Cilastatin, a new therapeutic promise for acute kidney injury.

Acute kidney injury is a devasting clinical syndrome resulting from multiple causes, characterized by an abrupt deterioration of kidney function for which there is no pharmacologic treatment. Cilastatin has demonstrated direct nephroprotective effects in acute kidney injury and now is shown to be effective to specifically target therapeutically loaded nanoparticles to the proximal tubule to treat acute kidney injury.

Combining ulinastatin with TIENAM improves the outcome of sepsis induced by cecal ligation and puncture in mice by reducing inflammation and regulating immune responses.

Despite the high mortality associated with sepsis, effective and targeted treatments remain scarce. The use of conventional antibiotics such as TIENAM (imipenem and cilastatin sodium for injection, TIE) is challenging because of the increasing bacterial resistance, which diminishes their efficacy and leads to adverse effects. Our previous studies demonstrated that ulinastatin (UTI) exerts a therapeutic impact on sepsis by reducing systemic inflammation and modulating immune responses. In this study, we examined the possibility of administering UTI and TIE after inducing sepsis in a mouse model using cecal ligation and puncture (CLP). We assessed the rates of survival, levels of inflammatory cytokines, the extent of tissue damage, populations of immune cells, microbiota in ascites, and important signaling pathways. The combination of UTI and TIE significantly improved survival rates and reduced inflammation and bacterial load in septic mice, indicating potent antimicrobial properties. Notably, the survival rates of UTI+TIE-treated mice increased from 10 % to 75 % within 168 h compared to those of mice that were subjected to CLP. The dual treatment successfully regulated the levels of inflammatory indicators (interleukin [IL]-6, IL-1ß, and tumor necrosis factor [TNF]-α) and immune cell numbers by reducing B cells, natural killer cells, and TNFR2+ Treg cells and increasing CD8+ T cells. Additionally, the combination of UTI and TIE alleviated tissue damage, reduced bacterial load in the peritoneal cavity, and suppressed the NF-κB signaling pathway. Our findings indicate that UTI and TIE combination therapy can significantly enhance sepsis outcomes by reducing inflammation and boosting the immune system. The results offer a promising therapeutic approach for future sepsis treatment.

Untargeted metabolomics analysis of serum and urine unveils the protective effect of cilastatin on altered metabolic pathways during cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) is one of the most serious complications of cisplatin anticancer therapies. Cilastatin is a highly promising nephroprotective agent to eventually enter clinical use, but its biochemical mechanism is still not fully understood. We have employed an untargeted metabolomics approach based on capillary electrophoresis mass spectrometry (CE-MS) analysis of serum and urine from an in vivo rat model, to explore the metabolic pathways involved in cisplatin-induced AKI and cilastatin nephroprotection. A total of 155 and 76 identified metabolites were found to be significantly altered during cisplatin treatment in urine and serum, respectively. Most of these altered metabolites were either partially or totally recovered by cilastatin and cisplatin co-treatment. The main metabolic pathways disturbed by cisplatin during AKI involved diverse amino acids metabolism and biosynthesis, tricarboxylic acids (TCA) cycle, nicotinate and nicotinamide metabolism, among others. Cilastatin was proved to protect diverse cisplatin-altered pathways involving metabolites related to immunomodulation, inflammation, oxidative stress and amino acid metabolism in proximal tubules. However, cisplatin-altered mitochondrial metabolism (especially, the energy-producing TCA cycle) remained largely unprotected by cilastatin, suggesting an unresolved mitochondrial direct damage. Multivariate analysis allowed effective discrimination of cisplatin-induced AKI and cilastatin renoprotection based on metabolic features. A number of potential serum and urine biomarkers could also be foreseen for cisplatin-induced AKI detection and cilastatin nephroprotection.

Megalin-related mechanism of hemolysis-induced acute kidney injury and the therapeutic strategy.

Hemolysis-induced acute kidney injury (AKI) is attributed to heme-mediated proximal tubule epithelial cell (PTEC) injury and tubular cast formation due to intratubular protein condensation. Megalin is a multiligand endocytic receptor for proteins, peptides, and drugs in PTECs and mediates the uptake of free hemoglobin and the heme-scavenging protein α1-microglobulin. However, understanding of how megalin is involved in the development of hemolysis-induced AKI remains elusive. Here, we investigated the megalin-related pathogenesis of hemolysis-induced AKI and a therapeutic strategy using cilastatin, a megalin blocker. A phenylhydrazine-induced hemolysis model developed in kidney-specific mosaic megalin knockout (MegKO) mice confirmed megalin-dependent PTEC injury revealed by the co-expression of kidney injury molecule-1 (KIM-1). In the hemolysis model in kidney-specific conditional MegKO mice, the uptake of hemoglobin and α1-microglobulin as well as KIM-1 expression in PTECs was suppressed, but tubular cast formation was augmented, likely due to the nonselective inhibition of protein reabsorption in PTECs. Quartz crystal microbalance analysis revealed that cilastatin suppressed the binding of megalin with hemoglobin and α1-microglobulin. Cilastatin also inhibited the specific uptake of fluorescent hemoglobin by megalin-expressing rat yolk sac tumor-derived L2 cells. In a mouse model of hemolysis-induced AKI, repeated cilastatin administration suppressed PTEC injury by inhibiting the uptake of hemoglobin and α1-microglobulin and also prevented cast formation. Hemopexin, another heme-scavenging protein, was also found to be a novel ligand of megalin, and its binding to megalin and uptake by PTECs in the hemolysis model were suppressed by cilastatin. Mass spectrometry-based semiquantitative analysis of urinary proteins in cilastatin-treated C57BL/6J mice indicated that cilastatin suppressed the reabsorption of a limited number of megalin ligands in PTECs, including α1-microglobulin and hemopexin. Collectively, cilastatin-mediated selective megalin blockade is an effective therapeutic strategy to prevent both heme-mediated PTEC injury and cast formation in hemolysis-induced AKI. © 2024 The Pathological Society of Great Britain and Ireland.

An elderly male with septic arthritis and bacteremia.

Rhodococcus hoagii is a gram positive actinomycete found in horses and cattle. Humans can be infected by ingestion or inhalation through contaminated food or soil. The organism usually infects immunosuppressed hosts with pneumonia being the common presentation. We present a case of an 89 years old, apparently immunocompetent host presenting with fever, encephalopathy and arthritis who grew Rhodococcus hoagii in blood and synovial fluid, The patient responded well to a combination of vancomycin, azithromycin and imipenem-cilastatin. Our case demonstrates that extra-pulmonary manifestations such as septic arthritis and bacteremia can be seen in immune competent hosts.

Real-world evaluation of imipenem/cilastatin/relebactam across US medical centres.

We assessed 160 patients who received imipenem/cilastatin/relebactam for ≥2 days. At treatment initiation, the median Charlson Comorbidity Index was 5, 45% were in the intensive care unit, and 19% required vasopressor support. The in-hospital mortality rate was 24%. These data advance our understanding of real-world indications and outcomes of imipenem/cilastatin/relebactam use.

Cilastatin as a Potential Anti-Inflammatory and Neuroprotective Treatment in the Management of Glaucoma.

Glaucoma is a neurodegenerative disease that causes blindness. In this study, we aimed to evaluate the protective role of cilastatin (CIL), generally used in the treatment of nephropathologies associated with inflammation, in an experimental mouse model based on unilateral (left) laser-induced ocular hypertension (OHT). Male Swiss mice were administered CIL daily (300 mg/kg, i.p.) two days before OHT surgery until sacrifice 3 or 7 days later. Intraocular Pressure (IOP), as well as retinal ganglion cell (RGC) survival, was registered, and the inflammatory responses of macroglial and microglial cells were studied via immunohistochemical techniques. Results from OHT eyes were compared to normotensive contralateral (CONTRA) and naïve control eyes considering nine retinal areas and all retinal layers. OHT successfully increased IOP values in OHT eyes but not in CONTRA eyes; CIL did not affect IOP values. Surgery induced a higher loss of RGCs in OHT eyes than in CONTRA eyes, while CIL attenuated this loss. Similarly, surgery increased macroglial and microglial activation in OHT eyes and to a lesser extent in CONTRA eyes; CIL prevented both macroglial and microglial activation in OHT and CONTRA eyes. Therefore, CIL arises as a potential effective strategy to reduce OHT-associated damage in the retina of experimental mice.

Therapeutic drug monitoring of imipenem/cilastatin and meropenem in critically ill adult patients.

OBJECTIVES: To investigate the factors influencing imipenem/cilastatin (IMI) and meropenem (MEM) concentrations in critically ill adult patients and the role of these concentrations in the clinical outcome. METHODS: Plasma trough concentrations of IMI and MEM were detected by high-performance liquid chromatography. A target value of 100%-time above MIC was used for the drugs. RESULTS: A total of 186 patients were included, with 87 receiving IMI and 99 receiving MEM. The percentages of patients reaching the target IMI and MEM concentrations were 44.8% and 38.4%, respectively. The proportions of patients infected with drug-resistant bacteria were 57.5% and 69.7% in the IMI group and MEM group, respectively. In the multivariate analysis, the risk factors for an IMI concentration that did not reach the target were infection with drug-resistant bacteria, and those for MEM were infection with drug-resistant bacteria, estimated glomerular filtration rate, and diabetes mellitus. A total of 47.1% of patients had good outcomes in the IMI cohort, and 38.1% of patients had good outcomes in the MEM cohort. The duration of mechanical ventilation and IMI concentration were associated with ICU stay in patients in the IMI cohort, while MEM concentration and severe pneumonia affected the clinical outcome of patients in the MEM cohort. CONCLUSION: Infection with drug-resistant bacteria is an important factor influencing whether IMI and MEM concentrations reach the target. Furthermore, IMI and MEM concentrations are associated with the clinical outcome, and elevated doses of IMI and MEM should be given to patients who are infected with drug-resistant bacteria.

Legal Performance-enhancing Drugs Alter Course and Treatment of Rhabdomyolysis-induced Acute Kidney Injury.

INTRODUCTION: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment. MATERIALS AND METHODS: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours. RESULTS: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI. CONCLUSIONS: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.

Pharmacokinetics, Safety, and Tolerability of Imipenem/Cilastatin/Relebactam in Children with Confirmed or Suspected Gram-Negative Bacterial Infections: A Phase 1b, Open-Label, Single-Dose Clinical Trial.

Imipenem/cilastatin/relebactam is approved for the treatment of serious gram-negative bacterial infections in adults. This study assessed the pharmacokinetics (PK), safety, and tolerability of a single dose of imipenem/cilastatin/relebactam (with a fixed 2:1 ratio of imipenem/cilastatin to relebactam, and with a maximum dose of 15 mg/kg imipenem and 15 mg/kg cilastatin [≤500 mg imipenem and ≤500 mg cilastatin] and 7.5 mg/kg relebactam [≤250 mg relebactam]) in children with confirmed/suspected gram-negative bacterial infections receiving standard-of-care antibacterial therapy. In this phase 1, noncomparative study (ClinicalTrials.gov identifier, NCT03230916), PK parameters from 46 children were analyzed using both population modeling and noncompartmental analysis. The PK/pharmacodynamic (PD) target for imipenem was percent time of the dosing interval that unbound plasma concentration exceeded the minimum inhibitory concentration (%fT>MIC) of ≥30% (MIC = 2 mcg/mL). For relebactam, the PK/PD target was a free drug area under the plasma concentration-time curve (AUC) normalized to MIC (at 2 mcg/mL) of ≥8.0 (equivalent to an AUC from time zero extrapolated to infinity of ≥20.52 mcg·h/mL). Safety was assessed up to 14 days after drug infusion. For imipenem, the ranges for the geometric mean %fT>MIC and maximum concentration (Cmax ) across age cohorts were 56.5%-93.7% and 32.2-38.2 mcg/mL, respectively. For relebactam, the ranges of the geometric mean Cmax and AUC from 0 to 6 hours across age cohorts were 16.9-21.3 mcg/mL and 26.1-55.3 mcg·h/mL, respectively. In total, 8/46 (17%) children experienced ≥1 adverse events (AEs) and 2/46 (4%) children experienced nonserious AEs that were deemed drug related by the investigator. Imipenem and relebactam exceeded plasma PK/PD targets; single doses of imipenem/cilastatin/relebactam were well tolerated with no significant safety concerns identified. These results informed imipenem/cilastatin/relebactam dose selection for further pediatric clinical evaluation.

Effectiveness and Safety of Intra-arterial Imipenem/Cilastatin Sodium Infusion for Patients with Hand Osteoarthritis-Related Interphalangeal Joint Pain.

PURPOSE: To evaluate the effectiveness and safety of intra-arterial imipenem/cilastatin sodium (IPM/CS) infusion for painful interphalangeal joint osteoarthritis (OA). MATERIALS AND METHODS: Fifty-eight patients with interphalangeal joint OA who underwent intra-arterial IPM/CS infusion were retrospectively evaluated. Intra-arterial infusions were performed via percutaneous wrist arterial access. The Numerical Rating Scale (NRS), Functional Index for Hand Osteoarthritis (FIHOA), and Patient Global Impression of Change (PGIC) scale scores were assessed at intervals of 1, 3, 6, 12, and 18 months. Clinical success was evaluated based on PGIC. RESULTS: All patients were followed up for at least 6 months after treatment. Of them, 30 and 6 patients were followed up for 12 and 18 months, respectively. No severe or life-threatening adverse events were encountered. The mean NRS score was 6.0 ± 1.4 at baseline, which significantly decreased to 2.8 ± 1.4, 2.2 ± 1.9, and 2.4 ± 1.9 at 1, 3, and 6 months after treatment, respectively (all P < .001). The mean NRS scores were 2.8 ± 1.7 and 2.9 ± 1.9 at 12 and 18 months, respectively, in the remaining patients. The mean FIHOA score significantly decreased from 9.8 ± 5.0 at the baseline to 4.1 ± 3.5 at 3 months (P < .001). The mean FIHOA score was 4.5 ± 3.3 at 12 months in the remaining 30 patients. The clinical success rates based on PGIC at 1, 3, 6, 12, and 18 months were 62.1%, 77.6%, 70.7%, 63.4%, and 50.0%, respectively. CONCLUSIONS: Intra-arterial IPM/CS infusion is a potential treatment option for interphalangeal joint OA refractory to medical management.

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.

A Retrospective Comparison of the Efficacy of Embolization with Imipenem/Cilastatin and Microspheres in the Management of Chronic Shoulder Pain.

PURPOSE: To compare the efficacy of embolization with imipenem/cilastatin and microspheres in chronic shoulder pain. METHODS: This retrospective study included 29 patients who underwent embolization for chronic shoulder pain between June 2017 and March 2022 with calibrated MSs from 100 to 250 µm or IMP/CS. The main objective was the clinical success evaluated by the Minimum Clinically Important Difference (MCID) at 3 months after the procedure, validated if the patient responded yes to 2 questions: (1) Is the pain less severe than before the procedure? (2) Are you satisfied with the procedure? The decrease in visual analogue pain scale scores and the safety of the procedure were evaluated. RESULTS: Embolization was achieved in all patients. In the MS group, 4/15 patients (26.7%) experienced clinical success at 3 months according to MCID versus 10/14 patients (71.4%) in the IMP/CS group (p = 0.02). The mean VAS decreases were respectively - 28.6% ± 34.6 in the MS group and - 36.8% ± 27.8 in the IMP/CS group at 1 month (p = 0.50), - 29.9% ± 29.0 and - 39.6% ± 23.0 at 3 months (p = 0.33) and - 30.6% ± 32.8 and - 46.6% ± 28.4 at 6 months after the procedure (p = 0.26). Eleven patients (73.3%) in the MS group and 3 patients (21.4%) in the IMP/CS group had complications (p = 0.01). Among them, 2/15 patients (13.3%) had transient skin ischaemia in the MS group. CONCLUSION: Embolization with IMP/CS may be more effective and safer than MSs in the management of chronic shoulder pain.

Cost-effectiveness of imipenem/cilastatin/relebactam for hospital-acquired and ventilator-associated bacterial pneumonia.

Aim: This study evaluates the cost-effectiveness of imipenem/cilastatin/relebactam (IMI/REL) for treating hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in an 'early adjustment prescribing scenario'. Methods: An economic model was constructed to compare two strategies: continuation of empiric piperacillin/tazobactam (PIP/TAZ) versus early adjustment to IMI/REL. A decision tree was used to depict the hospitalization period, and a Markov model used to capture long-term outcomes. Results: IMI/REL generated more quality-adjusted life years than PIP/TAZ, at an increased cost per patient. The incremental cost-effectiveness ratio of $17,529 per QALY is below the typical US willingness-to-pay threshold. Conclusion: IMI/REL may represent a cost-effective treatment for payers and a valuable option for clinicians, when considered alongside patient risk factors, local epidemiology, and susceptibility data.

Wasp venom-induced acute kidney injury: current progress and prospects.

Wasp venom can trigger local and systemic reactions, with the kidneys being commonly affected, potentially causing acute kidney injury (AKI). Despite of the recent advances, our knowledge on the underlying mechanisms of toxicity and targeted therapies remain poor. AKI can result from direct nephrotoxic effects of the wasp venom or secondary rhabdomyolysis and intravascular hemolysis, which will release myoglobin and free hemoglobin. Inflammatory responses play a central role in these pathological mechanisms. Noteworthily, the successful establishment of a suitable experimental model can assist in basic research and clinical advancements related to wasp venom-induced AKI. The combination of therapeutic plasma exchange and continuous renal replacement therapy appears to be the preferred treatment for wasp venom-induced AKI. In addition, studies on cilastatin and varespladib for wasp venom-induced AKI treatment have shown their potential as therapeutic agents. This review summarizes the available evidence on the mechanisms and treatment of wasp venom-induced AKI, with a particular focus on the role of inflammatory responses and potential targets for therapeutic drugs, and, therefore, aiming to support the development of clinical treatment against wasp venom-induced AKI.

Megalin blockade with cilastatin ameliorates multiple wasp sting-induced acute kidney injury in rats.

Cilastatin has been shown to prevent various drug-induced nephrotoxicities and confer renoprotection in a mouse model of glycerol-mediated rhabdomyolysis-induced acute kidney injury (AKI). The present study aimed to investigate whether cilastatin attenuates wasp sting-induced AKI in rats. Male Wistar rats were divided into the control, cilastatin, AKI, and AKI + cilastatin groups. Nephrotoxicity was assessed using renal function, rhabdomyolysis (creatine kinase, CK) and intravascular hemolysis (lactate dehydrogenase, LDH) markers, and histological changes. In addition, tubular injury biomarkers, apoptosis, oxidative stress markers, complement C3 expression, and urine and blood myoglobin levels were examined. Compared with the control or cilastatin group, the AKI group showed significant histological damage, increased levels of CK, LDH, and creatinine, and increased mRNA expression of tubular injury biomarkers. Cilastatin ameliorated wasp venom-induced kidney injury by attenuating oxidative stress and apoptosis. Cilastatin also reduced C3 expression in the renal tubular cells. In addition, cilastatin reduced serum myoglobin levels and increased urine myoglobin concentrations. Therefore, megalin blockade with cilastatin attenuates wasp venom-induced AKI owing to its antioxidative and antiapoptotic properties.

Direct Colorimetry of Imipenem Decomposition as a Novel Cost-Effective Method for Detecting Carbapenemase-Producing Enterobacteria.

In the absence of a molecule that would collectively inhibit both metallo-ß-lactamases and serine-reactive carbapenemases, containment of their genes is the main weapon currently available for confronting carbapenem resistance in hospitals. Cost-effective methodologies rapidly detecting carbapenemase-producing enterobacteria (CPE) would facilitate such measures. Herein, a low-cost CPE detection method was developed that was based on the direct colorimetry of the yellow shift caused by the accumulation of diketopiperazines-products of the acid-catalyzed imipenem oligomerization-induced by carbapenemase action on dense solutions of imipenem/cilastatin. The reactions were studied by spectrophotometry in the visible spectrum using preparations of ß-lactamases from the four molecular classes. The effects of various buffers on reaction mixtures containing the potent carbapenemases NDM-1 and NMC-A were monitored at 405 nm. Optimal conditions were used for the analysis of cell suspensions, and the assay was evaluated using 66 selected enterobacteria, including 50 CPE as well as 16 carbapenemase-negative strains overexpressing other ß-lactamases. The development of the yellow color was specific for carbapenemase-containing enzyme preparations, and the maximum intensity was achieved in acidic or unbuffered conditions in the presence of zinc. When applied on bacterial cell suspensions, the assay could detect CPE with 98% sensitivity and 100% specificity, with results being comparable to those obtained with the Carba NP technique. Direct colorimetry of carbapenemase-induced imipenem decomposition required minimum reagents while exhibiting high accuracy in detecting CPE. Therefore, it should be considered for screening purposes after further clinical evaluation. IMPORTANCE Currently, the spread of multidrug-resistant (MDR) carbapenemase-producing enterobacteria (CPE), mostly in the clinical setting, is among the most pressing public health problems worldwide. In order to effectively control CPE, use of reliable and affordable methods detecting carbapenemase genes or the respective ß-lactamases is of vital importance. Herein, we developed a novel method, based on a previously undescribed phenomenon, that can detect CPE with few reagents by direct colorimetry of bacterial suspensions and imipenem/cilastatin mixtures.

Imipenem/cilastatin/relebactam pharmacokinetics in critically ill patients with augmented renal clearance.

BACKGROUND: Imipenem and relebactam are predominantly excreted via glomerular filtration. Augmented renal clearance (ARC) is a common syndrome in critically-ill patients with sepsis, and sub-therapeutic antibiotic concentrations are of concern. Herein, we describe the pharmacokinetics of imipenem/relebactam in critically-ill patients with ARC. METHODS: Infected patients in the ICU with ARC (CLCR ≥ 130 mL/min) received a single dose of imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion. Blood samples were collected over 6 h for concentration determination. Protein binding was assessed by ultrafiltration. An 8 h urine creatinine collection confirmed ARC. Population pharmacokinetic models with and without covariates were fit using the non-parametric adaptive grid algorithm in Pmetrics. A 5000 patient Monte Carlo simulation assessed joint PTA using relebactam fAUC/MIC ≥8 and imipenem ≥40% fT>MIC. RESULTS: Eight patients with ARC completed the study. A base population pharmacokinetic model with two-compartments fitted the data best. The mean ±â€ŠSD parameters were: CL, 17.31 ±â€Š5.76 L/h; Vc, 16.15 ±â€Š7.75 L; k12, 1.62 ±â€Š0.99 h-1; and k21, 3.53 ±â€Š3.31 h-1 for imipenem, and 11.51 ±â€Š4.79 L/h, 16.54 ±â€Š7.43 L, 1.59 ±â€Š1.12 h-1, and 2.83 ±â€Š2.91 h-1 for relebactam. Imipenem/cilastatin/relebactam 1.25 g as a 30 min infusion every 6 h achieved 100% and 93% PTA at MICs of 1 and 2 mg/L, respectively. CONCLUSIONS: Despite enhanced clearance of both imipenem and relebactam, the currently approved dosing regimen for normal renal function was predicted to achieve optimal exposure in critically-ill patients with ARC sufficient to treat most susceptible pathogens.