As monotherapy, modified proline-rich antimicrobial peptides (PrAMPs) protect animals from experimental bacteremia in a dose-dependent manner. We evaluated the in vitro synergy of a modified PrAMP, A3-APO, a dimer, previously shown to inhibit the 70 kDa bacterial heat shock protein DnaK, with imipenem or colistin against two antibiotic-resistant pathogens; a carbapenemase-expressing Klebsiella pneumoniae strain K97/09 and Acinetobacter baumannii (ATCC BAA-1605). Combining antimicrobials resulted in synergy for PrAMP/colistin combination against both K. pneumoniae and A. baumannii (ΣFIC = 0.08 both) and additive activity for the A3-APO/imipenem combination against K. pneumoniae (ΣFIC = 0.53). Chex1-Arg20, (designated as ARV-1502 in preclinical development), the single chain PrAMP monomer of A3-APO, showed synergy with meropenem against a carbapenem-resistant uropathogenic Escherichia coli strain (ΣFIC = 0.38). In a murine bacteremia model using K97/09, A3-APO at 1 mg/kg demonstrated improved survival when co-administered with standard (10 mg/kg) or subtherapeutic (1 mg/kg) doses of colistin at 36 h (p < 0.05). Surprisingly, the survival benefit of A3-APO was augmented when the A3-APO dose was decreased by 50% to 0.5 mg/kg (p < 0.02) in conjunction with a subtherapeutic colistin dose (1 mg/kg). ARV-1502, as monotherapy demonstrated prolonged (>24 h) activity in a mouse Escherichia coli infection assay. Co-treatment with ARV-1502 and subtherapeutic doses of ceftazidime (150 mg/kg) was studied in a mouse model of melioidosis. ARV-1502 provided a 50% improvement in long-term (62 days) survival, but only at the lowest of 3 administered doses; survival advantage was demonstrated at 2.5 mg/kg but not at 5 or 10 mg/kg. The mortality benefit of combination therapies was not routinely accompanied by a parallel decline in blood or tissue bacterial counts in surviving animals, suggesting that the anti-infective activity of the host defense peptides (HDP) is broader than simply bacterial eradication. In fact, the hormetic effect observed in either animal models suggest that low dose HDP treatment may change the dominant mode of action in experimental bacteremia.
In vitro susceptibilities for 47 antibiotics were determined in 30 genetic diverse strains of Francisella tularensis by the broth microdilution method following Clinical and Laboratory Standards Institute (CLSI) methods. The F. tularensis strains demonstrated susceptibility to aminoglycosides, fluoroquinolones, and tetracyclines. There was a distinct difference in macrolide susceptibilities between A and B type strains, as has been noted previously. The establishment and comparison of antibiotic susceptibilities of a diverse but specific set of F. tularensis strains by standardized methods and the establishment of population ranges and MIC 50/90 values provide reference information for assessing new antibiotic agents and a baseline to monitor any future emergence of resistance, whether natural or intentional.KEYWORDS Francisella tularensis, antibiotics, susceptibility testing F rancisella tularensis is the causative agent of tularemia, a zoonotic infection in humans, usually transmitted as a result of contact with infected animals or insect bites (1). It also has potential misuse in biowarfare and bioterrorism (2). While the disease is not usually fatal, underlying medical conditions can lead to possibly fatal complications. Antibiotic therapy usually resolves the infection (1). The species is also divided into several biovars, based on metabolic differences, virulence, and geographic location (3). There is scattered information on MICs under a variety of nonstandardized testing conditions, with mostly type B (F. tularensis subsp. holarctica) strains (4-15). A more recent report utilizing standardized testing methods with a variety of North American type A strains (16) has provided some additional data; however, this study looked at only eight antibiotics representing five classes. With a lack of comparative data on type strains and with a variety of antibiotic classes, we report here specific antibiotic susceptibility results according to Clinical and Laboratory Standards Institute (CLSI) microdilution broth methodology for 30 strains of F. tularensis (17). This information will be highly useful as baseline data in the event of wartime or terrorist release, as well as for naturally acquired and laboratory-acquired infections.The F. tularensis strains used in this study are shown in Table 1, and they were obtained from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) collection and selected to represent the established biovars and geographic diversity (18). Most antibiotics were obtained from U.S. Pharmacopoeia (Rockville, MD), with the following exceptions: ceftriaxone and fusidic acid were from Sigma Chemical Co. (St. Louis, MO), cethromycin was from Advanced Life Sciences; telithromycin was from Sanofi-Aventis, garenoxacin was from Schering-Plough, gemifloxacin was from Oscient, ertapenem was from Merck, faropenem was from Replidyne, and tigecycline was from Wyeth. Most stock solutions (5 mg/ml) were prepared for each drug in the appropriate solvents, based on the current CLS...
Y ersinia pestis is the causative agent of plague, a rare infection in humans that usually appears in the bubonic form due to flea bites. Pneumonic plague is an infection of the respiratory tract which can be contagious and rapidly fatal. This form of plague has an incubation period of 3 to 5 days and a mortality rate near 100% (1, 2). Antibiotic intervention can offer relief but only if started very early in the infection (1). Because of the scattered information on MICs under a variety of nonstandardized testing conditions (3-6) and the lack of comparative data on type strains, we report specific antibiotic susceptibility results from use of the Clinical and Laboratory Standards Institute (CLSI) microdilution broth methodology for 30 strains of Y. pestis. This information will be highly useful as baseline data in the event of wartime or terrorist release and for natural and laboratory-acquired infections. MATERIALS AND METHODSThe Y. pestis strains used in this study (shown in Table 1) were obtained from the USAMRIID collection and selected to represent established biovars, genotypes, and isotypes (7,8). Most of the antibiotics were obtained from the U.S. Pharmacopoeia (Rockville, MD) except for ceftriaxone and fusidic acid (Sigma Chemical Co., St. Louis, Mo), cethromycin (Advanced Life Sciences), telithromycin (Sanofi-Aventis), garenoxacin (ScheringPlough), gemifloxacin (Oscient), ertapenem (Merck), faropenem (Replidyne), and tigecycline (Wyeth). Most of the stock solutions (5 mg/ml) were prepared for each drug in the appropriate solvents, based on the current CLSI recommendations (9), and stored until use at Ϫ70°C. The concentration of our amoxicillin-clavulanate (2:1) stock was 5 mg/2.5 mg per ml, and that of the co-trimoxazole stock was 5 mg/ml sulfamethoxazole and 0.26 mg/ml trimethoprim (19:1). The MICs were determined by the microdilution method in 96-well plates as previously described (10). Antibiotics were serially diluted 2-fold in 50 l of cation-adjusted Mueller-Hinton broth (CAMHB). The antibiotic range in the plates was 64 to 0.008 g/ml based on a final well volume of 100 l after inoculation. The inocula were prepared by picking several colonies from sheep blood agar (SBA) plates grown for 36 to 48 h at 28°C, suspended, and diluted with CAMHB to a bacterial cell density of 10 6 CFU/ml (conversion factor, 5 ϫ
The in vitro activity and in vivo efficacy of omadacycline (OMC) were evaluated against the causative pathogens of anthrax and plague, Bacillus anthracis and Yersinia pestis, respectively. MICs of OMC were determined by broth microdilution according to CLSI guidelines for 30 isolates each of Y. pestis and B. anthracis. The in vivo efficacy of omadacycline was studied at a range of dosages in both a postexposure prophylaxis (PEP) murine model of anthrax and plague as well as in a delayed treatment model of inhalational anthrax. Omadacycline was active in vitro against Y. pestis (MIC90 of 1 μg/ml) and B. anthracis (MIC90 of 0.06 μg/ml). Omadacycline was less active in vitro than ciprofloxacin (CIP) against Y. pestis (CIP MIC90 of 0.03 μg/ml) but was more potent in vitro against B. anthracis (CIP MIC90 of 0.12 μg/ml). In the mouse model of infection, the survival curves for all treatment cohorts differed significantly from the vehicle control (P = 0.004). The median survival for the vehicle-treated controls was 6 days postchallenge, while all antibiotic-treated mice survived the entire study. Omadacycline treatment with 5, 10, or 20 mg/kg of body weight twice daily for 14 days had significant efficacy over the vehicle control in the treatment of aerosolized B. anthracis. Additionally, for postexposure prophylaxis treatment of mice infected with Y. pestis, the survival curves for omadacycline (40 mg/kg twice daily), ciprofloxacin, and doxycycline cohorts differed significantly from the vehicle control (P < 0.0001). Omadacycline is potent and demonstrates efficacy against both B. anthracis and Y. pestis. The well-characterized oral and intravenous pharmacokinetics, safety, and tolerability warrant further assessment of the potential utility of omadacycline in combating these serious biothreat organisms.
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