Journal: Antimicrobial agents and chemotherapy
The recent discovery of a plasmid-borne colistin resistance gene, mcr-1, heralds the emergence of truly pan-drug resistant bacteria (1).….
The antimicrobial triclosan is used in a wide range of consumer products ranging from toothpaste, cleansers, socks, and baby toys. A bacteriostatic inhibitor of fatty acid synthesis, triclosan is extremely stable and accumulates in the environment. Approximately 75% of adults in the US have detectable levels of the compound in their urine, with a sizeable fraction of individuals (>10%) having urine concentrations equal to or greater than the minimal inhibitory concentration for Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). Previous work has identified connections between defects in fatty acid synthesis and accumulation of the alarmone guanosine tetraphosphate (ppGpp), which has been repeatedly associated with antibiotic tolerance and persistence. Based on these data, we hypothesized that triclosan exposure may inadvertently drive bacteria into a state in which they are able to tolerate normally lethal concentrations of antibiotics. Here we report that clinically relevant concentrations of triclosan increased E. coli and MRSA tolerance to bactericidal antibiotics as much as 10,000 fold in vitro and reduced antibiotic efficacy up to 100-fold in a mouse urinary tract infection model. Genetic analysis indicated that triclosan-mediated antibiotic tolerance requires ppGpp synthesis, but is independent of growth. These data highlight an unexpected and certainly unintended consequence of adding high concentrations of antimicrobials in consumer products, supporting an urgent need to reevaluate the costs and benefits of the prophylactic use of triclosan and other bacteriostatic compounds.
SCY-078 is an orally bioavailable ß-1,3-glucan synthesis inhibitor (GSI) and the first-in-class of structurally novel triterpine antifungals in clinical development for treating candidemia and invasive candidiasis. In vitro susceptibility by broth micro-dilution, antifungal carry-over, and time-kill dynamics were determined for 3 reference (ATCC) strains (C. albicans 90028, C. parapsilosis 90018, and C. tropicalis 750), a Quality Control (QC) strain (C krusei 6258), and 4 other strains (C. albicans MYA-2732, 64124, 76485 and C.glabrata 90030). Caspofungin (CASP), fluconazole (FLC), and voriconazole (VRC) were comparators. For time-kill experiments, SCY-078 and CASP were evaluated at 0.25, 1, 2, 4, 8, and 16x MIC80, and FLU and VORI were evaluated at 4x MIC80 The time to reach 50%, 90%, and 99.9% growth from starting innoculum was determined. Net change in CFU/mL was used to determine EC50, EC90, and Emax SCY-078 MIC range was between 0.0625 - 1 μg/mL and generally similar to CASP. Antifungal carryover was not observed for SCY-078. SCY-078 was fungicidal against 7 isolates at ≥4x MIC (kill ≥3log10) and achieved a 1.7 log10 reduction in CFUs/mL against C. albicans 90028. CASP behaved similarly against each isolate and achieved a 1.5 log10 reduction in CFUs/mL against C. albicans 90028. Reductions of 50% in CFUs/mL were achieved rapidly (1-2.8 h); fungicidal endpoints were reached at 12.1 - 21.8 h at ≥4x MIC. EC90 was reached at ∼5x MIC at each time point to 24 h. EC50 and EC90 were generally similar (8-24 h). Time-kill behavior of CASP was similar to SCY-078. FLC and VRC were fungistatic. Overall, SCY-078 has primarily fungicidal activity against Candida spp. and behaved comparably to CASP.
Multidrug resistance (MDR) plasmids frequently encode antibiotic resistance genes conferring qualitatively different mechanisms of resistance. We show that the antibiotic concentrations selecting for the RK2 plasmid in Escherichia coli depend upon the sociality of the drug resistance: Selection for a selfish drug resistance (efflux-pump) occurred at very low drug concentrations, just 1.3% of the sensitive’s MIC, whereas selection for a cooperative drug resistance (modifying-enzyme) occurred at drug concentrations exceeding the MIC of the plasmid-free strain.
Pathogenic Leptospira spp., the causative agents of leptospirosis, are slow-growing Gram-negative spirochetes. Isolation of Leptospira from clinical samples and testing of antimicrobial susceptibility are difficult and time-consuming. Here, we describe the development of a new solid medium that facilitates more-rapid growth of Leptospira spp. and the use of this medium to evaluate the Etest’s performance in determining antimicrobial MICs to drugs in common use for leptospirosis. The medium was developed by evaluating the effects of numerous factors on the growth rate of Leptospira interrogans strain NR-20157. These included the type of base agar, the concentration of rabbit serum (RS), and the concentration and duration of CO(2) incubation during the initial period of culture. The highest growth rate of NR-20157 was achieved using a Noble agar base supplemented with 10% RS (named LVW agar), with an initial incubation at 30°C in 5% CO(2) for 2 days prior to continuous culture in air at 30°C. These conditions were used to develop the Etest for three species, L. interrogans (NR-20161), L. kirschnerii (NR-20327), and L. borgpetersenii (NR-20151). The MICs were read on day 7 for all samples. The Etest was then performed on 109 isolates of pathogenic Leptospira spp. The MIC(90) values for penicillin G, doxycycline, cefotaxime, ceftriaxone, and chloramphenicol were 0.64 units/ml and 0.19, 0.047, 0.5, and 2 μg/ml, respectively. The use of LVW agar, which enables rapid growth, isolation of single colonies, and simple antimicrobial susceptibility testing for Leptospira spp., provides an opportunity for new areas of fundamental and applied research.
For its remarkable ability to acquire antibiotic resistance and to survive in nosocomial environments, Acinetobacter baumannii has become a significant nosocomial infectious agent worldwide. Tigecycline is one of the few therapeutic options to treat infections caused by A. baumannii isolates. However, tigecycline resistance has been increasingly reported. Our aim was to assess the prevalence and characteristics of efflux-based tigecycline resistance in clinical isolates of A. baumannii collected from a hospital in China. A total of 74 A. baumannii isolates including 64 tigecycline non-susceptible A. baumannii (TNAB) and 10 tigecycline susceptible A. baumannii (TSAB) isolates were analyzed. The majority of them were detected to be positive for adeABC, adeRS, adeIJK and abeM, while the adeE gene was found in only one TSAB isolate. Compared with TSAB isolates, the mean expression level of adeB, adeJ, adeG and abeM in TNAB isolates were observed to increase by 29-, 3-, 0.7- and 1-fold, respectively. The efflux pump inhibitors (EPIs) PAβN and carbonyl cyanide 3-chlorophenylhydrazone (CCCP) could partially reverse the resistance pattern of tigecycline. Moreover, tetX1 gene was detected in 12 (18.8%) TNAB isolates. To our knowledge, this is the first report that tetX1 gene was detected in the A. baumannii isolates. ST208 and ST191 which both clustered into clonal complex 92 (CC92) were the predominant sequence types (STs). This study showed that active efflux pump AdeABC appeared to play important roles in the tigecycline resistance of A. baumannii. The dissemination of TNAB isolates in our hospital is mainly attributable to the spread of CC92.
This study aimed to investigate the pharmacokinetics (PK), safety and tolerability of a single dose of ceftazidime-avibactam in pediatric patients.
This Phase I study assessed the intrapulmonary pharmacokinetic profiles of relebactam (MK-7655), a novel ß-lactamase inhibitor, and imipenem. Sixteen healthy subjects received 250 mg relebactam with 500 mg imipenem/cilastatin, given IV every 6 hours for 5 doses, and were randomized to bronchoscopy/broncho-alveolar lavage at 0.5, 1, 1.5, or 3 hours after the last dose (4 subjects per time point). Both drugs penetrated the epithelial lining fluid (ELF) to a similar degree, with profiles similar in shape to the corresponding plasma profiles and apparent terminal half-lives in plasma and ELF, respectively, of 1.2 and 1.3 hours for relebactam, and 1.0 hour in both compartments for imipenem. The relative exposure (AUC0-inf) in ELF:plasma was 54% for relebactam and 55% for imipenem, after adjusting for protein binding. ELF penetration for relebactam was further analyzed by fitting the data to a two-compartment pharmacokinetic model to capture behavior in the plasma, with a partitioning coefficient capturing behavior in the lung compartment. In this model, the time-invariant partition coefficient for relebactam was found to be 52% based on free drug levels. These results support further clinical evaluation of relebactam with imipenem/cilastatin for the treatment of bacterial pneumonia.
Widespread antibiotic use in clinical medicine and the livestock industry has contributed to the global spread of multidrug-resistant (MDR) bacterial pathogens, including Acinetobacter baumannii We report on a method used to produce a personalized bacteriophage-based therapeutic treatment for a 68-year old diabetic patient with necrotizing pancreatitis complicated by a MDR A. baumannii infection. Despite multiple antibiotic courses and efforts at percutaneous drainage of a pancreatic pseudocyst, the patient deteriorated over a four-month period. In the absence of effective antibiotics, two laboratories identified nine different bacteriophages with lytic activity for an A. baumannii isolate from the patient. Administration of these bacteriophages intravenously and percutaneously into the abscess cavities was associated with reversal of the patient’s downward clinical trajectory, clearance of the A. baumannii infection, and a return to health. The outcome of this case suggests that the methods described here for the production of bacteriophage therapeutics could be applied to similar cases and that more concerted efforts to investigate the use of therapeutic bacteriophages for MDR bacterial infections are warranted.
We present case histories of four patients treated with artemether-lumefantrine for falciparum malaria in UK hospitals in 2015-16. Each subsequently presented with recurrent symptoms and Plasmodium falciparum parasitaemia within 6 weeks of treatment with no intervening travel to malarious countries. Parasite isolates, all of African origin, harboured variants at some candidate resistance loci. No evidence of pfk13-mediated artemisinin resistance was found. Vigilance for signs of unsatisfactory antimalarial efficacy among imported cases of malaria is recommended.