Crinecerfont Lowers Elevated Hormone Markers in Adults With 21-Hydroxylase Deficiency Congenital Adrenal Hyperplasia.

CONTEXT: Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (21OHD) is characterized by impaired cortisol synthesis and excess androgen production. Corticotropin-releasing factor type 1 receptor (CRF1R) antagonism may decrease adrenal androgen production. OBJECTIVE: This work aimed to evaluate the safety, tolerability, and efficacy of crinecerfont (NBI-74788), a selective CRF1R antagonist, in 21OHD. METHODS: This open-label, phase 2 study, with sequential cohort design (NCT03525886), took place in 6 centers in the United States. Participants included men and women, aged 18 to 50 years, with 21OHD. Interventions included 4 crinecerfont regimens, each administered orally for 14 consecutive days: 50 or 100 mg once daily at bedtime (cohorts 1 and 2, respectively); 100 mg once daily in the evening (cohort 3); and 100 mg twice daily (cohort 4). Participants could enroll in more than 1 cohort. Main outcomes included changes from baseline to day 14 in adrenocorticotropin (ACTH), 17-hydroxyprogesterone (17OHP), androstenedione, and testosterone. RESULTS: Eighteen participants (11 women, 7 men) were enrolled: cohort 1 (n = 8), cohort 2 (n = 7), cohort 3 (n = 8), cohort 4 (n = 8). Mean age was 31 years; 94% were White. Median percent reductions were more than 60% for ACTH (-66%), 17OHP (-64%), and androstenedione (-64%) with crinecerfont 100 mg twice a day. In female participants, 73% (8/11) had a 50% or greater reduction in testosterone levels; male participants had median 26% to 65% decreases in androstenedione/testosterone ratios. CONCLUSION: Crinecerfont treatment for 14 days lowered ACTH and afforded clinically meaningful reductions of elevated 17OHP, androstenedione, testosterone (women), or androstenedione/testosterone ratio (men) in adults with 21OHD. Longer-term studies are required to evaluate the effects of crinecerfont on clinical end points of disordered steroidogenesis and glucocorticoid exposure in patients with 21OHD.

Pharmacokinetic/pharmacodynamic modelling to evaluate the efficacy of various dosing regimens of ceftazidime/avibactam in patients with pneumonia caused by Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae: a multicentre study in northern China.

OBJECTIVES: The objective of this study was to evaluate the efficacy of different dosing regimens of ceftazidime/avibactam (CZA) in patients with Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) pulmonary infections. METHODS: A total of 70 KPC-Kp strains were isolated from sputum and bronchoalveolar lavage samples of patients with pulmonary infections in three hospitals in northern China from April 2015 to October 2015. Monte Carlo simulation (MCS) was performed using population pharmacokinetic parameters of CZA combined with the minimum inhibitory concentration (MIC) distributions gained from antimicrobial susceptibility testing to predict the efficacy of different dosing regimens. Various CZA dosing regimens were modelled using MCS. RESULTS: The in vitro study showed potent activity of CZA against KPC-Kp strains with MIC50/90 values of 1/2 mg/L, with a susceptibility rate of 95.7%. The values of cumulative fraction of response (CFR) for bactericidal (50%fT>5 × MIC) target were as follows: for patients with creatinine clearance (CLCr) >51 mL/min, the CFR was 96.01% for 2.5 g CZA every 12 h (q12h) and 97.14% for 2.5 g CZA every 8 h (q8h); and for patients with moderate renal impairment (CLCr >30 to ≤50 mL/min), the CFR was 95.75% for 1.25 g CZA q12h and 97.09% for 1.25 g CZA q8h. CONCLUSION: This study indicated that the recommended dose of CZA can provide adequate pharmacodynamic exposure for treating KPC-Kp pneumonia.

The Potential Use of Ceftazidime-Avibactam Against Carbapenem Resistant Klebsiella pneumoniae Clinical Isolates Harboring Different Carbapenemase Types in a Thai University Hospital.

PURPOSE: MBL and OXA-48 genes in carbapenem-resistant Enterobacterales (CRE) have emerged as a major public health problem worldwide, including Thailand. Due to the lack of susceptibility data and dosing regimens of ceftazidime-avibactam (CZA) against CRE in Thailand, especially in colistin-resistant era, we aimed to demonstrate in vitro susceptibility data of CZA and optimal dose based on Monte Carlo simulation of CZA to expand the treatment options. PATIENTS AND METHODS: We collected 49 carbapenem-resistant Klebsiella pneumoniae (CRKP) clinical isolates from unique patients at Phramongkutklao Hospital (June-October 2020). CZA disk diffusion and E-test testing were performed to obtain minimum inhibitory concentration (MIC). Each drug regimen was simulated using the Monte Carlo technique to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR). RESULTS: The most common genotypes of CRKP were blaOXA-48 (53.1%) and blaOXA-48 +blaNDM (42.8%). CZA showed 47.7% and 90.5% susceptible rate against all genotypes of carbapenemases and OXA-48 type CRKP isolates. The MIC50 and MIC90 of CZA against CRKP were 2 and >256 µg/mL. The categorical agreement (CA) between disk diffusion and E-test testing of CZA against CRKP was 95.4%. The CZA dosing regimens of 2.5 g infused 2-3 h every 8 h achieved ≥90% of the target of free ceftazidime plasma concentration over MIC (%fTime >MIC) ≥50% and 100% against isolates MICs of ≤8 and ≤8 µg/mL, respectively. The avibactam regimens also provided 100%fTime at 0.5 µg/mL. Based on CFR ≥90%, no CZA regimens were effective against all of the studied CRKP isolates except CRKP carrying OXA-48. CONCLUSION: CZA exhibited a fairly susceptible rate among the OXA-48-positive isolates in Thailand. The current suggested dose of CZA with prolonged infusion appears appropriate to achieve the pharmacokinetic/pharmacodynamic targets of ceftazidime and avibactam against CRKP carrying blaOXA-48 .

Evaluation of Ceftazidime/Avibactam Administration in Enterobacteriaceae and Pseudomonas aeruginosa Bloodstream Infections by Monte Carlo Simulation.

PURPOSE: To evaluate the administration regimen of ceftazidime/avibactam (CZA) for bloodstream infections caused by Enterobacteriaceae and Pseudomonas aeruginosa. METHODS: The minimal inhibitory concentrations (MICs) of CZA against Enterobacteriaceae and P. aeruginosa isolated from blood cultures at member hospitals in BRICS (Blood Bacterial Resistant Investigation Collaborative System) in 2019 were determined by broth micro-dilution methodology. A 10,000-patient Monte Carlo simulation (MCS) was used to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) for different CZA dosage regimens to evaluate their efficacies and optimize the best initial dosage regimen. RESULTS: Altogether, 6487 Enterobacteriaceae and P. aeruginosa strains were isolated from the blood cultures. The overall CZA resistance rate was 2.31%, of which the Enterobacteriaceae and P. aeruginosa rates were 1.57% and 14.29%, respectively. The MCS showed that the greater the MIC value, the worse the therapeutic effect. When the CZA MIC was ≤8 mg/L, the standard dose (2.5g iv q8h) achieved 90% PTA in the subset of patients with creatinine clearance (CrCl) values from 51 to 120 mL/min. Although the high-dose regimen (3.75g iv q8h) achieved 90% PTA in patients with CrCl values from 121 to 190 mL/min, implementing the low-dose regimen (1.25g iv q8h) was also effective for patients in the 51-89 mL/min CrCl range. Generally, the high-dose regimen (3.75g iv q8h) reached 90% CFR against all of the strains. Conversely, in patients with CrCl values of 121-190 mL/min, the standard dose (2.5g iv q8h) failed to reach 90% CFR against some Enterobacteriaceae members and P. aeruginosa. When the dose was reduced to the low-dose regimen (1.25g iv q8h), no patients reached 90% CFR against some Enterobacteriaceae members and P. aeruginosa. CONCLUSION: CZA has good antibacterial activity against Enterobacteriaceae and P. aeruginosa in bloodstream infections. Clinicians could make individualized treatment regimens in accordance with the sensitivity of the strains and the level of renal function in their patients to best predict the drug-related clinical responses.

A randomized, double-blind, placebo- and positive-controlled crossover study of the effects of durlobactam on cardiac repolarization in healthy subjects.

Durlobactam (formerly ETX2514) is a diazabicyclooctane ß-lactamase inhibitor that inhibits class A, C, and D ß-lactamases. Sulbactam combined with durlobactam has in vitro and in vivo activity against Acinetobacter baumannii including carbapenem- and colistin-resistant isolates and is being developed for treating serious infections due to A. baumannii. The effect of a single supratherapeutic dose of durlobactam on the heart rate corrected QT interval (QTc) was evaluated in healthy subjects in a placebo- and active-controlled, single-infusion, three-way crossover study. Subjects were randomized to 1 of 6 sequences that included a single 3-h i.v. infusion of durlobactam 4 g (supratherapeutic dose), a single 3-h i.v. infusion of placebo, and a single 3-h i.v. infusion of placebo plus a single oral dose of moxifloxacin 400 mg given open-label at the end of the i.v. infusion. In each treatment period, Holter electrocardiogram (ECG) measurements were obtained from predose through 24 h post-start of infusion. For the primary ECG end point, placebo-corrected change-from-baseline corrected QT Fridericia's formula (ΔΔQTcF), no significant change was observed with durlobactam. A concentration-QT analysis demonstrated no significant effect of durlobactam on ECG parameters, including QT interval prolongation. Thus, durlobactam has a low risk for prolonging the QT interval and is unlikely to produce any proarrhythmic effects.

Advances in novel antibiotics to treat multidrug-resistant gram-negative bacterial infections.

Antimicrobial resistance is a growing threat to public health and an increasingly common problem for acute care physicians to confront. Several novel antibiotics have been approved in the past decade to combat these infections; however, physicians may be unfamiliar with how to appropriately utilize them. The purpose of this review is to evaluate novel antibiotics active against resistant gram-negative bacteria and highlight clinical information regarding their use in the acute care setting. This review focuses on novel antibiotics useful in the treatment of infections caused by resistant gram-negative organisms that may be seen in the acute care setting. These novel antibiotics include ceftolozane/tazobactam, ceftazidime/avibactam, meropenem/vaborbactam, imipenem/cilistatin/relebactam, cefiderocol, plazomicin, eravacycline, and omadacycline. Acute care physicians should be familiar with these novel antibiotics so they can utilize them appropriately.

Successful treatment of infective endocarditis due to pandrug-resistant Klebsiella pneumoniae with ceftazidime-avibactam and aztreonam.

Pandrug-resistant (PDR) K. pneumoniae refractory to conventional treatment has been reported worldwide, causing a huge burden on the healthcare system, patient safety and the economy. K. pneumoniae is a prominent opportunistic pathogen causing hospital-acquired and community-acquired infections, but is rarely associated with infective endocarditis. Currently, there are sparse data guiding the optimal regimen when commonly used antibiotics fail, notably for the treatment of endocarditis infections. Here we report our experience in treating a 40-year-old female with PDR K. pneumoniae infection of cardiovascular implantable electronic device (CIED) and right-sided infective endocarditis. Initial susceptibility testing of the incriminated pathogen showed an apparent susceptibility to colistin but the prolonged course of colistin, gentamicin and meropenem did not resolve the infection. However, the synergistic combinations of aztreonam with ceftazidime-avibactam was able to overcome resistance and clear the infection rapidly. Genome sequencing showed that the PDR K. pneumoniae isolate belongs to the international high-risk clone ST14. The isolate harbored genes encoding NDM-1, OXA-48, CTX-M-14b, SHV-28 and OXA-1, explaining resistance to all ß-lactams, including carbapenems. It carried the armA gene conferring resistance to all clinically important aminoglycosides and had alterations in GyrA, ParC and MgrB, explaining resistance to ciprofloxacin and colistin.

In vitro activity of cefepime/zidebactam (WCK 5222) against recent Gram-negative isolates collected from high resistance settings of Greek hospitals.

Cefepime/zidebactam is in clinical development for the treatment of carbapenem-resistant Gram-negative infections. MICs of cefepime/zidebactam (1:1) and comparators against Enterobacterales (n = 563), Pseudomonas (n = 172) and Acinetobacter baumannii (n =181) collected from 15 Greek hospitals (2014-2018) were determined by reference broth microdilution method. The isolates exhibited high carbapenem resistance rates [(Enterobacterales (75%), Pseudomonas (75%) and A. baumannii (98.3%)]. Cefepime/zidebactam showed MIC50/90 of 0.5/2 mg/L, against Enterobacterales including metallo-ß-lactamases (MBL)-producers. Reduced susceptibility rates to tigecycline (16.8%), colistin (47.4%), ceftazidime/avibactam (59.8%), and imipenem/relebactam (61%) indicated high prevalence of multi-drug resistance among Greek Enterobacterales. Cefepime/zidebactam exhibited MIC50/90 of 8/16 mg/L against Pseudomonas including MBL-producers. The MIC50/90 of ceftazidime/avibactam and imipenem/relebactam were high (≥32 mg/L). Cefepime/zidebactam showed MIC90 of 64 mg/L against A. baumannii which is within its therapeutic scope. Other antibiotics including colistin showed limited activity against A. baumannii. The activity of cefepime/zidebactam against multi-drug-resistant isolates is attributable to zidebactam mediated novel ß-lactam-enhancer mechanism.

Evaluation of the post-antibiotic effect in vivo for the combination of a ß-lactam antibiotic and a ß-lactamase inhibitor: ceftazidime-avibactam in neutropenic mouse thigh and lung infections.

The post-antibiotic effect (PAE) of ceftazidime-avibactam in vivo was evaluated using models of thigh- and lung-infection with Pseudomonas aeruginosa in neutropenic mice. In thigh-infected mice, the PAE was negative (-2.18 to -0.11 h) for three of four strains: caused by a 'burst' of rapid bacterial growth after the drug concentrations had fallen below their pre-specified target values. With lung infection, PAE was positive, and longer for target drug concentrations in ELF (>2 h) than plasma (1.69-1.88 h). The time to the start of regrowth was quantified as a new parameter, PAER, which was positive (0.35-1.00 h) in both thigh- and lung-infected mice. In the context that measurements of the PAE of ß-lactam/ß-lactamase inhibitor combinations in vivo have not previously been reported, it is noted that the negative values were consistent with previous measurements of the PAE of ceftazidime-avibactam in vitro and of ceftazidime alone in vivo.

Imipenem/Cilastatin/Relebactam: A Review in Gram-Negative Bacterial Infections.

Imipenem/cilastatin/relebactam (Recarbrio™) is an intravenously administered combination of the carbapenem imipenem, the renal dehydropeptidase-I inhibitor cilastatin, and the novel ß-lactamase inhibitor relebactam. Relebactam is a potent inhibitor of class A and class C ß-lactamases, conferring imipenem activity against many imipenem-nonsusceptible strains. Imipenem/cilastatin/relebactam is approved in the USA and EU for the treatment of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) in adults and other gram-negative infections, including complicated urinary tract infections (cUTIs) [including pyelonephritis] and complicated intra-abdominal infections (cIAIs), in adults with limited or no alternative treatment options. In pivotal phase II and III trials, imipenem/cilastatin/relebactam was noninferior to piperacillin/tazobactam in patients with HABP/VABP and to imipenem/cilastatin in patients with cUTIs and cIAIs. It was also effective in imipenem-nonsusceptible infections. Imipenem/cilastatin/relebactam was generally well tolerated, with a safety profile consistent with that of imipenem/cilastatin. Available evidence indicates that imipenem/cilastatin/relebactam is an effective and generally well tolerated option for gram-negative infections in adults, including critically ill and/or high-risk patients, and a potential therapy for infections caused by carbapenem-resistant pathogens.

SMARCA2 Is a Novel Interactor of NSD2 and Regulates Prometastatic PTP4A3 through Chromatin Remodeling in t(4;14) Multiple Myeloma.

NSD2 is the primary oncogenic driver in t(4;14) multiple myeloma. Using SILAC-based mass spectrometry, we demonstrate a novel role of NSD2 in chromatin remodeling through its interaction with the SWI/SNF ATPase subunit SMARCA2. SMARCA2 was primarily expressed in t(4;14) myeloma cells, and its interaction with NSD2 was noncanonical and independent of the SWI/SNF complex. RNA sequencing identified PTP4A3 as a downstream target of NSD2 and mapped NSD2-SMARCA2 complex on PTP4A3 promoter. This led to a focal increase in the permissive H3K36me2 mark and transcriptional activation of PTP4A3. High levels of PTP4A3 maintained MYC expression and correlated with a 54-gene MYC signature in t(4;14) multiple myeloma. Importantly, this mechanism was druggable by targeting the bromodomain of SMARCA2 using the specific BET inhibitor PFI-3, leading to the displacement of NSD2 from PTP4A3 promoter and inhibiting t(4;14) myeloma cell viability. In vivo, treatment with PFI-3 reduced the growth of t(4;14) xenograft tumors. Together, our study reveals an interplay between histone-modifying enzymes and chromatin remodelers in the regulation of myeloma-specific genes that can be clinically intervened. SIGNIFICANCE: This study uncovers a novel, SWI/SNF-independent interaction between SMARCA2 and NSD2 that facilitates chromatin remodeling and transcriptional regulation of oncogenes in t(4;14) multiple myeloma, revealing a therapeutic vulnerability targetable by BET inhibition.

Ceftazidime-avibactam, meropenen-vaborbactam, and imipenem-relebactam in combination with aztreonam against multidrug-resistant, metallo-ß-lactamase-producing Klebsiella pneumoniae.

The spread of multidrug-resistant (MDR), metallo-ß-lactamase (MBL)-producing Klebsiella pneumoniae represents a major therapeutic challenge. The newly introduced ß-lactam-ß-lactamase inhibitors (BLBLIs), ceftazidime/avibactam (CAZ/AVI), meropenem/vaborbactam (M/V), and imipenem/relebactam (I/R) are inactive against MBLs. The aim of this study was to evaluate the in vitro efficacy of aztreonam (ATM) in combination with CAZ/AVI, M/V, and I/R against 40 MDR, MBL-producing, and serine-ß-lactamases co-producing Klebsiella pneumoniae using the Etest method. Synergy was defined as a fractional inhibitory concentration index ≤0.5. All isolates were resistant to ATM, CAZ/AVI, and I/R and 38/40 (95%) were resistant to M/V. Synergy was observed in 97.5% in the combinations CAZ/AVI-ATM, and I/R-ATM and in 72.5% in the combination M/V-ATM. Further clinical studies are required to confirm the efficacy of these antimicrobial combinations.

Assessing sleep-wake survival dynamics in relation to sleep quality in a placebo-controlled pharmacological intervention study with people with insomnia and healthy controls.

RATIONALE: The mechanisms underlying impaired sleep quality in insomnia are not fully known, but an important role for sleep fragmentation has been proposed. OBJECTIVES: The aim of this study is to explore potential mechanisms of sleep fragmentation influencing alterations of perceived sleep quality. METHODS: We analyzed polysomnography (PSG) recordings from a double-blind crossover study with zopiclone 7.5 mg and placebo, in elderly participants with insomnia complaints and age-matched healthy controls. We compared survival dynamics of sleep and wake across group and treatment. Subsequently, we used a previously proposed model to estimate the amount of sleep onset latency (SOL) misperception from PSG-defined sleep fragmentation. Self-reported and model-estimated amount of SOL misperception were compared across group and treatment, as well as model prediction errors. RESULTS: In the zopiclone night, the average segment length of NREM sleep was increased (group F = 1.16, p = 0.32; treatment F = 8.89, p < 0.01; group x treatment F = 0.44, p = 0.65), while the segment length of wake was decreased (group F = 1.48, p = 0.23; treatment F = 11.49, p < 0.01; group x treatment F = 0.36, p = 0.70). The self-reported and model-estimated amount of SOL misperception were lower during the zopiclone night (self-reported group F = 6.08, p < 0.01, treatment F = 10.8, p < 0.01, group x treatment F = 2.49, p = 0.09; model-estimated F = 1.70, p = 0.19, treatment F = 16.1, p < 0.001, group x treatment F = 0.60, p = 0.55). The prediction error was not altered (group F = 1.62, p = 0.20; treatment F = 0.20, p = 0.65; group x treatment F = 1.01, p = 0.37). CONCLUSIONS: Impaired subjective sleep quality is associated with decreased NREM stability, together with increased stability of wake. Furthermore, we conclude that zopiclone-induced changes in SOL misperception can be largely attributed to predictable changes of sleep architecture.

Experience of Ceftazidime/avibactam in a UK tertiary cardiopulmonary specialist center.

OBJECTIVES: Antimicrobial resistance is a major threat to public health. New drugs such as Ceftazidime/avibactam have been developed for the treatment of Multi-Drug resistant (MDR) pathogens. Susceptibility can be variable and inappropriate use can add a financial strain on the National Health Service (NHS). There is a pressing need to ensure these new and invaluable antimicrobials are preserved and used effectively. METHODS: We undertook a retrospective observational study to assess the use of Ceftazidime/avibactam and evaluated prescribing against applied standards. RESULTS: Between August 2017 and January 2019, 28 patients received 31 courses of Ceftazidime/avibactam. Prescribing according to the approved indications was observed for 68% of prescriptions (p < 0.0001). Duration of therapy was often prolonged but improved with Antimicrobial stewardship interventions. We observed 56% susceptibility (15/27 isolates) of MDR organisms (Pseudomonas, Klebsiella, Burkholderia, Enterobacter aerogenes, Achromobacter). We also report first in vivo experience to treat pulmonary disease caused by Non-tuberculous mycobacteria (NTM). Ceftazidime/avibactam was well tolerated, with no evidence of development of resistance at 6-months follow-up. CONCLUSIONS: Our study showed that Antimicrobial stewardship interventions led to a more appropriate use of Ceftazidime/avibactam (as measured by duration of therapy), preserving it as a treatment option for MDR infections.

Equine metabolism of the selective androgen receptor modulator AC-262536 in vitro and in urine, plasma and hair following oral administration.

AC-262536 is one of a number of selective androgen receptor modulators that are being developed by the pharmaceutical industry for treatment of a range of clinical conditions including androgen replacement therapy. Though not available therapeutically, selective androgen receptor modulators are widely available to purchase online as (illegal) supplement products. The growth- and bone-promoting effects, along with fewer associated negative side effects compared with anabolic-androgenic steroids, make these compounds a significant threat with regard to doping control in sport. The aim of this study was to investigate the metabolism of AC-262536 in the horse following in vitro incubation and oral administration to two Thoroughbred horses, in order to identify the most appropriate analytical targets for doping control laboratories. Urine, plasma and hair samples were collected and analysed for parent drug and metabolites. Liquid chromatography-high-resolution mass spectrometry was used for in vitro metabolite identification and in urine and plasma samples. Nine phase I metabolites were identified in vitro; four of these were subsequently detected in urine and three in plasma, alongside the parent compound in both matrices. In both urine and plasma samples, the longest detection window was observed for an epimer of the parent compound, which is suggested as the best target for detection of AC-262536 administration. AC-262536 and metabolites were found to be primarily glucuronide conjugates in both urine and plasma. Liquid chromatography-tandem mass spectrometry analysis of post-administration hair samples indicated incorporation of parent AC-262536 into the hair following oral administration. No metabolites were detected in the hair.

Detection and identification of ACP-105 and its metabolites in equine urine using LC/MS/MS after oral administration.

ACP-105 is a novel nonsteroidal selective androgen receptor modulator (SARM) with a tissue-specific agonist effect and does not have side effects associated with the use of common androgens. This research reports a comprehensive study for the detection of ACP-105 and its metabolites in racehorses after oral administration (in vivo) and postulating its structures using mass spectrometric techniques. To obtain the metabolic profile of ACP-105, a selective and reliable LC-MS/MS method was developed. The chemical structures of the metabolites were determined based on their fragmentation pattern, accurate mass, and retention time. Under the current experimental condition, a total of 19 metabolites were detected in ACP-105 drug administered equine urine samples. The study results suggest the following: (1) ACP-105 is prone to oxidation, which gives corresponding monohydroxylated, dihydroxylated, and trihydroxylated metabolites; (2) along with oxidation, there is a possibility of elimination of water molecule (dehydration) from the third position of the tropine moiety, resulting in the dehydrated analogs of corresponding monohydroxylated, dihydroxylated, and trihydroxylated metabolites; (3) from the study on the metabolites using LC-MS/MS, it is clear that the fragmentation pattern is identical and a great number of fragment ions are common in all the metabolites and the parent drug. (4) The ACP-105 and its metabolites were detected for up to 72 h; thus, the result is a valuable tool for evaluating its use and/or misuse in sport.

Antiallodynic effect of PhAR-DBH-Me involves cannabinoid and TRPV1 receptors.

The antiallodynic effect of PhAR-DBH-Me was evaluated on two models of neuropathic pain, and the potential roles of CB1, CB2, and TRPV1 receptors as molecular targets of PhAR-DBH-Me were studied. Female Wistar rats were submitted to L5/L6 spinal nerve ligation (SNL) or repeated doses of cisplatin (0.1 mg/kg, i.p.) to induce experimental neuropathy. Then, tactile allodynia was determined, and animals were treated with logarithmic doses of PhAR-DBH-Me (3.2-100 mg/kg, i.p.). To evaluate the mechanism of action of PhAR-DBH-Me, in silico studies using crystallized structures of CB1, CB2, and TRPV1 receptors were performed. To corroborate the computational insights, animals were intraperitoneally administrated with antagonists for CB1 (AM-251, 3 mg/kg), CB2 (AM-630, 1 mg/kg), and TRPV1 receptors (capsazepine, 3 mg/kg), 15 min before to PhAR-DBH-Me (100 mg/kg) administration. Vagal stimulation evoked on striated muscle contraction in esophagus, was used to elicited pharmacological response of PhAR-DBH-ME on nervous tissue. Systemic administration of PhAR-DBH-Me reduced the SNL- and cisplatin-induced allodynia. Docking studies suggested that PhAR-DBH-Me acts as an agonist for CB1, CB2, and TRPV1 receptors, with similar affinity to the endogenous ligand anandamide. Moreover antiallodynic effect of PhAR-DBH-Me was partially prevented by administration of AM-251 and AM-630, and completely prevented by capsazepine. Finally, PhAR-DBH-Me decreased the vagally evoked electrical response in esophagus rat. Taken together, results indicate that PhAR-DBH-Me induces an antiallodynic effect through partial activation of CB1 and CB2 receptors, as well as desensitization of TRPV1 receptors. Data also shed light on the novel vanilloid nature of the synthetic compound PhAR-DBH-Me.

Successful Treatment of Early Post-Transplant Bloodstream and Pulmonary Infection Caused by Carbapenem-Resistant Klebsiella pneumoniae With a Combination of Ceftazidime-Avibactam and Carbapenem: A Case Report.

Bloodstream infection with carbapenem-resistant Klebsiella pneumoniae (CRKP) is a severe and challenging complication in the early post-transplantation period. Pulmonary infection secondary to sepsis caused by CRKP has been reported only rarely in kidney transplant recipients. Here we report an interesting and complicated case in which CRKP was initially isolated in a culture of renal graft preservation solution, yet was not detected in the daily cultures from collection of surgical drainage. Prophylactic tigecycline was terminated at post-transplantation day 10 because of the occurrence of acute pancreatitis. Five days later, the patient suddenly developed a multisite infection with CRKP involving the bloodstream, urinary tract, and lungs, indicating probable transmission from the donor. Fortunately, the infection was controlled quickly and effectively with a combination therapy consisting of ceftazidime-avibactam (CZA) and carbapenem, which was suggested by the results of disc diffusion susceptibility testing. However, the CRKP infection reappeared in the bloodstream and urinary tract soon after the treatment of acute rejection. The combination regimen was continued for another 15 days, and the patient ultimately recovered. During the following 15 months of observation, the patient's renal graft function remained stable, without recurrence of the CRKP infection. In conclusion, the combined use of CZA and carbapenem was safe and produced an optimal therapeutic effect on the severe multisite infection caused by CRKP in a renal transplant recipient, thus providing a reference case for treating such patients.

Evaluating imipenem + cilastatin + relebactam for the treatment of complicated urinary tract infections.

INTRODUCTION: The addition of the ß-lactamase inhibitor relebactam to imipenem restores the antibacterial activity against the majority of multidrug resistant Gram-negative bacteria. Complicated urinary tract infections (UTIs) are predominantly caused by Gram-negative uropathogens. The rise in antibiotic resistance, including to carbapenems, is an increasing challenge in daily practice. AREAS COVERED: In the current review, the use of imipenem/relebactam in complicated UTI is evaluated by discussing its chemistry, pharmacokinetics/dynamics, microbiology, safety, and clinical efficacy. The authors also provide their expert perspectives onto its use and its future place in the treatment armamentarium. EXPERT OPINION: With respect to complicated UTI, it should be noted that, to our knowledge, there are no data yet upon the clinical efficacy of imipenem/relebactam in patients with severe urosepsis or men with suspected prostatitis. Further studies upon these specific groups of UTI patients are needed including additional pharmacokinetic studies upon its tissue penetration of the prostate which is currently unknown. However, in our opinion, imipenem/relebactam can be used in complicated UTI when other treatment options are limited.