Penicillin-binding proteins (PBPs) are the high-affinity target sites of all β-lactam antibiotics in bacteria. It is well known that each β-lactam covalently binds to and thereby inactivates different PBPs with various affinities. Despite β-lactams serving as the cornerstone of our therapeutic armamentarium against , PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant β-lactams and β-lactamase inhibitors in PBP binding was determined using isolated membrane fractions from strains ATCC 43816 and ATCC 13883. Binding reactions were conducted using β-lactam concentrations from 0.0075 to 256 mg/liter (or 128 mg/liter). After β-lactam exposure, unbound PBPs were labeled by Bocillin FL. Binding affinities (50% inhibitory concentrations [IC]) were reported as the β-lactam concentrations that half-maximally inhibited Bocillin FL binding. PBP occupancy patterns by β-lactams were consistent across both strains. Carbapenems bound to all PBPs, with PBP2 and PBP4 as the highest-affinity targets (IC, <0.0075 mg/liter). Preferential PBP2 binding was observed by mecillinam (amdinocillin; IC, <0.0075 mg/liter) and avibactam (IC, 2 mg/liter). Aztreonam showed high affinity for PBP3 (IC, 0.06 to 0.12 mg/liter). Ceftazidime bound PBP3 at low concentrations (IC, 0.06 to 0.25 mg/liter) and PBP1a/b at higher concentrations (4 mg/liter), whereas cefepime bound PBPs 1 to 4 at more even concentrations (IC, 0.015 to 2 mg/liter). These PBP binding data on a comprehensive set of 13 clinically relevant β-lactams and β-lactamase inhibitors in enable, for the first time, the rational design and optimization of double β-lactam and β-lactam-β-lactamase inhibitor combinations.
Acinetobacter baumannii is emerging with resistance to polymyxins. In 24-h time-kill experiments, high-dose ampicillin-sulbactam in combination with meropenem and polymyxin B achieved additivity or synergy against 10 8 CFU/ml of two clinical A. baumannii isolates resistant to all three drugs (maximum reductions, 1.6 and 3.1 logs). In a 14-day hollow-fiber infection model, high-dose ampicillinsulbactam (8/4 g every 8 h, respectively) in combination with meropenem (2 g every 8 h) and polymyxin B (1.43 mg/kg of body weight every 12 h with loading dose) resulted in rapid (96 h) eradication of A. baumannii. KEYWORDS Acinetobacter, antibiotic resistance, antimicrobial combinations, meropenem, polymyxins, sulbactam, synergism A cinetobacter baumannii is a troubling nosocomial pathogen with an exceptional propensity for acquiring resistance mechanisms against commonly used antimicrobials (1). Although carbapenems have traditionally been the drug of choice for treating A. baumannii infection, enzyme-mediated hydrolysis of carbapenems has forced clinicians to utilize polymyxins as a drug of last resort against extensively drug-resistant A. baumannii (2, 3). Unfortunately, the emergence of A. baumannii strains resistant to polymyxins has prompted the search for novel dosing schemes and combination regimens that overcome such extreme levels of drug resistance (4-6).One proposed strategy for combating drug resistance in A. baumannii is the use of high-dose ampicillin-sulbactam regimens that have been evaluated in exploratory clinical studies (7,8). The combination of ampicillin-sulbactam with a carbapenem and a polymyxin has also demonstrated a promising mortality benefit against colistinresistant A. baumannii (9); however, the pharmacodynamics of high-dose ampicillinsulbactam alone and in combination with other agents has yet to be fully defined. In the present study, time-kill experiments were utilized to investigate the level of killing by high-dose ampicillin-sulbactam, meropenem, and polymyxin B alone and in double/ triple combinations against A. baumannii resistant to each of these antibiotics based on MIC testing. A hollow-fiber infection model (HFIM) was subsequently used to fully define the time course of A. baumannii killing over 14 days.
To combat polymyxin-resistant A. baumannii , the triple combination of polymyxin B, meropenem and ampicillin/sulbactam holds great promise.
There is a great need for efficacious therapies against Gram-negative bacteria. Double -lactam combination(s) (DBL) are relatively safe, and preclinical data are promising; however, their clinical role has not been well defined. We conducted a metaanalysis of the clinical and microbiological efficacy of DBL compared to -lactam plus aminoglycoside combinations (BLAG). PubMed, Embase, ISI Web of Knowledge, and Cochrane Controlled Trials Register database were searched through July 2018. We included randomized controlled clinical trials that compared DBL with BLAG combinations. Clinical response was used as the primary outcome and microbiological response in Gram-negative bacteria as the secondary outcome; sensitivity analyses were performed for Pseudomonas aeruginosa, Klebsiella spp., and Escherichia coli. Heterogeneity and risk of bias were assessed. Safety results were classified by systems and organs. Thirteen studies evaluated 2,771 cases for clinical response and 665 cases for microbiological response in various Gram-negative species. DBL achieved slightly, but not significantly, better clinical response (risk ratio, 1.05; 95% confidence interval [CI], 0.99 to 1.11) and microbiological response in Gram-negatives (risk ratio, 1.11; 95% CI, 0.99 to 1.25) compared with BLAG. Sensitivity analyses by pathogen showed the same trend. No significant heterogeneity across studies was found. DBL was significantly safer than BLAG regarding renal toxicity (6.6% versus 8.8%, P ϭ 0.0338) and ototoxicity (0.7 versus 3.1%, P ϭ 0.0137). Other adverse events were largely comparable. Overall, empirically designed DBL showed comparable clinical and microbiological responses across different Gramnegative species, and were significantly safer than BLAG. Therefore, DBL should be rationally optimized via the latest translational approaches, leveraging mechanistic insights and newer -lactams for future evaluation in clinical trials.
Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently, there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potentials of the approved broad-spectrum antiviral agents favipiravir (FAV), interferon alpha (IFN), and ribavirin (RBV) as single agents and in combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for 4 days. Supernatants were harvested daily, and the viral burden was quantified by a plaque assay on Vero cells. The time course of the viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model, which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing the viral burden by 4.4 log 10 PFU/ml at concentrations of 250 M FAV and 100 IU/ml IFN. Importantly, these concentrations are achievable in humans. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burdens in humans, resulting in at least a 10,000-fold reduction in the amount of the virus during the first 4 days of treatment. These findings highlight the substantial promise of rationally optimized combination dosage regimens of FAV plus IFN, which should be further investigated to combat ZIKV.
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