Early outcomes of transcatheter arterial embolization using imipenem/cilastatin for plantar fasciitis refractory to conservative therapy.

OBJECTIVE: The conservative therapy for chronic plantar fasciitis works for a few patients, while surgical options have drawbacks. Before considering surgical options, transcatheter arterial embolization may help patients with plantar fasciitis who are experiencing discomfort resistant to conservative treatment. METHODS: We report evaluation data of 10 patients treated with transcatheter arterial embolization using imipenem/cilastatin as embolic agents to relieve chronic pain due to plantar fasciitis. All the patients were refractory to conservative therapy. RESULTS: The technical success of the procedure was found to be 100%. Further, effective pain relief was observed as there was no pain relapse in 6 months, and patients did not require any other form of therapy. CONCLUSION: This report warrants further adequately designed randomized clinical studies for evaluating the efficacy of transcatheter arterial embolization in plantar fasciitis. ADVANCES IN KNOWLEDGE: Resorting to surgical option for chronic pain relief in plantar fasciitis might be reconsidered and replaced with arterial embolization. However, adequately designed long-term clinical studies are required to prove its long-term efficacy.

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.

Flucloxacillin worsens while imipenem-cilastatin protects against vancomycin-induced kidney injury in a translational rat model.

BACKGROUND AND PURPOSE: Vancomycin is one of the most common clinical antibiotics, yet acute kidney injury is a major limiting factor. Common combinations of antibiotics with vancomycin have been reported to worsen and improve vancomycin-induced kidney injury. We aimed to study the impact of flucloxacillin and imipenem-cilastatin on kidney injury when combined with vancomycin in our translational rat model. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats received allometrically scaled (1) vancomycin, (2) flucloxacillin, (3) vancomycin + flucloxacillin, (4) vancomycin + imipenem-cilastatin or (5) saline for 4 days. Kidney injury was evaluated via drug accumulation and urinary biomarkers including urinary output, kidney injury molecule-1 (KIM-1), clusterin and osteopontin. Relationships between vancomycin accumulation in the kidney and urinary kidney injury biomarkers were explored. KEY RESULTS: Urinary output increased every study day for vancomycin + flucloxacillin, but after the first dose only in the vancomycin group. In the vancomycin + flucloxacillin group, urinary KIM-1 increased on all days compared with vancomycin. In the vancomycin + imipenem-cilastatin group, urinary KIM-1 was decreased on Days 1 and 2 compared with vancomycin. Similar trends were observed for clusterin. More vancomycin accumulated in the kidney with vancomycin + flucloxacillin compared with vancomycin and vancomycin + imipenem-cilastatin. The accumulation of vancomycin in the kidney tissue correlated with increasing urinary KIM-1. CONCLUSIONS AND IMPLICATIONS: Vancomycin + flucloxacillin caused more kidney injury compared with vancomycin alone and vancomycin + imipenem-cilastatin in a translational rat model. The combination of vancomycin + imipenem-cilastatin was nephroprotective.

Microbiological profile of patients treated for postoperative peritonitis: temporal trends 1999-2019.

BACKGROUND: Temporal changes in the microbiological resistance profile have been reported in several life-threatening infections. However, no data have ever assessed this issue in postoperative peritonitis (POP). Our purpose was to assess the rate of multidrug-resistant organisms (MDROs) in POP over a two-decade period and to analyse their influence on the adequacy of empirical antibiotic therapy (EAT). METHODS: This retrospective monocentric analysis (1999-2019) addressed the changes over time in microbiologic data, including the emergence of MDROs and the adequacy of EAT for all intensive care unit adult patients treated for POP. The in vitro activities of 10 antibiotics were assessed to determine the most adequate EAT in the largest number of cases among 17 antibiotic regimens in patients with/without MDRO isolates. Our primary endpoint was to determine the frequency of MDRO and their temporal changes. Our second endpoint assessed the impact of MDROs on the adequacy of EAT per patient and their temporal changes based on susceptibility testing. In this analysis, the subgroup of patients with MDRO was compared with the subgroup of patients free of MDRO. RESULTS: A total of 1,318 microorganisms were cultured from 422 patients, including 188 (45%) patients harbouring MDROs. The growing proportions of MDR Enterobacterales were observed over time (p = 0.016), including ESBL-producing strains (p = 0.0013), mainly related to Klebsiella spp (p < 0.001). Adequacy of EAT was achieved in 305 (73%) patients. Decreased adequacy rates were observed when MDROs were cultured [p = 0.0001 vs. MDRO-free patients]. Over the study period, decreased adequacy rates were reported for patients receiving piperacillin/tazobactam in monotherapy or combined with vancomycin and imipenem/cilastatin combined with vancomycin (p < 0.01 in the three cases). In patients with MDROs, the combination of imipenem/cilastatin + vancomycin + amikacin or ciprofloxacin reached the highest adequacy rates (95% and 91%, respectively) and remained unchanged over time. CONCLUSIONS: We observed high proportions of MDRO in patients treated for POP associated with increasing proportions of MDR Enterobacterales over time. High adequacy rates were only achieved in antibiotic combinations involving carbapenems and vancomycin, while piperacillin/tazobactam is no longer a drug of choice for EAT in POP in infections involving MDRO.

Aortic endograft infection by Mycobacterium abscessus subsp. massiliense with acquired clarithromycin resistance: a case report.

BACKGROUND: Mycobacterium abscessus subsp. massiliense (MMA) comprises a group of non-tuberculous, rapidly growing mycobacteria. Although MMA can cause pulmonary diseases, surgical site infections, and disseminated diseases, aortic endograft infection has not been reported. Here, we describe the first case of aortic endograft infection caused by MMA. CASE PRESENTATION: Two months after stent-graft insertion for an abdominal aortic aneurysm, an 85-year-old man was admitted with fever and abdominal pain and was diagnosed with aortic endograft infection. Despite 14 days of meropenem and vancomycin intravenous administration, periaortic fluid pooling increased as compared to that before antibiotic administration. The abscess was drained, and fluorescent acid-fast staining of the abscess fluid revealed bacilli. We conducted genetic tests on the genes hsp65, rpoB, and sodA, performed Whole Genome Sequencing (WGS), and identified the organism as MMA. Intravenous imipenem-cilastatin (IPM/CS), amikacin (AMK), and oral clarithromycin (CAM) were administered. After 2 months, oral CAM and sitafloxacin were administered because the abscess had decreased in size. However, after 6 weeks, the abscess increased in size again. Antimicrobial susceptibility testing of the drainage fluid from the abscess resulted in the isolation of an MMA strain that had acquired resistance to CAM. Intravenous IPM/CS, AMK, and oral linezolid were added to the treatment regimen along with oral CAM and STFX. However, he was not fully cured and died 6 months later. Neither the full-length erythromycin ribosome methyltransferase (erm)(41) gene nor the rrl or rpIV gene mutations were found by Sanger sequencing in the pre- and post-treatment strains. Whole-genome sequence analysis of the post-treatment strain revealed mutations in genes with no previous reports of association with macrolide resistance. CONCLUSIONS: Aortic endograft infection caused by MMA strain is extremely rare; nonetheless, MMA should be suspected as the causative microorganism when broad-spectrum antimicrobials are ineffective.

Increased antibiofilm and growth inhibitory effect of Imipenem/Cilastatin nanoliposomes against clinical Pseudomonas aeruginosa isolates.

Numerous infections are linked to Pseudomonas aeruginosa. It is one of the major medical concerns because of virulence and antibiotic resistance. Antibiotic encapsulation in liposomes is a good strategy for controlling infections caused by this microorganism. Evaluation of anti-Pseudomonas aeruginosa effect of liposomal form of Imipenem/Cilastatin in vitro condition. By using the disk agar diffusion technique, the isolates' pattern of antibiotic resistance was identified. The antibiotic was placed into the nanoliposome after it had been made using the thin layer and ethanol injection techniques. SEM and DLS were used to determine the size, shape, and zeta potential of the encapsulated drug form and the empty nanoliposome. Additionally, Imipenem/Cilastatin encapsulation in nanoliposomes was studied using FT-IR spectroscopy. In the microbial assay experiments the MIC, MBC and MBEC of liposomal and free drug forms were determined. The nanoparticles were spherical, with a diameter ranging from 30 to 39 nm, and the EE% in the thin layer and ethanol injection procedures were 97 and 98, respectively. Imipenem/Cilastatin nanoliposomes showed peaks at 3009 cm-1 and 1650 cm-1, demonstrating the thermodynamic stability for the chemical structure of the drug enclosed and validating the encapsulation of antibiotic in the nanoliposomes. When compared to free drug forms, nanoliposomes had lower MIC and MBC values in the majority of the isolates and had a greater ability to eradicate the biofilm formation. It was shown that the two nanoliposome preparation techniques were more efficient in 80% of the isolates, which had outcomes that were consistent with those of numerous other investigations. Overall, we demonstrated that the antibacterial activity of nanoliposomes was higher than that of the free drug form based on the evaluation of their MIC and MBC. Pharmaceutical nanoliposome techniques provide an excellent future perspective on how to manage microbial infections that are resistant to antibiotics.

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.

Efficacy and safety of sulbactam-durlobactam versus colistin for the treatment of patients with serious infections caused by Acinetobacter baumannii-calcoaceticus complex: a multicentre, randomised, active-controlled, phase 3, non-inferiority clinical trial (ATTACK).

BACKGROUND: An urgent need exists for antibiotics to treat infections caused by carbapenem-resistant Acinetobacter baumannii-calcoaceticus complex (ABC). Sulbactam-durlobactam is a ß-lactam-ß-lactamase inhibitor combination with activity against Acinetobacter, including multidrug-resistant strains. In a phase 3, pathogen-specific, randomised controlled trial, we compared the efficacy and safety of sulbactam-durlobactam versus colistin, both in combination with imipenem-cilastatin as background therapy, in patients with serious infections caused by carbapenem-resistant ABC. METHODS: The ATTACK trial was done at 59 clinical sites in 16 countries. Adults aged 18 years or older with ABC-confirmed hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, ventilated pneumonia, or bloodstream infections were randomised 1:1 using a block size of four to sulbactam-durlobactam (1·0 g of each drug in combination over 3 h every 6 h) or colistin (2·5 mg/kg over 30 min every 12 h) for 7-14 days. All patients received imipenem-cilastatin (1·0 g of each drug in combination over 1 h every 6 h) as background therapy. The primary efficacy endpoint was 28-day all-cause mortality in patients with laboratory-confirmed carbapenem-resistant ABC (the carbapenem-resistant ABC microbiologically modified intention-to-treat population). Non-inferiority was concluded if the upper bound of the 95% CI for the treatment difference was less than +20%. The primary safety endpoint was incidence of nephrotoxicity assessed using modified Risk, Injury, Failure, Loss, End-stage renal disease criteria measured by creatinine level or glomerular filtration rate through day 42. This trial is registered at ClinicalTrials.gov, NCT03894046. FINDINGS: Between Sep 5, 2019, and July 26, 2021, 181 patients were randomly assigned to sulbactam-durlobactam or colistin (176 hospital-acquired bacterial pneumonia, ventilator-associated bacterial pneumonia, or ventilated pneumonia; and five bloodstream infections); 125 patients with laboratory-confirmed carbapenem-resistant ABC isolates were included in the primary efficacy analysis. 28-day all-cause mortality was 12 (19%) of 63 in the sulbactam-durlobactam group and 20 (32%) of 62 in the colistin group, a difference of -13·2% (95% CI -30·0 to 3·5), which met criteria for non-inferiority. Incidence of nephrotoxicity was significantly (p<0·001) lower with sulbactam-durlobactam than colistin (12 [13%] of 91 vs 32 [38%] of 85). Serious adverse events were reported in 36 (40%) of 91 patients in the sulbactam-durlobactam group and 42 (49%) of 86 patients in the colistin group. Treatment-related adverse events leading to study drug discontinuation were reported in ten (11%) of 91 patients in the sulbactam-durlobactam group and 14 (16%) of 86 patients in the colistin group. INTERPRETATION: Our data show that sulbactam-durlobactam was non-inferior to colistin, both agents given in combination with imipenem-cilastatin, for the primary endpoint of 28-day all-cause mortality. Sulbactam-durlobactam was well tolerated and could be an effective intervention to reduce mortality from serious infections caused by carbapenem-resistant ABC, including multidrug-resistant strains. FUNDING: Entasis Therapeutics and Zai Lab.

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.

Two-year outcomes comparing Embosphere® microspheres versus Imipenem Cilastatin for genicular artery embolization in patients with moderate to severe knee osteoarthritis.

BACKGROUND: Genicular artery embolization (GAE) is a novel technique and has the potential to provide midterm relief of pain for patients with mild-to-moderate knee osteoarthritis resistant to conservative management. This study compares the efficacy and safety of trisacryl gelatin microspheres to Imipenem/Cilastatin particles for GAE with 2 years of clinical follow-up. METHODS: In this retrospective study, eight patients with knee osteoarthritis (11 knees) who underwent GAE with 100-300 µm trisacryl gelatin microspheres particles were compared with six patients (nine knees) who underwent GAE with Imipenem/Cilastatin particles. Clinical outcomes were evaluated at 3-month and 24-month follow-ups and compared to baseline using the WOMAC questionnaire. RESULTS: The median follow-up was 796 days (range: 736-808). There were no significant differences in clinical outcome measures at the 3-month or 24-month follow-up. Both embolic materials resulted in a decrease in Pain WOMAC and Total WOMAC scores at 3 months (p < 0.05), and the effect of treatment on Pain WOMAC and Total WOMAC score reduction was sustained until the 24-month follow-up (p < 0.05). Minor events (Clavien-Dindo classification grade I) included transient cutaneous color change (n = 3) and transient leg numbness (n = 1) after embolization with trisacryl gelatin microspheres particles (p = 0.08). All minor adverse events resolved spontaneously. There were no major adverse events. CONCLUSION: One hundred to three hundred µm trisacryl gelatin microspheres particles can be considered for genicular artery embolization and is comparable to Imipenem/Cilastatin particles in pain reduction of moderate to severe knee osteoarthritis. A sustained effect is observed for up to 2 years of follow-up.

Efficacy and safety of novel carbapenem-ß-lactamase inhibitor combinations: Results from phase II and III trials.

Objectives: The addition of novel ß-lactamase inhibitors to carbapenems restores the activity against multidrug-resistant Gram-negative bacteria. The aim of this study was to summarize the evidence on the efficacy and safety of novel carbapenem-ß-lactamase inhibitor combinations. Methods: We conducted a meta-analysis of clinical trials comparing novel carbapenem-ß-lactamase inhibitor combinations with comparators to assess the clinical and microbiological responses, mortality, and adverse events (AEs). Results: A total of 1,984 patients were included. The pooled risk ratios (RRs) of clinical cure, microbiological eradication, all-cause mortality, and 28-day mortality were 1.11 (95% CI: 0.98-1.26), 0.98 (95% CI: 0.82-1.16), 0.90 (95% CI: 0.49-0.94), and 0.68 (95% CI: 0.49-0.94) between the novel carbapenem-ß-lactamase inhibitor combinations and control groups. Sensitivity analysis revealed that the phase II trial of imipenem-cilastatin/relebactam (ICR) against complicated urinary tract infections could be the most important factor of heterogeneity for the microbiological response. The therapeutic effect of novel carbapenem-ß-lactamase inhibitor combinations was better in meropenem-vaborbactam (MEV), phase III trials, and number of patients less than 200. The RRs of AEs from any cause and serious adverse events (SAEs) for patients receiving novel carbapenem-ß-lactamase inhibitor combinations were 0.98 (95% CI: 0.93-1.04) and 1.01 (95% CI: 0.75-1.36), respectively. Conclusions: ICR and MEV were superior to comparators for clinical cure and survival rate in the treatment of complicated infections, and both were as tolerable as the comparators.

Evaluating the usefulness of the estimated glomerular filtration rate for determination of imipenem dosage in critically ill patients.

BACKGROUND: Antibiotic dosing in critically ill patients is complicated by variations in the pharmacokinetics of antibiotics in this group. The dosing of imipenem/cilastatin is usually determined by severity of illness and renal function. OBJECTIVES: To determine the correlation between estimated glomerular filtration rates (eGFRs) calculated with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and imipenem trough levels in critically ill patients. METHODS: This prospective observational study was done in the surgical intensive care unit (ICU) at Steve Biko Academic Hospital, Pretoria, South Africa. Imipenem trough levels were measured by high-performance liquid chromatography and compared with eGFRs calculated with the CKD-EPI equation. Correlation was evaluated by the Pearson product-moment correlation coefficient. RESULTS: The study population consisted of 68 critically ill patients aged between 18 and 81 years; 43 (63%) were male, and the mean weight was 78 kg (range 40 - 140). On admission, 30 patients (44%) had sepsis, 16 (24%) were admitted for trauma, and 22 (32%) were admitted for miscellaneous surgical conditions. Acute Physiology and Chronic Health Evaluation II (APACHE II) scores ranged from 4 to 39 (mean 18). The 28-day mortality rate was 29%. The mean albumin level was 16 g/L (range 7 - 25), the mean creatinine level 142 µmol/L (range 33 - 840), and the mean eGFR 91 mL/min/1.73 m2 (range 6 - 180). Imipenem trough levels ranged between 3.6 and 92.2 mg/L (mean 11.5). The unadjusted Pearson product-moment correlation coefficient between eGFR and imipenem trough level was -0.04 (p=0.761). CONCLUSION: Considering the high mortality rate of sepsis in ICUs and the rapid global increase in antimicrobial resistance, it is crucial to dose antibiotics appropriately. Owing to the variability of antibiotic pharmacokinetics in critically ill patients, this task becomes almost impossible when relying on conventional dosing guidelines. This study found that eGFRs do not correlate with imipenem blood levels in critically ill patients and should not be used to determine the dose of imipenem/cilastatin. Instead, the dose should be individualised for patients through routine therapeutic drug monitoring.

Pharmacokinetics/Pharmacodynamics and tolerability of cefiderocol in the clinical setting.

Cefiderocol is a new cephalosporin with a catechol in its chemical structure faciliting its access to the interior of bacteria through iron channels. In addition, it is broadly stable to beta-lactamases. The pharmacokinetic profile is a beta-lactam one: no oral absorption, and with a wide distribution within the vascular space and the interstitial fluid of well vascularized tissues, reaching therapeutic concentrations in the alveolar lavage fluid and within the macrophage. The binding of cefiderocol to human plasma proteins, primarily albumin, is moderate (range 40-60%). The terminal elimination half-life in healthy adult subjects was 2 to 3 hours. Cefiderocol is mainly renally eliminated, so dose adjustments are recommended in subjects with moderate / severe renal impairment, in case of dialysis, and probably in patients with external clearance. Like other beta-lactams, the PK / PD parameter that has been shown to best correlate with efficacy is the efficacy time of unbound plasma concentrations (%fT>MIC), which must be close to 100% to achieve a bactericidal effect. This is possible with 2 g in a 3-hour infusion every 8 hours. In controlled trials appears to be well tolerated, similar to comparators: meropenem or imipenem-cilastatin. Cefiderocol has no apparent clinically significant effect on ECG parameters nor on plasma iron values.

Postexposure Prophylaxis and Treatment of Bacillus anthracis Infections: A Systematic Review and Meta-analyses of Animal Models, 1947-2019.

BACKGROUND: Anthrax is endemic to many countries, including the United States. The causative agent, Bacillus anthracis, poses a global bioterrorism threat. Without effective antimicrobial postexposure prophylaxis (PEPAbx) and treatment, the mortality of systemic anthrax is high. To inform clinical guidelines for PEPAbx and treatment of B. anthracis infections in humans, we systematically evaluated animal anthrax treatment model studies. METHODS: We searched for survival outcome data in 9 scientific search engines for articles describing antimicrobial PEPAbx or treatment of anthrax in animals in any language through February 2019. We performed meta-analyses of efficacy of antimicrobial PEPAbx and treatment for each drug or drug combination using random-effects models. Pharmacokinetic/pharmacodynamic relationships were developed for 5 antimicrobials with available pharmacokinetic data. Monte Carlo simulations were used to predict unbound drug exposures in humans. RESULTS: We synthesized data from 34 peer-reviewed studies with 3262 animals. For PEPAbx and treatment of infection by susceptible B. anthracis, effective monotherapy can be accomplished with fluoroquinolones, tetracyclines, ß-lactams (including penicillin, amoxicillin-clavulanate, and imipenem-cilastatin), and lipopeptides or glycopeptides. For naturally occurring strains, unbound drug exposures in humans were predicted to adequately cover the minimal inhibitory concentrations (MICs; those required to inhibit the growth of 50% or 90% of organisms [MIC50 or MIC90]) for ciprofloxacin, levofloxacin, and doxycycline for both the PEPAbx and treatment targets. Dalbavancin covered its MIC50 for PEPAbx. CONCLUSIONS: These animal studies show many reviewed antimicrobials are good choices for PEPAbx or treatment of susceptible B. anthracis strains, and some are also promising options for combating resistant strains. Monte Carlo simulations suggest that oral ciprofloxacin, levofloxacin, and doxycycline are particularly robust choices for PEPAbx or treatment.

[Imipenem-cilastatin-relebactam used to treat ventilator-associated pneumonia developing after infection with SARS-CoV-2].

The article describes the use of the last-resort carbapenem antibiotic imipenem in combination with relebactam, a novel b-lactamase inhibitor, in the treatment of ventilator-associated pneumonia developing after SARS-CoV-2 infection in a young pregnant patient. The introduction briefly describes the mechanism and spectrum of activity of the antibiotic, including its dosage.

Cefoxitin-based combination for ESBL-producing Enterobacteriaceae endocarditis.

BACKGROUND: Endocarditis due to extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae is a rare but challenging condition. Its treatment relies on carbapenems alone or in combination, and no alternative has been described to date. The cephamycin cefoxitin has been used for treatment of mild ESBL-producing Enterobacteriaceae infections. CASE PRESENTATION: We report two patients with nosocomial endocarditis due to ESBL-producing Escherichia coli and Klebsiella pneumoniae who underwent clinical failure or adverse event, respectively, during treatment with imipenem-cilastatin. The first patient was subsequently treated with cefoxitin combined with ciprofloxacin with a favorable outcome. In the second patient, the endocarditis relapsed following a 6-week treatment with cefoxitin and fosfomycin. In time-kill assays, the cefoxitin/ciprofloxacin and cefoxitin/fosfomycin combinations showed synergistic effect. CONCLUSION: These cases illustrate that cefoxitin is an interesting alternative to carbapenems, even in severe infections such as endocarditis. Pharmacokinetic optimization and combination with another synergistic antibiotic should be considered whenever possible.

Imipenem cilastatin sodium-associated thrombocytopenia in an older patient: A case report and literature review.

Imipenem cilastatin sodium, as a member of a new generation of ß-lactam antibiotics, has a broad spectrum of antibacterial activity and a very wide range of application. Thrombocytopenia has been reported as a rare adverse event in several studies of patients treated with imipenem cilastatin sodium. In this study, we present a case of thrombocytopenia associated with imipenem cilastatin sodium in an older patient. The 78-year-old male patient with pulmonary infection was initiated on anti-infection therapy with imipenem cilastatin sodium. On the 9th day after imipenem cilastatin sodium administration, the patient experienced a sudden and dramatic decrease in platelet count. Similarly, on the 4th day after the re-administration of imipenem cilastatin sodium for anti-infection therapy, the patient's platelet count showed a remarkable downward trend again. A time correlation between the drug therapy and the occurrence of platelet reaction was found. The patient's platelet count gradually returned to the normal level on the 6th day after the first drug withdrawal and the 13th day after the second drug withdrawal, respectively. Considering the widespread use of imipenem cilastatin sodium, healthcare providers should improve the notification of thrombocytopenia associated with imipenem cilastatin sodium.

Challenges in Treating Mycobacterium chelonae/abscessus Prosthetic Joint Infection.

Prosthetic joint infections (PJIs) remain a major complication of arthroplasty, most of which are caused by Staphylococcus aureus and gram-negative bacteria. Unfortunately, cultures are false negative in upward of 7 percent of patients with suspected PJIs, and commonly in infections caused by rare rapidly growing mycobacterium (RGM) species. Guidelines recommend 6 months of antimycobacterial therapy for bone diseases caused by RGM, with empiric therapy consists of an oral macrolide (clarithromycin or azithromycin) plus tobramycin and imipenem-cilastatin. Definitive treatment of PJI due to RGM should be guided by antimicrobial susceptibility, however, most microbiology laboratories are unable to differentiate between M. chelonae and M. abscessus. Furthermore, treatment of M. chelonae PJI is challenging due to multidrug resistance and the dearth of oral antibiotics for therapy. This case report investigates a patient with PJI caused by M. chelonae and M. abscessus. The initial treatment with imipenem-cilastatin was complicated by drug induced seizures, further limiting therapy options.