty-seven patients (60.7%) had a history of receiving intravenous antibiotics within three months of the diagnosis. Fifty-one (83.6%) cases were mixed with other bacterial infections. Extensively drug-resistant infections have been reported since 2018. The best sensitivity rate to Alcaligenes faecalis was 66.7% for three antibiotics (imipenem, meropenem, and ceftazidime) in 2019. Two antibiotics (ciprofloxacin and piperacillin/tazobactam) sensitivity rates to A. faecalis were less than 50%. CONCLUSIONS: The most frequent Alcaligenes faecalis infection sites, in order, are the bloodstream, urinary tract, skin and soft tissue, and middle ear. The susceptibility rate of Alcaligenes faecalis to commonly used antibiotics is decreasing. Extensively drug-resistant Alcaligenes faecalis infections have emerged.

The role of new antimicrobials for Gram-negative infections in daily clinical practice.

PURPOSE OF REVIEW: To discuss a possible clinical reasoning for treating resistant Gram-negative bacteria (GNB) infections in daily clinical practice, as well as developing a research agenda for the field. RECENT FINDINGS: Novel agents, both belonging to ß-lactams and to other classes of antimicrobials, have recently become available, likely replacing polymyxins or polymyxin-based combination regimens as the preferred choices for the first-line treatment of severe resistant GNB infections in the near future. SUMMARY: The peculiar characteristics of novel agents for severe resistant GNB infections have abruptly made the structure of previous therapeutic algorithms somewhat obsolete, in view of the differential activity of most of them against different classes of carbapenemases. Furthermore, other agents showing activity against resistant GNB are in late phase of clinical development. Optimizing the use of novel agents in order both to guarantee the best available treatment to patients and to delay the emergence and spread of resistance is an important task that cannot be postponed, especially considering the unavailability of well tolerated and fully efficacious options for treating resistant GNB infections that we faced in the last 15 years.

Imipenem plus Fosfomycin as Salvage Therapy for Vertebral Osteomyelitis.

We applied combination antibiotic therapy to treat vertebral osteomyelitis and a psoas abscess caused by glycopeptide-intermediate (MIC, 2 µg/ml) and daptomycin-nonsusceptible (>2 µg/ml) methicillin-resistant Staphylococcus aureus The Etest synergy test showed the largest synergistic effects for imipenem/cilastatin and fosfomycin. Whole-gene sequencing showed amino acid changes in SA0802, SA1193 (mprF), and SA1531 (ald). Four weeks of combination treatment using imipenem/cilastatin (1.5 g per day) and fosfomycin (4.0 g per day) resulted in clinical improvement.

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.

First description of antimicrobial resistance in carbapenem-susceptible Klebsiella pneumoniae after imipenem treatment, driven by outer membrane remodeling.

BACKGROUND: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) poses a looming threat to human health. Although there are numerous studies regarding porin alteration in association with the production of ESBLs and/or AmpC ß-lactamase, a systematic study on the treatment-emergence of porins alteration in antibiotic resistance does not yet exist. The aim of this study was to investigate the underlying mechanism of resistance of K. pneumoniae during carbapenem treatment. RESULTS: Here, we report three strains (FK-2624, FK-2723 and FK-2820) isolated from one patient before and after imipenem treatment during hospitalization. Antibiotic susceptibility testing indicated that that the first isolate, FK-2624, was susceptible to almost all tested antimicrobials, being resistant only to fosfomycin. The subsequent isolates FK-2723 and FK-2820 were multidrug resistant (MDR). After imipenem therapy, FK-2820 was found to be carbapenem-resistant. PCR and Genome Sequencing analysis indicated that oqxA, and fosA5, were identified in all three strains. In addition, FK-2624 also harbored blaSHV-187 and blaTEM-116. The blaSHV-187 and blaTEM-116 genes were not detected in FK-2723 and FK-2820. blaDHA-1, qnrB4, aac (6')-IIc, and blaSHV-12, EreA2, CatA2, SulI, and tetD, were identified in both FK-2723 and FK-2820. Moreover, the genes blaDHA-1, qnrB4, aac (6')-IIc were co-harbored on a plasmid. Of the virulence factors found in this study, ybtA, ICEKp6, mrkD, entB, iroN, rmpA2-6, wzi16 and capsular serotype K57 were found in the three isolates. The results of pairwise comparisons, multi-locus sequencing typing (MLST) and pulsed-field gel electrophoresis (PFGE) revealed high homology among the isolates. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) results showed that isolate FK-2820 lacked OmpK36, with genome sequence data validating that there was a premature stop codon in the ompK36 gene and real-time RT-PCR suggesting high turnover of the ompK36 non-sense transcript in FK-2820, with the steady-state mRNA level 0.007 relative to the initial isolate. CONCLUSION: This study in China highlight that the alteration of outer membrane porins due to the 14-day use of imipenem play a potential role in leading to clinical presentation of carbapenem-resistance. This is the first description of increased resistance developing from a carbapenem-susceptible K. pneumoniae with imipenem treatment driven by outer membrane remodeling.

Comparison of Treatment Outcomes between Analysis Populations in the RESTORE-IMI 1 Phase 3 Trial of Imipenem-Cilastatin-Relebactam versus Colistin plus Imipenem-Cilastatin in Patients with Imipenem-Nonsusceptible Bacterial Infections.

The RESTORE-IMI 1 phase 3 trial demonstrated the efficacy and safety of imipenem-cilastatin (IMI) combined with relebactam (REL) for treating imipenem-nonsusceptible infections. The objective of this analysis was to compare the outcomes among patients meeting eligibility requirements based on central laboratory susceptibility versus local laboratory susceptibility. Patients with serious infections caused by imipenem-nonsusceptible, colistin-susceptible, and imipenem-REL-susceptible pathogens were randomized 2:1 to IMI-REL plus placebo or colistin plus IMI for 5 to 21 days. The primary endpoint was a favorable overall response. Key endpoints included the clinical response and all-cause mortality. We compared outcomes between the primary microbiological modified intent-to-treat (mMITT) population, where eligibility was based on central laboratory susceptibility testing, and the supplemental mMITT (SmMITT) population, where eligibility was based on local, site-level testing. The SmMITT (n = 41) and MITT (n = 31) populations had similar baseline characteristics, including sex, age, illness severity, and renal function. In both analysis populations, favorable overall response rates in the IMI-REL treatment group were >70%. Favorable clinical response rates at day 28 were 71.4% for IMI-REL and 40.0% for colistin plus IMI in the mMITT population, whereas they were 75.0% for IMI-REL and 53.8% for colistin plus IMI in the SmMITT population. Day 28 all-cause mortality rates were 9.5% for IMI-REL and 30.0% for colistin plus IMI in the mMITT population, whereas they were 10.7% for IMI-REL and 23.1% for colistin plus IMI in the SmMITT population. The outcomes in the SmMITT population were generally consistent with those in the mMITT population, suggesting that outcomes may be applicable to the real-world use of IMI-REL for treating infections caused by imipenem-nonsusceptible Gram-negative pathogens. (This study has been registered at ClinicalTrials.gov under identifier NCT02452047.).

Imipenem-Cilastatin-Relebactam: A Novel ß-Lactam-ß-Lactamase Inhibitor Combination for the Treatment of Multidrug-Resistant Gram-Negative Infections.

Imipenem-cilastatin-relebactam (IMI-REL) is a novel ß-lactam-ß-lactamase inhibitor combination recently approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intraabdominal infections (cIAIs). Relebactam is a ß-lactamase inhibitor with the ability to inhibit a broad spectrum of ß-lactamases such as class A and class C ß-lactamases, including carbapenemases. The addition of relebactam to imipenem restores imipenem activity against several imipenem-resistant bacteria, including Enterobacteriaceae and Pseudomonas aeruginosa. Clinical data demonstrate that IMI-REL is well tolerated and effective in the treatment of cUTIs and cIAIs due to imipenem-resistant bacteria. In a phase III trial comparing IMI-REL with imipenem plus colistin, favorable clinical response was achieved in 71% and 70% of patients, respectively. Available clinical and pharmacokinetic data support the approved dosage of a 30-minute infusion of imipenem 500 mg-cilastatin 500 mg-relebactam 250 mg every 6 hours, along with dosage adjustments based on renal function. In this review, we describe the chemistry, mechanism of action, spectrum of activity, pharmacokinetics and pharmacodynamics, and clinical efficacy, and safety and tolerability of this new agent. The approval of IMI-REL represents another important step in the ongoing fight against multidrug-resistant gram-negative pathogens.

Outcome and Adequacy of Empirical Antibiotherapy in Post-Operative Peritonitis: A Retrospective Study.

Background: Empirical antibiotherapy (EA) should target all bacteria in post-operative peritonitis (PP). Nevertheless, recent studies failed to prove a link between adequacy of EA and prognosis of PP. We sought to confirm this loss of association between adequate EA and prognosis and to analyze the evolution of patients' characteristics and antimicrobial strategies. Methods: This is was retrospective study. Patients with a positive fungal culture were excluded. The cohort was divided into two time periods. Data of survivors and non-survivors were compared within each time period. Differences between the two periods were assessed. A multivariable analysis searched for parameters associated with a higher hospital mortality rate. Results: Two hundred fifty-one patients were included, with 92 patients in the first period (P1) and 152 patients in the second period (P2). Inadequate EA was associated with a worse outcome only in P1. The multivariable analysis in the whole cohort showed that inadequate EA was associated with a higher mortality rate. When the differences noticed between the two periods were entered in the model (presence of resistant gram-positive cocci and EA comprising glycopeptides), inadequate EA was no longer associated with worse outcome. In P1, the most severe patients had more resistant bacteria, hence, had a higher rate of inadequate EA. This artifact disappeared in P2, during which broader antibiotherapies with triple EA were more often prescribed for the most severe patients. Conclusion: This study showed that the link between inadequate EA and outcome of patients with PP was at least partly artifactual in older studies.

Therapeutic Efficacy of LN-1-255 in Combination with Imipenem in Severe Infection Caused by Carbapenem-Resistant Acinetobacter baumannii.

The carbapenem-hydrolyzing class D ß-lactamases (CHDLs) are the main mechanism of carbapenem resistance in Acinetobacter baumannii CHDLs are not effectively inactivated by clinically available ß-lactam-type inhibitors. We have previously described the in vitro efficacy of the inhibitor LN-1-255 in combination with carbapenems. The aim of this study was to compare the efficacy of LN-1-255 with that of imipenem in murine pneumonia using A. baumannii strains carrying their most extended carbapenemases, OXA-23 and OXA-24/40. The blaOXA-23 and blaOXA-24/40 genes were cloned into the carbapenem-susceptible A. baumannii ATCC 17978 strain. Clinical isolates Ab1 and JC12/04, producing the enzymes OXA-23 and OXA-24/40, respectively, were used in the study. Pharmacokinetic (PK) parameters were determined. An experimental pneumonia model was used to evaluate the efficacy of the combined imipenem-LN-1-255 therapy. MICs of imipenem decreased between 32- and 128-fold in the presence of LN-1-255. Intramuscular treatment with imipenem-LN-1-255 (30/50 mg/kg) decreased the bacterial burden by (i) 4 and 1.7 log10 CFU/g lung in the infection with the ATCC 17978-OXA-23 and Ab1 strains, respectively, and by (ii) 2.5 and 4.5 log10 CFU/g lung in the infection produced by the ATCC 17978-OXA-24/40 and the JC12/04 strains, respectively. In all assays, combined therapy offered higher protection against pneumonia than that provided by monotherapy. No toxicity was observed in treated mice. Imipenem treatment combined with LN-1-255 treatment significantly reduced the severity of infection by carbapenem-resistant A. baumannii strains carrying CHDLs. Preclinical assays demonstrated the potential of LN-1-255 and imipenem therapy as a new antibacterial treatment.

Treatment with andrographolide sulfonate provides additional benefits to imipenem in a mouse model of Klebsiella pneumoniae pneumonia.

Klebsiella pneumoniae is a primary cause of community-acquired and nosocomial respiratory infections, and K. pneumoniae resistance to the current treatment approach with carbapenem is worsening. Andrographolide is a natural diterpenoid from Andrographis paniculata that was shown to exert anti-inflammatory activity. We herein show that pretreatment with a water-soluble andrographolide sulfonate significantly attenuate lung injury and infiltration of inflammatory cells. Interestingly, mice receiving combined treatment with andrographolide sulfonate displayed perfect survival rate than the mice treatment with imipenem alone, and monocyte chemotactic protein 5 (MCP-5) level was decreased further. These findings suggest that andrographolide sulfonate could as a potential synergist for antibiotic treatment of bacteria-induced inflammation.