International Journal of Antimicrobial Agents

ObjectivesTo provide real-world evidence on piperacillin exposure and outcomes in critically ill patients following the implementation of pharmacokinetic (PK)/pharmacodynamic (PD)-guided dosing in routine care. MethodsThis retrospective observational study included critically ill adults who received continuous piperacillin/tazobactam infusion between 2011 and 2019. Empiric doses were individualized using dosing software based on renal function and subsequently adjusted according to therapeutic drug monitoring (TDM) results. Drug exposure was defined as subtherapeutic (<32 mg/L), therapeutic (32-64 mg/L), moderately high (64-96 mg/L), or supratherapeutic (>96 mg/L). ResultsA total of 1538 critically ill patients with severe infections and sepsis of varying severity were included, and 3,090 piperacillin serum concentrations were analysed. Median daily piperacillin dose was 8,000 mg, median steady-state concentration 55 mg/L, and median clearance 6.25 L/h. At the first measurement, individualized empiric dosing resulted in 45.7% of patients being within the therapeutic range; after TDM-guided adjustment, target attainment increased to 62.4%. Subtherapeutic and supratherapeutic concentrations were uncommon among all TDM samples collected during individualized dosing (<32 mg/L: 12.8%; < 16 mg/L: 0.8%; > 96 mg/L: 11%). ICU mortality was 21.1 % in patients within the therapeutic range, 30.3 % in those with moderately high concentrations, and 44.1 % in those with supratherapeutic concentrations (p = 0.05). Women were 1.8 times more likely to present supratherapeutic concentrations. ConclusionsA multimodal approach combining individualized empiric dosing, TDM, and continuous infusion ensured target attainment while reducing drug consumption. These findings support the integration of individualized, PK/PD-guided dosing into routine care for critically ill patients and highlight the need for further studies addressing sex-related pharmacokinetic variability.

Linezolid is an alternative to vancomycin for treating Gram-positive central nervous system (CNS) healthcare-associated infections. The recommended dosing regimen remains debated. PK-Pop-LCR is a prospective population pharmacokinetic-pharmacodynamic multicenter study which included brain injured patients with an external ventricular drainage receiving linezolid at different dosing regimens. The cerebrospinal fluid (CSF) penetration of linezolid was investigated and a population pharmacokinetic model developed using plasma and CSF data. Monte Carlo simulations were conducted to calculate probability of target attainment (PTA) and cumulative fraction of response (CFR) in CSF against methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant Staphylococcus epidermidis (MRSE), for different dosing regimens. The plasma pharmacodynamic target, AUC/MIC > 100, was used in CSF. Over 25 patients included, blind adjudication confirmed 14 cases of CNS infections. The mean AUCCSF/fAUCplasma ratio was close to 80% with no difference between patients with and without CNS infection, despite higher CSF cytokines levels in CNS-infected patients. The recommended dose of 1200 mg/24h allowed to reach PTAs [&ge;] 90% only for MICs [&le;] 0.5 mg/L, and CFR of 3.2% and 40% for MRSA and MRSE, respectively. 2 700 mg/24h would allow to achieve PTA > 90% for MIC up to 1 mg/L and CFR of 90% for MRSE but none of dosing regimens tested was appropriate for MRSA infections. We confirmed the extensive CSF distribution of linezolid. Higher doses than those recommended should be considered to treat CNS infection in critically brain injured patients. However, pharmacodynamic target for CNS infections should be further investigated to confirm these findings. FundingsFrench Ministry of Health.

LYSC98 is a vancomycin derivative used for gram-positive bacterial infections therapy. We reported the pharmacokinetic/pharmacodynamic (PK/PD) targets of LYSC98 against Staphylococcus aureus using a murine thigh infection model. Three Staphylococcus aureus strains were utilized. Single-dose plasma pharmacokinetics of LYSC98 were determined in infected mice after the tail vein injection of 2, 4, and 8mg/kg. The results showed maximum plasma concentration (Cmax) 11466.67 - 48866.67 ng/mL, area under the concentration-time curve from 0 to 24 h(AUC0-24) 14788.42 -91885.93 ng/mL{middle dot}h, and elimination half-life(T1/2) 1.70-2.64 h, respectively. The Cmax (R2 0.9994) and AUC0-24 (R2 0.981) were positively correlated with the dose of LYSC98 in the range of 2-8 mg/kg. Dose fractionation studies using total doses of 2 to 8 mg/kg administered with q6h, q8h, q12h, and q24h were performed to evaluate the correlation of different PK/PD indices with efficacy. Sigmoid model analysis showed Cmax/MIC (R2 0.8941) was the best PK/PD index to predict the efficacy of LYSC98. In the dose ranging studies, two Methicillin-resistant Staphylococcus aureus (MRSA) clinical strains were used to infect the mice and 2-fold-increasing doses (1 to 16 mg/kg) of LYSC98 were administered. The magnitude of LYSC98 Cmax/MIC associated with net stasis, 1, 2, 3 and 4 - log10 kill were 5.78, 8.17, 11.14, 15.85 and 30.58, respectively. The results of this study showed LYSC98 a promising antibiotic with in vivo potency against MRSA, and will help in the dose design of phase one study for LYSC98.

BackgroundCurrent FDA-approved label recommends polymyxin B dosing should be adjusted according to renal function, despite several studies proved poor correlation between polymyxin B PK and creatinine clearance. The study aims to assess the impact of renal function on polymyxin B metabolism and identify an alternate dosing strategy by population analysis. MethodsBlood samples from adult patients were collected at steady state during routine therapeutic drug monitoring. Nonlinear mixed effects modeling was employed to build a population PK model of polymyxin B. Monte Carlo simulations were performed to design polymyxin B dosing regimens across various renal function. ResultsPharmacokinetic analyses included 112 polymyxin B concentrations at steady state from 32 adult patients aged 37-93 received intravenous polymyxin B (100-200 mg/d). The creatinine clearance in patients was 5.91-244 mL/min. In the final population PK model, CrCL was the significant covariate on CL (typical value, 1.59 L/hr; between-subject variability, 13%). Mean (SD) individual empirical Bayesian estimates of CL was 1.75 (0.43) L/hr. A new dosing strategy combining the PK/PD targets and Monte Carlo simulation indicated that polymyxin B dose reductions improved the probability of achieving optimal exposures in simulated patients with renal insufficiency. For severe infections caused by organisms with MIC of [&ge;] 2 mg/L, though a high daily dose (e.g. 200mg/day) would possible for bacterial eradication, the risk of nephrotoxicity is significantly increased. ConclusionA population PK model was established to develop individualized polymyxin B dosage regimens that the dose of polymyxin B should be adjusted according to CrCL.

Antimicrobial resistance (AMR) continues to be a major public threat due to dwindling supplies of effective antibiotics due to its excessive usage in humans and food producing animals. The objective of our study was to identify and predict future trends in multi-drug resistance amongst enterobacteriaceae and non-enterobacteriaceae family in India for four common broad-spectrum antibiotics. We focussed on four broad spectrum antibiotics levofloxacin, gentamicin, cefepime, and ceftazidime and classified the GEARS program study dataset into sensitive (S), intermediate(I) and resistant (R) isolates based on CLSI breakpoints. Levofloxacin (98.3%) was found to be the most susceptible broad spectrum antibiotic for treatment of non-enterobacteriaceae while it was relatively resistant (56.5%) for enterobacteriaceae treatment. As levofloxacin are among ICMR list of alert antimicrobial agents,hospitals and clinicans can exercise greater care before prescribing them.

Enterococcal bacteremia is associated with high mortality and long-term hospitalization. Here, we aimed to investigate the clinical outcomes and evaluate risk factors for mortality in adult patients treated with vancomycin (VCM) for penicillin-resistant Enterococcus faecium (E. faecium) bacteremia. Data were collected from inpatients at a single university hospital between January 2009 and December 2020. The area under the curve (AUC) of VCM was calculated using the Bayesian approach. The primary outcome was 30-day in-hospital mortality. Univariate analysis showed significant differences in the combined use of vasopressors, history of the use of inactive antimicrobial agents against E. faecium, VCM plasma trough concentration, and renal dysfunction during VCM administration between 30-day mortality and survival groups. However, the AUC/minimum inhibitory concentration (MIC) was not significantly different. Multivariate analysis revealed that concomitant vasopressors were an independent risk factor for 30-day all-cause mortality (odds risk, 7.81; 95% confidence interval, 1.16-52.9; P = 0.035). VCM plasma trough concentrations and AUC/MIC in the mortality group were higher than those in the surviving group. Depending on the drug-susceptibility results of E. faecium, it is considered that the AUC/MIC is calculated at a double AUC value. No association between AUC/MIC and treatment effect in E. faecium bacteremia was assumed because the known target AUC/MIC was sufficiently achieved in the mortality group. When an immunocompromised host develops E. faecium bacteremia with septic shock, especially in situations where the hemodynamics of using a pressor agent is unstable, treating it exclusively by sufficient exposure to antibacterial agents may be difficult.

1.Background & AimCo-amoxiclav is a commonly used antibiotic. Although, the dose administered during renal replacement therapy may be subtherapeutic. This study aims to describe the current literature on the pharmacokinetics and pharmacodynamics of co-amoxiclav in patientss undergoing renal replacement therapy. MethodWe carried out a systematic review of the available literature in MEDLINE, Embase, Pubmed, and Google Scholar from inception to Oct 2023. Studies were included if they reported pharmacokinetic data on adults given amoxicillin or clavulanic acid during renal replacement therapy. ResultsSeven studies were identified which were published between 1984 to 2021. Variability was observed in the participant characteristics within the studies, the renal replacement therapy settings, the drug exposure, drug assay methods, and the analysis of the pharmacokinetic parameters. ConclusionFurther pharmacokinetic-pharmacodynamic studies are needed on co-amoxiclav during renal replacement therapy.

Cefepime is widely used in the intensive care unit (ICU) for the treatment of complicated Gram-negative infections. Cefepime is a candidate for therapeutic drug monitoring (TDM) and model-informed precision dosing (MIPD), especially in critically ill patients, notably because of its concentration-dependent neurological toxicity. In this study, we aimed to evaluate the impact of the implementation of cefepime MIPD on PK/PD targets attainment in intensive care. We performed a monocentric, retrospective, before-after study, including all adult patients hospitalized in our ICU and for whom at least two cefepime plasma through concentrations (Cmin) were measured on separate days. The main endpoint was a Cmin between 4xMIC (or 10mg/L if the MIC was unavailable) and 20mg/L. We modelled the odds of target attainment via a mixed-effect logistic model and the rate of target attainment with a spline of time. A total of 281 patients were included, of whom 121 were in the MIPD group and 160 in the control group. Median age, weight and follow-up duration were 65 years, 76 kg and 3 days respectively. The two most common infections were pneumonia (n=239) and peritonitis (n=16). A total of 728 cefepime through concentrations were collected. MIPD was non-significantly associated with higher odds of being in the therapeutic range (aOR 1.40 [0.88 - 2.22]) and significantly associated with lower odds of being over-exposed (aOR 0.58 [0.35 - 0.96]). HR of target attainment was 1.1 [0.7 - 1.9] at day 1 and 1.6 [0.9 - 2.9] at day 7. In summary, we demonstrated that cefepime MIPD in the ICU reduces the risk of over-exposure, and may be beneficial on the odds and on the rate of PK/PD targets attainment. What is already known about this subjectO_LICefepime is a candidate for TDM/MIPD programs, with established PK/PD targets for both antimicrobial efficacy and neurological toxicity (100% f T >4xMIC and Cmin>20mg/L, respectively). C_LIO_LIPrevious randomized controlled trials (RCT) of beta-lactams model-informed precision dosing (MIPD) versus standard dosing approaches failed to demonstrate a superiority of MIPD in clinical endpoints attainment, and provided conflicting results on pharmacokinetic target attainment. C_LI What this study addsO_LICefepime MIPD in the intensive care units reduces the odds of being over-exposed, and thus, possibly, the risk of elicit dose-dependent neurological toxicity. C_LIO_LIFurther RCT evaluating MIPD efficacy should focus on evaluating target attainment rate instead of probability alone. C_LI

BackgroundThe incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. MethodsThis was a retrospective study of adult patients who had received [&ge;] 5 days of cefepime with [&ge;] 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. ResultsOne-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L {+/-} 41.1 vs. 46.6 mg/L {+/-} 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) ([&ge;]72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN. ConclusionCefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM ([&le;] 72 hours) had lower risk of CIN.

Antimicrobial resistance (AMR) is one of the greatest public health challenges of the current time, and it is primarily associated with Gram-negative bacterial infections. Among these infections, Klebsiella pneumoniae is the most notorious bacterial pathogen in the context of AMR dissemination. In this dire circumstance, clinicians explored old regimes such as colistin to treat these multidrug-resistant infections; however, unfortunately, the resistance towards these last-resort drugs is also emerging rapidly. In this study, we examined the occurrence of colistin resistance in K. pneumoniae concerning its mechanism of resistance, chronology, and geographical distribution. We found that resistance towards these last-resort drugs, colistin and polymyxin B, is emerging rapidly, with evolving multiple mechanisms of resistance. While efforts continue to develop new antibacterial drugs, a combination of approved antibacterial drugs may be one of the most suitable strategies to fight against AMR in the current time-ticking situation. In this series, we evaluated the efficacy of a therapeutically viable combination of polymyxin B and triclosan using a set of standard antibacterial assays, used for in vitro preclinical efficacy. We found that the combination is highly effective in colistin-resistant clinical strains of K. pneumoniae, as triclosan sensitizes the pathogen towards polymyxin B. Furthermore, the results of additional complementary experiments, such as time-kill kinetics, biofilm inhibition, frequency of resistance, cell viability, and cytotoxicity assays, show very encouraging results for the feasibility and validation of this combination. Finally, we examined the presence of mutations in field isolates of K. pneumoniae FabI enzyme, as it has been hypothesized previously that triclosan may cause mutation in its binding target, FabI. Interestingly, we could not detect any mutation in the triclosan binding site of FabI in the genome of field isolates. Altogether, this study provides an overview of the current situation on colistin resistance, a promising solution for colistin resistance comprising a combination of two already being used antibacterial ingredients based on in vitro efficacy studies.

Rabbits are frequently used for the examination of the pharmacokinetics and effectiveness of antibiotic substances. However, antibiotics vary substantially in protein binding affecting the concentration of the antimicrobially effective unbound drug. We hypothesized that the binding properties of vancomycin, meropenem and ceftriaxone might vary between human and rabbit plasma. In an in-vitro study we observed dose dependent variability in protein binding of antibiotics between species. Thus, in-vitro-pre-studies are required to guarantee for translational conditions.

SynopsisO_ST_ABSBackgroundC_ST_ABSMeropenem, gentamicin and ciprofloxacin have been used as empiric broad-spectrum combination therapy in different combinations. Recent restrictions on the use of quinolones jeopardises the rational of administering this combination to increase the spectrum of coverage for this particular case. A mechanistic understanding of pharmacodynamic interaction for these combinations is lacking but can provide insight in the necessity of using the different moieties. ObjectivesTo study pharmacodynamic drug-drug interaction between meropenem, gentamicin and ciprofloxacin against Escherichia coli. MethodsStatic time kill curve experiments were conducted with Escherichia coli (NCTC(R) 12241) at 0.25 - 16 x MIC for a duration of 24 hours with samples being collected at 0, 2, 4, 6, 8, and 24 hour. Meropenem, gentamicin and ciprofloxacin were tested alone, in two- and three-way combinations. Bacterial load time series data were enumerated on Meuller Hinton plates and Colony Forming Unit data was modelled using nonlinear mixed-effects models in nlmixr. ResultsMeropenem, gentamicin and ciprofloxacin two- and three-way combinations prevented regrowth, but did not when these moieties were studied alone. Gentamicin and meropenem were synergistic by decreasing ciprofloxacin IC50 and the combination effects of meropenem and gentamicin and the addition of meropenem on top of a gentamicin and ciprofloxacin combination were indifferent. ConclusionsOur findings emphasize the added value of a quinolone in the drug combination. In light of the recent move towards reduced use of quinolones, a quinolone free combination still prevented regrowth, it just did not display further synergy on IC50 and was indifferent in initial killing.

Abstract Multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria are a major worldwide public health problem. In the last decades, resistance to last-resort antibiotics such as polymyxin B (PB) have been increasingly observed among these superbugs, compromising the effectiveness of antimicrobial therapy. The present study aimed (i) to assess the ultrapure Cannabidiol (CBD) antibacterial activity against a broad diversity of Gram-negative (GN) and Gram-positive (GP) bacteria (44 different species, 95 strains), comprising standard strains and clinical isolates, and (ii) to investigate the antibacterial activity of the combination CBD + PB against GN bacteria, including chromosomal- and plasmid-acquired PB-resistant and intrinsically PB-resistant GNB. We evaluated CBD in vitro antibacterial activity using the standard broth microdilution method, and the antibacterial activity of the combination CBD + PB was screened using the standard broth microdilution and confirmed by checkerboard assay. CBD exhibited antibacterial activity against different GP bacterial species, lipooligosaccharide (LOS)-expressing GN diplococcus (GND) (Neisseria gonorrhoeae, Neisseria meningitidis, and Moraxella catarrhalis), and Mycobacterium tuberculosis. The combination CBD + PB exhibited antibacterial activity against PB-resistant GNB (e.g., Klebsiella pneumoniae) as well as additive and/or synergistic effect against LOS-expressing GND. The antibacterial activity of the combination CBD + PB against Pseudomonas aeruginosa and plasmid-mediated colistin-resistant (MCR-1) E. coli strains could be only demonstrated in the presence of phenylalanine-arginine-{beta}-naphthylamide (PA{beta}N). In conclusion, our results show promising translational potential of the combination CBD + PB against MDR and XDR GNB, including PB-resistant K. pneumoniae, highlighting its potential as a rescue treatment for life-threatening infections caused by these superbugs. One Sentence SummaryPromising combination of cannabidiol (CBD) + polymyxin B (PB) against superbugs (e.g., PB-resistant Gram-negative bacilli): Repurposing CBD

Drug repurposing is a novel strategy for the development of new therapies against antibiotic-resistant bacteria. Zidovudine, an antiviral largely used in the HIV-therapy, exerts antibacterial activity against Gram-negative bacteria. Zidovudine was identified in a previous drug repurposing synergy screening as fosfomycin enhancer against Klebsiella pneumoniae ATCC 13883. Our aim was to evaluate the antibacterial in vitro activity of zidovudine-based combinations with last-line antibiotics against MDR/XDR K. pneumoniae isolates. We validated the zidovudine/fosfomycin combination against a collection of 12 MDR K. pneumoniae isolates by the checkerboard assay (CBA). In addition, we performed time-kill assays (TKA) to analyze synergistic and bactericidal activities of zidovudine paired combinations with fosfomycin, ceftazidime-avibactam, colistin and tigecycline. These were compared with frequent clinical combinations in the treatment of MDR Enterobacteriaceae. The potential of the triple zidovudine/fosfomycin/colistin was also assessed by TKA. CBA synergy confirmation rate between zidovudine/fosfomycin was 83.33%. TKA yielded synergy confirmation rates of 83.3% for zidovudine/ceftazidime-avibactam, 75% for zidovudine/fosfomycin, 75% for zidovudine/colistin and 66.6% for zidovudine/tigecycline with potent killing activities. Frequent clinical combinations displayed synergy rates of 41.6% for meropenem/ertapenem, 33.33% for meropenem/colistin, 75% for fosfomycin/colistin and 66.6% for fosfomycin/tigecycline with lower bactericidal efficacy than zidovudine-based combinations. The triple zidovudine/fosfomycin/colistin combination exhibited activities similar to fosfomycin/colistin and fosfomycin/zidovudine. As conclusion, zidovudine is an effective partner in in vitro combinations with existing antibiotics against MDR K. pneumoniae, especially with ceftazidime-avibactam, fosfomycin or colistin. Further studies are needed to elucidate the clinical potential of zidovudine as a repurposed drug in the antibacterial therapy.

This paper proposes both a rationale and potential study design for evaluation of low dose doxycycline (20mg BID) for the prevention of COVID-19 infection in exposed health care workers. More generally, it provides a potential study design blueprint to other investigators for any interventional COVID-19 study looking to evaluate interventions for prevention or treatment of COVID-19 infection. This specific study described is a randomized, double blind, placebo controlled study to evaluate the efficacy and safety of doxycycline for the prevention of COVID-19 infection and disease in healthcare workers with ongoing high risk exposure to COVID-19. This study would consist of a 50-day Treatment Period (Day 0-Day 50), followed by an End of Study Visit, approximately 30 days after completion of study drug dosing. Initially, for approximately the first 4 to 6 weeks, an initial open-label arm would be enrolled with up to 1938 subjects who will be assigned to take 20mg doxycycline BID. In the double blind, placebo controlled arms approximately 3,692 participants would be randomized to either doxycycline or placebo for 50 days. Doxycycline is a rational candidate drug to be evaluated for repurposing against SARS-CoV-2. Doxycycline is a generally safe tetracycline derivative that has been available for decades, most commonly dosed at 100mg BID to treat bacterial infections. However, in addition to its antimicrobial properties, doxycycline (and more generally tetracycline derivatives) may have a role as an effective anti-viral agent and as an anti-inflammatory drug. Early studies indicate potential efficacy of minocycline against respiratory syncytial virus (RSV) [12], and doxycycline against Dengue and Chikungunya infection[9, 10]. In addition, doxycycline is known or proposed to target several pathways that regulate viral replication. [13, 14, 15]. Doxycycline is a particularly attractive candidate as a COVID-19 prophylactic given it has been used in clinical practice for decades and maintains an excellent safety profile as demonstrated in multiple clinical studies. Any effective prophylaxis for COVID-19 should be able to demonstrate high efficacy at preventing infection and/or lowering severity of disease. Equally important, it should demonstrate this efficacy at dosing levels that are highly unlikely to precipitate any untoward severe side effects. Doxycycline has been selected based on its ability to: 1) inhibit metalloproteinases (MMPs), implicated in initial viral entry into the cell as well as in acute respiratory distress syndrome (ARDS) associated with severe COVID-19 infection [13, 16]; 2) potential to inhibit Papain-like proteinase (PLpro) responsible for proteolytic cleavage of the replicase polyprotein to release non-structural proteins 1, 2 & 3 (Nsp1, Nsp2 and Nsp3) all essential for viral replication. [19]; 3) potential to inhibit 3C-like main protease (3CLpro) or Nsp5 which is cleaved from the polyproteins causes further cleavage of Nsp4-16 and mediates maturation of Nsps which is essential in the virus lifecycle. [19]; 4) act as an ionophore help transport Zinc intracellularly, increasing cellular concentrations of Zinc to inhibit viral replication. [6, 15]; 5) inhibit Nf-kB which may lower inflammatory response to COVID-19 infection, and lower risk of viral entry due to decreasing DPP4 cell surface receptor. [20, 21]; 6) inhibits (specifically low-dose doxycycline) expression of CD147/EMMPRIN that may be necessary for SARS-CoV-2 entry into T lymphocytes [22, 23].

Multi-drug resistance in Pseudomonas aeruginosa is often associated with overexpression of drug efflux pumps which limit antibiotics exposure. So far, successful development of efflux pump inhibitors (EPIs) has been plagued by undesirable toxicities and inconsequential in vivo efficacy. TAXIS Pharmaceuticals Inc. has discovered an effective anti-pseudomonal therapy involving a novel indole carboxamide class of EPI, TXA11114, with a fluorine substituted diamine sidechain, as an adjunctive to levofloxacin. TXA11114 has demonstrated excellent potentiation of levofloxacin MIC by [&ge;] 8-fold in 90% of Walter-Reed and CDC multi-drug resistant (MDR) isolates. Biophysical and genetic studies with TXA11114 support efflux inhibition while ruling out membrane disruption as a mechanism of action. TXA11114 enhanced the levofloxacin killing and diminished the frequency of resistance emergence to levofloxacin to undetectable levels. Moreover, in murine thigh and lung P. aeruginosa infection models, the TXA11114-levofloxacin combination showed pronounced killing compared to levofloxacin alone, achieving a validated in vivo efficacy milestone that previous EPIs could not. Most importantly, TXA11114 exhibits a safe toxicology profile when screened for cytotoxicity, hERG channel inhibition, in vitro nephrotoxicity, and acute toxicity. Further, pharmacokinetic (PK) parameters of TXA11114 have a complementary profile with that of levofloxacin in plasma and bronchoalveolar lavage fluid (BALF) samples of infected mice, maximizing pharmacodynamic (PD) benefits. Overall, studies on the TXA11114-levofloxacin combination highlight its potential as an anti-pseudomonal agent for combating multidrug-resistant infections.

Colistin is one of the last resort of antibiotics used specifically in the treatment of multidrug resistant gram negative bacilli. Though an older class of antibiotic with no use in last four decades, resurgence of colistin use is also causing emergence of colistin resistant gram negative bacilli.The aim of this cross sectional study was to investigate the colistin susceptibility and resistant pattern along with colistin resistant genes in gram negative bacilli among different samples in Dhaka medical college hospital. Total 300 samples (wound swab, urine, endotracheal aspirate, blood and sputum) were collected from 2015 to 2016. 204 gram negative bacilli were isolated and tested for resistance to colistin by disc diffusion method. Then, the prevalence of colistin resistant genes (pmrA, pmrB, pmrC, mgrB, phoP, phoQ, lpxA, lpxC, lpxD, mcr-1) was detected by polymerase chain reaction method (PCR). Among 204 gram negative bacilli, 22 (10.78%) colistin resistance was identified. PCR analysis revealed that 50% of these isolates contained pmrA gene, followed by phoP gene (27.27%). The prevalence of pmrB, phoQ, mgrB, lpxC and lpxD were 22.72%, 13.63%, 13.63%, 13.63%, 13.63%, and 13.63% respectively among the isolates. Colistin resistance is widespread among gram negative bacilli isolated from human infections. Colistin resistance (10.78%) found in the study is quite alarming. A restricted and rational use of the colistin is the need of hour.

Background & aimsAn extensively-drug resistant (XDR) NDM and OXA-48 producing E. coli contributing to repeat episodes of biliary sepsis was isolated from the blood stream of a 45-55 year-old male with a background of IgG4 related sclerosing cholangitis. The patient was awaiting orthotopic liver transplant (OLT). There is no standardized antibiotic prophylaxis regimen however in line with the Infectious Diseases Society of America (IDSA) guidance an antibiotic prophylactic regimen of Ceftazidime-Avibactam (CZA) 2.5g TDS with Aztreonam (ATM) 2g TDS IV was proposed. MethodsTo inform the individualised pharmacodynamic outcome likelihood prior to prophylaxis dosing the hollow fibre infection model (HFIM) was applied to simulate the in vivo antibiotic exposures of the CZA-ATM regimen. The HFIM was inoculated with [~]10 x 105 bacterial CFU/mL of the XDR E. coli strain and CFUs/mL were measured for a total of 120 hours to determine the in vitro PK/PD killing dynamics. ResultsA 4-log reduction in CFU/mL in the first ten hours of the regimen exposure was observed however the killing dynamics were slow and six eight-hourly infusions were required to reduce bacterial cells to below the limit of quantification. Thus, the HFIM supported the use of the regimen for infection clearance however highlighted the need for several infusions. Standard local practise is to administer prophylaxis antibiotics at induction of OLT however the HFIM provided data to rationalise earlier dosing therefore the patient was dosed at 24 hours prior to their OLT induction. The patient was subsequently discharged 8 days after surgery. ConclusionsThe HFIM provides a dynamic culture solution for informing individualised medicine by testing antibiotic combinations and exposures against the bacterial isolates cultured from the patients infection.

BackgroundIn high dose, cefepime causes neurotoxicity in patients with kidney injury; however, the relationship between exposure and observed neurotoxicity is not clear, and no animal model presently recapitulates the human condition. ObjectivesThis study sought to describe plasma and tissue pharmacokinetics and pharmacodynamics (PK/PD) of cefepime in rats experiencing neurotoxicity. MethodsMale Sprague-Dawley rats (n=21) received escalating cefepime total daily doses ranging from 531-1593 mg/kg body weight/day administered as a short infusion (0.5 mL/min) every 24h for 5 days. Cefepime was quantified in plasma, cerebral cortex and hippocampus via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple PK/PD models of cefepime transit between plasma and brain compartments (i.e. cerebral cortex and hippocampus) and neurotoxic response were explored using Monolix 2021R1 (LixoftPK). ResultsExposure estimation of cerebral cortex demonstrated a median (IQR) AUC0 -24 and Cmax 0 -24 of 181.8 (85.2-661.3) mg {middle dot} 24 h/liter and 13.9 (1.0-30.1) mg/L, respectively. The median cerebral cortex/blood percentage of penetration was 1.7%. Exposure estimation of hippocampus demonstrated a median (IQR) AUC0 -24 and Cmax 0 -24 of 291.4 (126.6-1091.6) mg {middle dot} 24 h/liter and 8.8 (3.4-33.4) mg/L, respectively. The median hippocampus/blood percentage of penetration was 4.5%. Rats that reached a cefepime Cmax of {square}17 mg/L in the hippocampus exhibited signs of neurotoxicity. A hippocampal cefepime concentration of 4.1 {micro}g/100 mg brain tissue best described seizure stages >1 for cefepime-induced neurotoxicty. ConclusionsA cefepime plasma AUC0 -24 of 28,000 mg*24h/L and hippocampal concentrations of 4.1 {micro}g/100 mg brain tissue may be a threshold for cefepime-induced neurotoxicity. This model provides a methodology for future interrogation of the relationship between plasma concentrations, brain tissue concentrations, and neurotoxicity.

ObjectivesSeveral recent studies highlight the high prevalence of resistance to multiple antibiotic classes used in current treatment regimens for neonatal sepsis and new treatment options are urgently needed. We aimed to identify potential new combination antibiotic treatment regimens by investigating the drug-resistance and genetic profiles of the most frequently isolated Gram-negative bacteria causing neonatal sepsis in low- and middle-income countries (LMICs) in the NeoOBS study. Material and methodsGram-negative bacteria isolated from neonates with culture-confirmed sepsis from 13 clinical sites in nine countries, mainly LMICs, were analyzed. Culture-based identification was followed by whole-genome sequencing (WGS). Minimal inhibitory concentrations (MICs) for 8 antibiotics were determined for a representative subset of 108 isolates. ResultsFive bacterial species, Klebsiella pneumoniae (n=135), Acinetobacter baumannii (n=80), Escherichia coli (n=34), Serratia marcescens (n=33) and Enterobacter cloacae complex (ECC) (n=27) accounted for most Gram-negative bacterial isolates received (309/420, 74%). Extended-spectrum {beta}-lactamases (ESBL) genes mostly belonging to CTX-M-15 were found in 107 (79%) K. pneumoniae isolates and 13 (38%) E. coli, as well as in 6 (18%) and 10 (37%) S. marcescens and ECC isolates, respectively. Carbapenem resistance genes were present in 41 (30%) K. pneumoniae, while 73 (91%) of A. baumannii isolates were predicted to be MDR based on carbapenem resistance genes. Apart from A. baumannii, in which two major pandemic lineages predominated, a wide genetic diversity occurred at the intraspecies level with different MDR clones occurring at the different sites. Phenotypic testing showed resistance to the WHO first- and second- line recommended treatment regimens: 74% of K. pneumoniae isolates were resistant to gentamicin and 85% to cefotaxime; E. coli isolates showed resistance to ampicillin, gentamicin and cefotaxime in 90%, 38% and 47%, respectively. For the novel antibiotic regimens involving different combinations of flomoxef, fosfomycin and amikacin, the overall predicted MIC-determined susceptibility for Enterobacterales isolates was 71% (n=77) to flomoxef-amikacin, 76% (n=82) to flomoxef-fosfomycin and 79% (n=85) to fosfomycin-amikacin combinations, compared to 31% and 22% isolates susceptible to ampicillin-gentamicin and cefotaxime, respectively. ESBL-producing Enterobacterales isolates were 100% susceptible both to flomoxef-fosfomycin and flomoxef-amikacin and 92% to fosfomycin-amikacin. ConclusionEnterobacterales carried multiple resistance genes to cephalosporins, carbapenems and aminoglycosides. ESBL-producing K. pneumoniae and E. coli isolates were highly susceptible to the three new antibiotic combination regimens planned to be evaluated in the currently recruiting GARDP-sponsored NeoSep1 trial.