Doses Of Imipenem Research Articles

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

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

Evolution of carbapenem resistance in klebsiella pneumoniae and escherichia coli carrying blaNDM−1 gene: imipenem exposure results in sustained resistance memory of strains in vitro

BackgroundAntibiotics exert an outstanding selective pressure on bacteria, forcing their chromosomal gene mutations and drug resistance genes to spread. The objective of this study is to evaluate the expression of the New Delhi Metallo-β-Lactamase-1 gene (blaNDM−1) in the clinical isolate (Klebsiella pneumoniae TH-P12158), transformant strains Escherichia coli BL21 (DE3)-blaNDM−1, and Escherichia coli DH5α- blaNDM−1 when exposed to imipenem.Methodsβ-Lactamase genes (blaSHV, blaTEM−1, blaCTX−M−9, blaIMP, blaNDM−1, blaKPC, blaOXA, blaGES, and blaDHA) from randomly selected carbapenems-sensitive K.pneumoniae (n = 20) and E.coli (n = 20) strains were amplified by PCR. The recombinant plasmid of pET-28a harboring blaNDM−1 was transformed into E.coli BL21 (DE3) and E.coli DH5α by electroporation. The resistance phenotype and higher blaNDM−1 expression in K.pneumoniae TH-P12158, transformant E.coli BL21 (DE3)-blaNDM−1, and E.coli DH5α-blaNDM−1 were observed when exposed to imipenem with grade increasing, decreasing, and canceling doses, respectively.ResultsAfter being exposed to different doses of imipenem, the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of antimicrobial drugs and blaNDM−1 expression of strains increased, which was positively correlated with doses of imipenem. On the contrary, with the decrease or cancellation of imipenem doses, the blaNDM−1 expression was deteriorated, while the MIC and MBC values remained relatively stable. These results demonstrated that low doses of imipenem (˂MIC) could press blaNDM−1 positive strains producing stable drug resistance memory and altered blaNDM−1 expression.ConclusionsLow doses of imipenem could press blaNDM−1 positive strains producing sustained resistance memory and altered blaNDM−1 expression. In particular, the positive correlation between the resistance genes expression and antibiotics exposure shows promising guiding significance for clinical medication.

Effects of Sub-Minimum Inhibitory Concentrations of Imipenem and Colistin on Expression of Biofilm-Specific Antibiotic Resistance and Virulence Genes in Acinetobacter baumannii Sequence Type 1894.

Antibiotics at suboptimal doses promote biofilm formation and the development of antibiotic resistance. The underlying molecular mechanisms, however, were not investigated. Here, we report the effects of sub-minimum inhibitory concentrations (sub-MICs) of imipenem and colistin on genes associated with biofilm formation and biofilm-specific antibiotic resistance in a multidrug-tolerant clinical strain of Acinetobacter baumannii Sequence Type (ST) 1894. Comparative transcriptome analysis was performed in untreated biofilm and biofilm treated with sub-MIC doses of imipenem and colistin. RNA sequencing data showed that 78 and 285 genes were differentially expressed in imipenem and colistin-treated biofilm cells, respectively. Among the differentially expressed genes (DEGs), 48 and 197 genes were upregulated exclusively in imipenem and colistin-treated biofilm cells, respectively. The upregulated genes included those encoding matrix synthesis (pgaB), multidrug efflux pump (novel00738), fimbrial proteins, and homoserine lactone synthase (AbaI). Upregulation of biofilm-associated genes might enhance biofilm formation when treated with sub-MICs of antibiotics. The downregulated genes include those encoding DNA gyrase (novel00171), 30S ribosomal protein S20 (novel00584), and ribosome releasing factor (RRF) were downregulated when the biofilm cells were treated with imipenem and colistin. Downregulation of these genes affects protein synthesis, which in turn slows down cell metabolism and makes biofilm cells more tolerant to antibiotics. In this investigation, we also found that 5 of 138 small RNAs (sRNAs) were differentially expressed in biofilm regardless of antibiotic treatment or not. Of these, sRNA00203 showed the highest expression levels in biofilm. sRNAs regulate gene expression and are associated with biofilm formation, which may in turn affect the expression of biofilm-specific antibiotic resistance. In summary, when biofilm cells were exposed to sub-MIC doses of colistin and imipenem, coordinated gene responses result in increased biofilm production, multidrug efflux pump expression, and the slowdown of metabolism, which leads to drug tolerance in biofilm. Targeting antibiotic-induced or repressed biofilm-specific genes represents a new strategy for the development of innovative and effective treatments for biofilm-associated infections caused by A. baumannii.

Imipenem dosing recommendations for patients undergoing continuous renal replacement therapy: systematic review and Monte Carlo simulations

BackgroundThe appropriate dosing of imipenem for critically ill AKI patients undergoing CRRT remains scarce.PurposeThis study aimed to (1) gather the available published pharmacokinetic studies conducted in septic patients receiving continuous renal replacement therapy (CRRT) and (2) to define the optimal imipenem dosing regimens in these populations via Monte Carlo simulations.MethodsThe databases of PubMed, Embase, and ScienceDirect were searched from inception to May 2020. We used the Medical Subject Headings of “Imipenem,” “CRRT,” and “pharmacokinetics” or related terms or synonym to identify the studies for systematic reviews. A one-compartment pharmacokinetic model was conducted to predict imipenem levels for the initial 48 h of therapy. The pharmacodynamic target was 40% of free drug level above 4 times of the MIC (40% fT > 4 MIC). The dose that achieved at least 90% of the probability of target attainment was defined as an optimal dose.ResultsEleven articles were identified and included for our systematic review. The necessary pharmacokinetic parameters such as the volume of distribution and the CRRT clearance were mentioned in 100 and 90.9%, respectively. None of the current studies reported the complete necessary parameters. A regimen of 750 mg q 6 h was the optimal dose for the predilution-CVVH and CVVHD modality with two effluent rates (25 and 35 mL/kg/h) for the pharmacodynamic target of 40% fT > 4MIC.ConclusionsNone of the current studies showed the complete necessary pharmacokinetic parameters for drug dosing. Pharmacodynamic target significantly contributed to imipenem dosing regimens in these patients. Different effluent rates and types of CRRT had minimal impact on dosing regimens. Clinical validation of the recommendation is necessary.

RpoS-mutation variants are selected in Pseudomonas aeruginosa biofilms under imipenem pressure

BackgroundPseudomonas aeruginosa is a notorious opportunistic pathogen causing various types of biofilm-related infections. Biofilm formation is a unique microbial strategy that allows P. aeruginosa to survive adverse conditions such as antibiotic treatment and human immune clearance.ResultsIn this study, we experimentally evolved P. aeruginosa PAO1 biofilms for cyclic treatment in the presence of high dose of imipenem, and enriched hyperbiofilm mutants within six cycles in two independent lineages. The competition assay showed that the evolved hyperbiofilm mutants can outcompete the ancestral strain within biofilms but not in planktonic cultures. Whole-genome sequencing analysis revealed the hyperbiofilm phenotype is caused by point mutations in rpoS gene in all independently evolved mutants and the same mutation was found in P. aeruginosa clinical isolates. We further showed that mutation in rpoS gene increased the intracellular c-di-GMP level by turning on the expression of the diguanylate cyclases. Mutation in rpoS increased pyocyanin production and virulence in hyperbiofilm variants.ConclusionHere, our study revealed that antibiotic treatment of biofilm-related P. aeruginosa infections might induce a hyperbiofilm phenotype via rpoS mutation, which might partially explain antimicrobial treatment failure of many P. aeruginosa biofilm-related infections.

CARBAPENEM ANTIBIOTIC DOSE MODE FOR PEDIATRIC PATIENT AT CAN THO CHILDREN’S HOSPITAL

Objective: Analyzing the dose regimen of carbapenem antibiotics used in pediatric patients at Can Tho Children’s Hospital.Objects and methods: retrospective-descriptive study on 140 medical records of patients being treated at departments of Can Tho Children’s Hospital during the period from June 1st, 2020 toDecember 31st, 2020. Results: Regarding the dosage regimen characteristics of meropenem showed that 20.3% and 10.8%of meropenem’s indications for the dose of meropenem for non-central nervous system infections and meningitis treament was appropriate according to the recommendations. Meanwhile, up to63.5% of the dose was higher than the recommended dose and 5.5% of the treatment dose was lower than the recommended dose. Regarding imipenem dosage regimen characteristics from the resultsshowed that 71.2% of the dose of imipenem for the treatment of infections non-central nervous system complied with recommendations according to the literature. However, more than 20% of the recommended dose for patients was lower than recommended dose. Conclusion: The meropenem dose regimen was consistent with the recommendation was low. The imipenem dose regimen was consistent with the relatively high recommendation.

Pharmacokinetic and Pharmacodynamic Analysis of Critically Ill Patients Undergoing Continuous Renal Replacement Therapy With Imipenem

PurposeThis study explores factors that affect behavior in critically ill patients receiving continuous renal replacement therapy (CRRT) with imipenem and provides dosing regimens for these patients. MethodsA prospective, open-label study was conducted in a clinical setting. Both blood and effluent samples were collected pairwise at the scheduled time points. Plasma and effluent imipenem concentrations were determined by HPLC-UV. A population pharmacokinetic model was developed using a nonlinear mixed-effects modeling method. The final model was evaluated by a bootstrap and visual predictive check. A population pharmacokinetic and pharmacodynamic analysis using Monte Carlo simulations was performed to explore the effects of empirically used dosing regimens (0.5 g q6h, 0.5 g q8h, 0.5 g q12h, 1 g q6h, 1 g q8h, and 1 g q12h) on the probability of target attainment. FindingsThirty patients were included in the population model analysis. Imipenem concentration data were best described by a 3-compartment model (central, peripheral, and dialysis compartments). The clearance of the dialysis compartment (CLd) was used to characterize drug elimination from the dialyzer. Creatinine clearance (CrCl) was the covariate that influenced the central clearance (CLc), and the effects of dialysate flow (Qd) was significant for CLd. Model validation revealed that the final model had qualified stability and acceptable predictive properties. A pharmacokinetic and pharmacodynamic analysis was conducted by Monte Carlo simulation, and patients were categorized into 12 subgroups based on different CrCl values (<30, 31–60, 61–90, and >90 mL/min) and Qd values (300, 500, and 1000 mL/h). Under the same MIC value and administration regimen, probability of target attainment values decreased with an increase of CrCl and Qd. ImplicationsCrCl and Qd had significant effects on CLc and CLd, respectively. The proposed final model may be used to guide practitioners in imipenem dosing in this specific patient population.

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

IntroductionThe present study aimed to compare the pharmacokinetic/pharmacodynamic (PK/PD) parameters of imipenem administered by two-step (50% delivered in a 30-min bolus, 50% for the following 90 min) or extended (administered continuously for 2 h) infusion.MethodsPatients with sepsis and septic shock were prospectively enrolled and randomized into four groups. Subjects in the two-step or extended groups were given two doses of imipenem (0.5 g q6h and 1.0 g q8h). The plasma imipenem concentrations were measured at given time points after the fifth dose. The PK/PD target was defined as the achievement of a fractional time above the minimal inhibitory concentration (MIC) of > 40%.ResultsThirty-five patients were eventually enrolled. No significant difference was observed in the percentage of patients achieving 40% T > MIC between the different infusion modes with the same dosage, although the two-step groups exhibited a significantly shorter Tmax compared with the extended groups (0.5 g q6h: 1.5 ± 0.8 vs. 2.0 ± 0.0 h; 1.0 g q8h: 1.0 ± 0.6 vs. 2.0 ± 0.0 h; both, p < 0.05). All four groups achieved 40% T > MIC when MIC was 0.5–4.0 μg/ml, but only regimens with a higher dose (1.0 g q8h) achieved target when MIC was 8 μg/ml.ConclusionThe two-step and extended regimens of imipenem are comparable to the PK/PD target in the treatment of sepsis and septic shock. A higher dose (1.0 g q8h) should be considered for target achievement at an MIC of > 8 μg/ml.Trial RegistrationClinicalTrials.gov identifier, NCT02616354.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01339-5) contains supplementary material, which is available to authorized users.

PHARMECMO: Therapeutic drug monitoring and adequacy of current dosing regimens of antibiotics in patients on Extracorporeal Life Support

IntroductionOptimisation of antibiotic therapy for extracorporeal membrane oxygenation (ECMO) patients remains a pharmacological challenge. The objective of this study was to observe the plasma concentrations of commonly used antibiotics in intensive care for patients treated with extracorporeal membrane oxygenation. Patients and methodsThe PHARMECMO study was a pilot, prospective study, conducted in a cardiac surgery intensive care unit. Every adult patient under ECMO support, with known or suspected sepsis and receiving antibiotic therapy, was eligible for inclusion. Plasma concentrations of antibiotics were determined by a combination of liquid chromatography and mass spectrometry. ResultsForty-four eligible patients were enrolled for 68 inclusions on a twelve-month period. For the association piperacillin-tazobactam (n=19), 68.7% of CT50 and 93.7% of Cmin reached the pharmacokinetic goals defined (64 mg.L-1 for CT50 and 16 mg.L-1 for Cmin). For cefotaxime (n=12), the pharmacokinetic goals (4 mg.L-1 for CT50 and 1 mg.L-1 for Cmin) were achieved in 100% of the cases for CT50 and in 81.8% of the cases for Cmin. Regarding imipenem (n=10), the pharmacokinetic goals were 16 mg.L-1 for CT50 and 4 mg.L-1 for Cmin. Only one CT50 was above 16 mg.L-1. For Cmin, 60% of the doses did not reach the target concentration. In our 10 patients, only one patient was considered as reaching the pharmacokinetic goals. Finally, for amikacin (n=6), four Cmax (66.7%) were infra-therapeutics for a target between 60 and 80 mg.L-1. ConclusionThese preliminary results suggest that therapeutic drug monitoring could optimise the achievement of pharmacokinetic objectives associated with an effective antibiotic therapy. For most patients, the recommended doses of imipenem and amikacin did not achieve the pK targets

Imipenem toxicity in male reproductive organs as a result of inflammatory microenvironment and oxidative stress in germinal cells

Imipenem is a beta-Lactam antibiotic characterized by a broad spectrum of activity. It is prescribed to treat severe infections. Our goal is to investigate toxicity induced in male rat reproductive systems following exposure to this drug (15, 50 or 100 mg/kg) compared to gentamicin (50 mg/kg) treatment.Effects of imipenem on reproductive organ weights, histoarchitecture, sperm parameters, and oxidative stress parameters were evaluated. Serum testosterone levels were measured. Apoptosis and inflammatory behaviors were investigated by immunohistochemical proteins expression analysis of apoptosis regulator BAX (Bax), B-cell lymphoma 2 (Bcl-2), and interleukin-1 beta (IL-1 beta) in testis.Results showed a significant decrease in male fertility parameters including sperm count, sperm motility, reproductive organ weights and serum testosterone levels after imipenem administration as compared to the control and gentamicin treated groups. Increased sperm abnormality was significant in animals treated with high doses of imipenem. Oxidative stress analysis revealed an expressed increase in lipid peroxidation and carbonyl groups levels in testicular tissues compared to control. Similar results were observed with superoxide dismutase and catalase activities from testicular tissues. In addition, severe testicular lesions were observed in the seminiferous tubules as well as important impairments in spermatogenesis testifying an inflammatory microenvironment confirmed by the intensive expression of IL1-beta and Bax protein by germinal cells and Bcl-2 by Leydig cells.In conclusion, imipenem treatment with high doses was found to lead to oxidative stress in male reproductive organs and an inflammatory microenvironment leading to spermatogenesis dysfunction and histopathological changes in the testis.

Mycobacterium chelonae osteomyelitis presenting as a mycobacterial spindle cell pseudotumor

We report a case of an 88-year-old man with osteomyelitis of the right ankle, with histopathology demonstrating a Mycobacterium spindle cell pseudotumor. The Mycobacterium contained in this spindle cell pseudotumor was Mycobacterium chelonae. M. chelonae spindle cell pseudotumors are rare and have only been reported twice previously in the literature. Similarly, M. chelonae presenting as the pathogen in bone infection is rare. Due to this unusual presentation of M. chelonae, the antibiotic rationale was based largely on case reports and consisted of imipenem, clarithromycin, and linezolid. Antibiotic complications were experienced by the patient. Despite a renally adjusted dose of imipenem, the patient experienced imipenem toxicity and his antibiotics were modified to tigecycline and clarithromycin. Although his symptoms were clinically resolving, the patient sadly passed away before completing treatment.

Pharmacokinetic changes of antibiotic, antiviral, antituberculosis and antifungal agents during extracorporeal membrane oxygenation in critically ill adult patients.

Extracorporeal membrane oxygenation (ECMO) is a life-saving system used for critically ill patients with cardiac and/or respiratory failure. The pharmacokinetics (PK) of drugs can change in patients undergoing ECMO, which can result in therapeutic failure or drug toxicity requiring further management of drug complications. In this review, we discussed changes in the PK of antibiotic, antiviral, antituberculosis and antifungal agents administered to adult patients on ECMO. These drugs are crucial for managing infections, which commonly occur during ECMO. A literature search was conducted using the PubMed and EMBASE databases with the following keywords: "extracorporeal membrane oxygenation OR extracorporeal membrane oxygenations OR ECMO" and "PK OR pharmacokinetics OR pharmacokinetic*" and "anti infective* OR antibiotic* OR antiviral* OR antituberculosis OR antifungal*." Generally, the volume of distribution (Vd) increases and drug clearance (CL) and elimination decrease during ECMO. Highly significant changes in drug PK can occur by interactions with the ECMO device itself, drug characteristics, pathological changes and patient characteristics. This may affect the blood concentrations of drugs, which influence the success of therapy. The PK of vancomycin, piperacillin-tazobactam, meropenem, azithromycin, amikacin and caspofungin did not change significantly in adult patients receiving ECMO. However, there were significant changes in the PK of imipenem, oseltamivir, rifampicin and voriconazole. The trough concentrations of imipenem were highly variable; oseltamivir had a decreased CL and increased Vd, and rifampicin concentrations were below therapeutic levels, even when a higher-than-standard dose was used in patients treated with ECMO. Additionally, voriconazole exhibited high mean peak concentrations during ECMO. The impact of ECMO on PK varies among drugs in adult patients, and there is no consistent correlation between the effects observed in adult and infant studies. This review suggested that doses of imipenem, oseltamivir, rifampicin and voriconazole should be adjusted and therapeutic drug monitoring is needed when ECMO is used in adult patients. In the future, large PK trials in adults on ECMO are needed to provide optimal dosing guidelines. A PK/PD modelling approach will be useful for determining the precise impact of ECMO and other factors that contribute to PK changes for each drug. Finally, it is important to develop dosing guidelines based on PK/PD modelling studies that can be used in clinical practice.

Can We Make Small Molecules Lean? Optimization of a Highly Lipophilic TarO Inhibitor.

We describe our optimization efforts to improve the physicochemical properties, solubility, and off-target profile of 1, an inhibitor of TarO, an early stage enzyme in the biosynthetic pathway for wall teichoic acid (WTA) synthesis. Compound 1 displayed a TarO IC50 of 125 nM in an enzyme assay and possessed very high lipophilicity (clogP = 7.1) with no measurable solubility in PBS buffer. Structure-activity relationship (SAR) studies resulted in a series of compounds with improved lipophilic ligand efficiency (LLE) consistent with the reduction of clogP. From these efforts, analog 9 was selected for our initial in vivo study, which in combination with subefficacious dose of imipenem (IPM) robustly lowered the bacterial burden in a neutropenic Staphylococci murine infection model. Concurrent with our in vivo optimization effort using 9, we further improved LLE as exemplified by a much more druglike analog 26.

Effect of continuous renal replacement therapy on the plasma concentration of imipenem in severe infection patients with acute renal injury

To investigate the extracorporeal clearance rate of imipenem in severe infection patients in the mode of continuous vena-venous hemofiltration (CVVH) during continuous renal replacement therapy (CRRT), in order to approach if the concentration of imipenem in plasma could achieve effective levels of anti-infection, and to explore the effect of time and anticoagulation measure on imipenem clearance during CRRT treatment. A prospective observational study was conducted. All adult severe infection patients complicating acute kidney injury (AKI) in the Department of Critical Care Medicine of the Fourth Hospital of Hebei Medical University from March 2013 to September 2014, who were prescribed imipenem as part of their required medical care, and CRRT for treatment of AKI were enrolled. 0.5 g doses of imipenem was administered intravenously every 6 hours or 8 hours according to random number table, and infused over 0.5 hour. The unfractionated heparin was used for anticoagulation in the patients without contraindications, and no anticoagulation strategy was used in the patients with high risk of bleeding. At 24 hours after first time of administration, postfilter venous blood and ultrafiltrate samples were collected at 0, 0.25, 0.5, 0.75, 1, 2, 5, 6, and 8 hours after imipenem administration. The concentration of imipenem in above samples was determined with liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS). A total of 25 patients were enrolled. Thirteen patients received imipenem intravenously every 6 hours, and 12 patients, every 8 hours. The anticoagulation was conducted with heparin in 13 cases, and 12 cases without anticoagulation. The intra-day precision, inter-day precision, matrix effect, and recovery rate in low, medium, and high concentration of plasma and ultrafiltrate, and the stability of samples under different conditions showed a good result, the error of accuracy was controlled in the range of ±15%. With the application of Prismaflex blood filtration system and AN69-M100 filter, under the mode with CVVH, the total clearance rate of imipenem was (8.874±2.828) L/h when the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹, the total CRRT clearance rate of imipenem in vitro was (2.211±0.539) L/h, which accounting for (30.1±15.7)% of the total drug clearance. In 6 hours interval dosage regimen, the percentages of the time > 4× minimum inhibitory concentration (MIC) at specific 4×MIC of 2, 4, 6, and 8 μg/mL of imipenem were more than 40% of the dosing interval. But in the 8 hours interval dosage regimen, when the level was above the 4×MIC of 4 μg/mL, maintaining time would drop below 40% of the dosing interval, with significant differences compared with that in 6 hours interval dosage regimen [4×MIC = 2 μg/mL: (60.84±20.25)% vs. (94.01±12.46)%, t = 4.977, P = 0.001; 4×MIC = 4 μg/mL: (39.85±15.88)% vs. (68.74±9.57)%, t = 5.562, P = 0.000; 4×MIC = 6 g/mL: (27.58±13.70)% vs. (53.97±8.36)%, t = 5.867, P = 0.000; 4×MIC = 8 μg/mL: ( 8.87±12.43)% vs. (43.48±7.83)%, t = 5.976, P = 0.000]. No significant change in sieving coefficient of imipenem was found within a short time (6 hours), which indicated that there was no effect of anticoagulation on clearance of imipenem by AN69-M100 filter, and no statistical significance was found with repeated measure analysis (F = 0.186, P > 0.05 ). The clearance rate of imipenem is increased significantly in vitro under the mode of CVVH with the actual dose of replacement fluid was (31.63±1.48) mL×kg⁻¹×h⁻¹ in severe infective patients with severe sepsis complicating AKI, affecting the level of plasma drug concentration, need to adjust the dosage regimen. When the time of the dosing interval was shortened, the concentration of imipenem in patients' plasma could be increased significantly. In a short period of time, the sieving coefficient of imipenem through AN69 filter is not affected by anticoagulation measures and time cleaning efficiency will not decline.

Bacterial resistance in India: Studying plasma antibiotic levels.

Escalating bacterial resistance to modern antibiotics has been posing a great challenge while treating patients with serious infections in hospitals. The dreaded problem is often further compounded by sub-therapeutic dosages and/or indiscriminate overuse of antibiotics in developing as well as developed countries. As per the estimates made available by the Center for Disease Control and Prevention, over 2 million people are sick due to bacterial infections resistant to one or more antibiotics, and that 23,000 individuals die from drug resistance in the United States. Ironically, 40% of the world's antibiotic drugs are produced in India, and that over 58,000 babies succumbed to death in 1 year as a direct result of infection with highly-resistant bacteria transmitted from their mothers.[1] A simulation by the Rand Corporation estimated that resistant micro-organisms could kill about 10 million individuals worldwide in 2050, which is greater than cancer deaths. However, we are yet unaware of the full impact in the absence of an efficient global tracking system overseeing the issue. Bacterial resistance evolves as a result of mutations in these organisms as well as selection pressure exerted by unrestrained antibiotic use which provides a competitive advantage to such mutated strains; thereby decreasing overall effectiveness of antibiotics in treating even common infections. In addition, suboptimal use of antibiotic agents further allows to foster stepwise selection of resistance. Thus, mutations, in part, herald resistance genes which may now become transmissible via extrachromosomal elements and/or bacterial plasmids, which are DNA structures that mediate the transfer of resistance genes between bacteria. The resultant resistant clones are amenable to rapid worldwide spread which is facilitated by interspecies gene transmission, poor sanitation and hygiene in communities and hospitals, and the ever increasing global travel, trade, and disease transmission.[1] One of the infamous examples of this is the New Delhi matallo-beta-lactamase-1 (NDM-1) resistance gene discovered by Dr. Timothy Walsh and a team of collaborators.[2] It was first discovered in the United Kingdom in patients returning from India, detected in the wastewater of New Delhi, and hence named “NDM-1.” NDM-1 has been disseminated to 18 countries including the United States and the European countries over the span of 1 year. Such are the epidemiological consequences of the resistant gene travel in our modern “close-knit” world. In response to the emerging antibiotic resistance threat, healthcare providers are increasingly being pushed toward the use of newer and higher antibiotics. Not surprisingly, for more than two decades, life-saving broad spectrum antibiotics such as carbapenems are favorably being administered to critically ill patients in hospitals. The carbapenems belong to the beta-lactam family of antibiotics with an exceptional activity against a broad spectrum of microbes, and with a long history of safety and efficacy for serious infections.[3] They are beta-lactams of choice for the treatment of infections caused by multi-drug resistant organisms.[3] However, unfortunately, now they also have met with resistant bacteria, for example, the arrival of untreatable strains of carbapenem-resistant Enterobacteriaceae. An older carbapenem, imipenem, is degraded by a renal tubular enzyme, dehydropeptidase-1 (DHP-1), and requires co-administration of cilastatin, a DHP-1 inhibitor. However, newer carbapenems such as doripenem, ertapenem, and meropenem are relatively immune to the DHP-1 degradation.[4] Resistant bacteria acquire or develop various strategies to render carbapenems ineffective including structural changes within penicillin-binding proteins, production of metallo-beta-lactamases, and altered membrane permeability due to loss of specific outer membrane proteins, for example, porins.[4] Toward developing effective interventions to address the emergence of microbial resistance as well as understanding the underlying mechanism (s) of resistance, multi-pronged remedial measures are required to put in place. Of these, a major contributing arm is basic sciences as well as clinical research. In this issue of IJCCM the article by Abhilash et al.[6] exemplifies such a contribution to research in India, albeit at a smaller scale, and is a welcome step forward. Here, authors investigate the plasma concentration of imipenem at different loci of infection and conclude that loci variability does not constitute a major factor in affecting the drug plasma concentration within their sample. They further recommend imipenem dosing regimen revisions for the treatment of infection with recalcitrant organisms. Imipenem, indeed, is a tricky antibiotic to use in the case of critically ill patients as compared to that in other patient populations owing to its variable pharmacokinetic activity in the former. Moreover, a very weak correlation exists between its dosage and serum concentration.[5] Importantly, as discussed in the article, a large polymerase chain reaction-based gene screen of isolated bacteria would potentially provide valuable insights into the current/emerging mechanisms of bacterial resistance. Therefore, additional large-scale clinical and microbial gene studies in India are warranted to formulate effective antibiotic dosing regimens, and to deal with the menace of bacterial resistance thereof.

Experimental protection of diabetic mice against Lethal P. aeruginosa infection by bacteriophage.

The emergence of antibiotic-resistant bacterial strains has become a global crisis and is vulnerable for the exploration of alternative antibacterial therapies. The present study emphasizes the use of bacteriophage for the treatment of multidrug resistant P. aeruginosa. P. aeruginosa was used to induce septicemia in streptozotocin (STZ) induced diabetic and nondiabetic mice by intraperitoneal (i.p.) injection of 3 × 108 CFU, resulting in a fatal bacteremia within 48 hrs. A single i.p. injection of 3 × 109 PFU phage GNCP showed efficient protection in both diabetic (90%) and nondiabetic (100%) bacteremic mice. It was further noted that the protection rate was reduced in diabetic mice when phage GNCP was administered after 4 h and 6 h of lethal bacterial challenge. In contrast, nondiabetic bacteremic mice were rescued even when treatment was delayed up to 20 h after lethal bacterial challenge. Evaluation of results confirmed that a single intraperitoneal injection of the phage dose (3 × 109 PFU/mL) was more effective than the multiple doses of imipenem. These results uphold the efficacy of phage therapy against pernicious P. aeruginosa infections, especially in cases of immunocompromised host.

In Vitro Activity of MK-7655, a Novel β-Lactamase Inhibitor, in Combination with Imipenem against Carbapenem-Resistant Gram-Negative Bacteria

Carbapenem-resistant bacteria represent a significant treatment challenge due to the lack of active antimicrobials available. MK-7655 is a novel β-lactamase inhibitor under clinical development. We investigated the combined killing activity of imipenem and MK-7655 against four imipenem-resistant bacterial strains, using a mathematical model previously evaluated in our laboratory. Time-kill studies (TKS) were conducted with imipenem and MK-7655 against a KPC-2-producing Klebsiella pneumoniae isolate (KP6339) as well as 3 Pseudomonas aeruginosa isolates (PA24226, PA24227, and PA24228) with OprD porin deletions and overexpression of AmpC. TKS were performed using 25 clinically achievable concentration combinations in a 5-by-5 array. Bacterial burden at 24 h was determined in triplicate by quantitative culture and mathematically modeled using a three-dimensional response surface. Mathematical model assessments were evaluated experimentally using clinically relevant dosing regimens of imipenem, with or without MK-7655, in a hollow-fiber infection model (HFIM). The combination of imipenem and MK-7655 was synergistic for all strains. Interaction indices were as follows: for KP6339, 0.50 (95% confidence interval [CI], 0.42 to 0.58); for PA24226, 0.60 (95% CI, 0.58 to 0.62); for PA24227, 0.70 (95% CI, 0.66 to 0.74); and for PA24228, 0.55 (95% CI, 0.49 to 0.61). In the HFIM, imipenem plus MK-7655 considerably reduced the bacterial burden at 24 h, while failure with imipenem alone was seen against all isolates. Sustained suppression of bacterial growth at 72 h was achieved with simulated doses of 500 mg imipenem plus 500 mg MK-7655 in 2 (KP6339 and PA24227) strains, and it was achieved in an additional strain (PA24228) when the imipenem dose was increased to 1,000 mg. Additional studies are being conducted to determine the optimal dose and combinations to be used in clinical investigations.

Novel Modeling Framework To Guide Design of Optimal Dosing Strategies for β-Lactamase Inhibitors

The scarcity of new antibiotics against drug-resistant bacteria has led to the development of inhibitors targeting specific resistance mechanisms, which aim to restore the effectiveness of existing agents. However, there are few guidelines for the optimal dosing of inhibitors. Extending the utility of mathematical modeling, which has been used as a decision support tool for antibiotic dosing regimen design, we developed a novel mathematical modeling framework to guide optimal dosing strategies for a beta-lactamase inhibitor. To illustrate our approach, MK-7655 was used in combination with imipenem against a clinical isolate of Klebsiella pneumoniae known to produce KPC-2. A theoretical concept capturing fluctuating susceptibility over time was used to define a novel pharmacodynamic index (time above instantaneous MIC [T>MIC(i)]). The MK-7655 concentration-dependent MIC reduction was characterized by using a modified sigmoid maximum effect (E(max))-type model. Various dosing regimens of MK-7655 were simulated to achieve escalating T>MIC(i) values in the presence of a clinical dose of imipenem (500 mg every 6 h). The effectiveness of these dosing exposures was subsequently validated by using a hollow-fiber infection model (HFIM). An apparent trend in the bacterial response was observed in the HFIM with increasing T>MIC(i) values. In addition, different dosing regimens of MK-7655 achieving a similar T>MIC(i) (69%) resulted in comparable bacterial killing over 48 h. The proposed framework was reasonable in predicting the in vitro activity of a novel beta-lactamase inhibitor, and its utility warrants further investigations.

Overview of Seizure-Inducing Potential of Doripenem

The seizure-inducing potential of carbapenems has been debated since the introduction of imipenem/cilastatin over 20 years ago. Doripenem is a new carbapenem, recently approved in the US for the treatment of adults with complicated urinary tract infections (cUTI) or complicated intra-abdominal infections (cIAI), and additionally in the EU for nosocomial pneumonia, including ventilator-associated pneumonia. Here, the seizure-inducing potential of doripenem is evaluated, using data from in vitro and in vivo animal studies, doripenem clinical trials and doripenem postmarketing reports of seizures. Animal studies indicate that doripenem has low binding affinity for GABA receptors and does not induce seizures at doses greater than seizure-inducing doses of imipenem or meropenem. In clinical studies of cUTI or cIAI, no seizures were reported in the 1332 patients treated with doripenem (500-mg infusion every 8 hours). In two studies, patients with nosocomial pneumonia were treated with doripenem 500 mg (1- or 4-hour infusion every 8 hours), and the incidence of seizures was lower for doripenem (1.2% [6/485]) than imipenem (3.8% [10/263]) or piperacillin/tazobactam (2.7% [6/221]). For patients with seizure-predisposing conditions, seizures occurred during treatment for 3/193 (1.5%) in doripenem, 1/66 (1.5%) in piperacillin/tazobactam and 6/116 (5.2%) in the imipenem group. The review of data from both clinical trials and postmarketing surveillance supports the low seizure-inducing potential of doripenem. The seizure potential of doripenem should be evaluated further in patients at increased risk for seizure.

Population pharmacokinetics and pharmacodynamics of continuous versus short-term infusion of imipenem-cilastatin in critically ill patients in a randomized, controlled trial.

Beta-lactams are regularly administered in intermittent short-term infusions. The percentage of the dosing interval during which free drug concentrations exceed the MIC (fT(>MIC)) is the measure of drug exposure that best correlates with clinical outcome for beta-lactams. Therefore, administration by continuous infusion has gained increasing interest recently. We studied 20 critically ill patients with nosocomial pneumonia and investigated whether continuous infusion with a reduced total dose, compared to the standard regimen of intermittent short-term infusion, results in a superior probability of target attainment as assessed by the fT(>MIC) value of imipenem. In this prospective, randomized, controlled clinical study, patients received either a loading dose of 1 g/1 g imipenem and cilastatin (as a short-term infusion) at time zero, followed by 2 g/2 g imipenem-cilastatin per 24 h as a continuous infusion for 3 days (n = 10), or 1 g/1 g imipenem-cilastatin three times per day as a short-term infusion for 3 days (total daily dose, 3 g/3 g; n = 10). Imipenem concentrations in plasma were determined by using a validated liquid chromatography-tandem mass spectrometry assay. A two-compartment open model was employed for population pharmacokinetic modeling. We simulated 10,000 intensive-care-unit patients via Monte Carlo simulations for pharmacodynamic evaluation using the target 40% fT(>MIC). The probability of target attainment by MIC for intermittent infusion was robust (>90%) up to MICs of 1 to 2 mg/liter. The corresponding value for continuous infusion was 2 to 4 mg/liter. Although all 20 patients had an fT(>MIC) of 100%, 3 patients died. Patient survival was best described by employing a sepsis-related organ failure assessment score as a covariate in a logistic regression analysis. Larger clinical trials are warranted for evaluation of continuous infusions at a reduced dose of imipenem for critically ill patients.