dWe recently investigated the pharmacokinetics-pharmacodynamics (PK-PD) of tazobactam in combination with ceftolozane against an isogenic CTX-M-15-producing Escherichia coli triplet set, genetically engineered to transcribe different levels of bla CTX-M-15 . The percentage of the dosing interval that tazobactam concentrations remained above a threshold (%Time>threshold) was identified as the PK-PD exposure measure that was most closely associated with efficacy. Moreover, the tazobactam concentration was dependent upon the enzyme transcription level. Given that the aforementioned strains were genetically engineered to transcribe a single ␤-lactamase enzyme and that clinical isolates typically produce multiple ␤-lactamase enzymes with various transcription levels, it is likely that the tazobactam threshold concentration is isolate/enzyme dependent. Our first objective was to characterize the relationship between the tazobactam %Time>threshold in combination with ceftolozane and efficacy using clinical isolates in an in vitro PK-PD infection model. Our second objective was to identify a translational relationship that would allow for the comodeling across clinical isolates. The initial challenge panel included four well-characterized ␤-lactamase-producing E. coli strains with variable enzyme expression and other resistance determinants. As evidenced by r 2 values of ranging from 0.90 to 0.99 for each clinical isolate, the observed data were well described by fitted functions describing the relationship between the tazobactam %Time>threshold and change in log 10 CFU from baseline; however, the data from the four isolates did not comodel well. The threshold concentration identified for each isolate ranged from 0.5 to 4 mg/liter. We identified an enabling translational relationship for the tazobactam threshold that allowed comodeling of all four clinical isolates, which was the product of the individual isolate's ceftolozane-tazobactam MIC value and 0.5. As evidenced by an r 2 value of 0.90, the transformed data were well described by a fitted function describing the relationship between tazobactam %Time>threshold and change in log 10 CFU from baseline. Due to these findings, the challenge panel was expanded to include three well-characterized ␤-lactamase-producing Klebsiella pneumoniae strains with variable enzyme expression and other resistance determinants. The translational relationship for the tazobactam threshold that allowed for the comodeling of the four E. coli isolates performed well for the expanded data set (seven isolates in total; four E. coli and three K. pneumoniae), as evidenced by an r 2 value of 0.84. This simple translational relationship is especially useful as it is directly linked to in vitro susceptibility test results, which are used to guide the clinician's choice of drug and dosing regimen.

Background The nine-valent human papillomavirus (9vHPV) vaccine protects against infection and disease related to HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58. The pivotal 36-month Phase III immunogenicity study of 9vHPV vaccine in 9- to 15-year-old girls and boys was extended to assess long-term immunogenicity and effectiveness through approximately 10 years after vaccination. We describe results of an interim analysis based on approximately 8 years of follow-up after vaccination. Methods Participants aged 9–15 years who received three doses of 9vHPV vaccine (at day 1, month 2, and month 6) in the base study and consented to follow-up were enrolled in the long-term follow-up study extension (N = 1272 [females, n = 971; males, n = 301]). Serum was collected at months 66 and 90 to assess antibody responses. For effectiveness analysis, genital swabs were collected (to assess HPV DNA by polymerase chain reaction [PCR]) and external genital examination was conducted (to detect external genital lesions) every 6 months starting when the participant reached 16 years of age. Cervical cytology tests were conducted annually when female participants reached 21 years of age; participants with cytological abnormalities were triaged to colposcopy based on a protocol-specified algorithm. External genital and cervical biopsies of abnormal lesions were performed, and histological diagnoses were adjudicated by a pathology panel. Specimens were tested by PCR to detect HPV DNA. Results Geometric mean titers for each 9vHPV vaccine HPV type peaked around month 7 and gradually decreased through month 90. Seropositivity rates remained >90% through month 90 for each of the 9vHPV vaccine types by HPV immunoglobulin Luminex Immunoassay. No cases of HPV6/11/16/18/31/33/45/52/58-related high-grade intraepithelial neoplasia or genital warts were observed in the per-protocol population (n = 1107) based on a maximum follow-up of 8.2 years (median 7.6 years) post-Dose 3. Incidence rates of HPV6/11/16/18/31/33/45/52/58-related 6-month persistent infection in females and males were 49.2 and 37.3 per 10,000 person-years, respectively, which were within ranges expected in vaccinated cohorts. There were no vaccine-related SAEs or deaths during the period covered by this interim analysis. Conclusions The 9vHPV vaccine provided sustained immunogenicity and durable effectiveness through approximately 7 and 8 years, respectively, following vaccination of girls and boys aged 9–15 years.

c Fosfomycin, a phosphonic class antibiotic with a broad spectrum of antibacterial activity, has been used outside the United States since the early 1970s for the treatment of a variety of infections. In the United States, an oral (tromethamine salt) formulation is used for uncomplicated urinary tract infections. Recently, there has been interest in the use of an intravenous solution (ZTI-01) for the treatment of a broad range of infections associated with multidrug-resistant bacteria. In this era of multidrugresistant bacteria with few treatment options, it is critical to understand the pharmacokinetic-pharmacodynamic (PK-PD) determinants for fosfomycin efficacy. Since such data are limited, a one-compartment in vitro infection model was used to determine the PK-PD index associated with efficacy and the magnitude of this measure necessary for various levels of effect. One challenge isolate (Escherichia coli ATCC 25922, for which the fosfomycin agar MIC is 0.5 mg/liter and the broth microdilution MIC is 1 mg/liter) was evaluated in the dose fractionation studies, and two additional clinical E. coli isolates were evaluated in the doseranging studies. Mutation frequency studies indicated the presence of an inherently fosfomycin resistant E. coli subpopulation (agar MIC ‫؍‬ 32 to 64 mg/liter) within the standard starting inoculum of a susceptibility test. Due to the presence of this resistant subpopulation, we identified the percentage of the dosing interval that drug concentrations were above the inherent resistance inhibitory concentration found at baseline to be the PK-PD index associated with efficacy (r 2 ‫؍‬ 0.777). The magnitudes of this PK-PD index associated with net bacterial stasis and 1-and 2-log 10 CFU/ml reductions from baseline at 24 h were 11.9, 20.9, and 32.8, respectively. These data provide useful information for modernizing and optimizing ZTI-01 dosing regimens for further study. In 1969, Hendlin and colleagues reported the discovery of phosphonomycin (later renamed fosfomycin) in a Streptomyces fradiae culture (1). Fosfomycin antibacterial activity is dependent upon its entry into the cell through the L-alpha-glycerophosphate transport and hexose monophosphate systems, which are glucose-6-phosphate dependent (2). Once it is inside the bacterial cell, fosfomycin inhibits peptidoglycan synthesis by the inactivation of UDP-N-acetylglucosamine-3-enolpyruvyltransferase (MurA) (3). Through this mechanism of action, fosfomycin has a broad spectrum of in vitro activity against a variety of clinically important Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, and Gram-negative pathogens, including extended-spectrum-␤-lactamase (ESBL)-producing members of the family Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae (CRE) (4, 5).While oral fosfomycin has long been utilized as single-dose therapy for uncomplicated urinary tract infections (6), there has been considerable recent interest in the use of this agent in both intravenous (IV) and oral formulations for t...

dIt is important to understand the relationship between antibiotic exposure and the selection of drug resistance in the context of therapy exposure. We sought to identify the ceftolozane-tazobactam exposure necessary to prevent the amplification of drugresistant bacterial subpopulations in a hollow-fiber infection model. Two Pseudomonas aeruginosa challenge isolates were selected for study, a wild-type ATCC strain (ceftolozane-tazobactam MIC, 0.5 mg/liter) and a clinical isolate (ceftolozane-tazobactam MIC, 4 mg/liter). The experiment duration was 10 days, and the ceftolozane-tazobactam dose ratio (2:1) and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The studied ceftolozane-tazobactam dosing regimens ranged from 62.5/31.25 to 2,000/1,000 mg per dose in step fold dilutions. Negative-control arms included no treatment and tazobactam at 500 mg every 8 h. Positive-control arms included ceftolozane at 1 g every 8 h and piperacillin-tazobactam dosed at 4.5 g every 6 h. For the wild-type ATCC strain, resistance was not selected by any ceftolozane-tazobactam regimen evaluated. For the clinical isolate, an inverted-U-shaped function best described the relationship between the amplification of a drug-resistant subpopulation and drug exposure. The least (62.5/31.25 mg) and most (2,000/1,000 mg) intensive ceftolozane-tazobactam dosing regimens did not select for drug resistance. Drug resistance selection was observed with intermediately intensive dosing regimens (125/62.5 through 1,000/500 mg). For the intermediately intensive ceftolozane-tazobactam dosing regimens, the duration until the selection for drug resistance increased with dose regimen intensity. These data support the selection of ceftolozanetazobactam dosing regimens that minimize the potential for on-therapy drug resistance selection.

dIn an era of rapidly emerging antimicrobial-resistant bacteria, it is critical to understand the importance of the relationships among drug exposure, duration of therapy, and selection of drug resistance. Herein we describe the results of studies designed to determine the ceftolozane-tazobactam exposure necessary to prevent the amplification of drug-resistant bacterial subpopulations in a hollow-fiber infection model. The challenge isolate was a CTX-M-15-producing Escherichia coli isolate genetically engineered to transcribe a moderate level of bla CTX-M-15 . This organism's bla CTX-M-15 transcription level was confirmed by relative quantitative reverse transcription-PCR (qRT-PCR), ␤-lactamase hydrolytic assays, and a ceftolozane MIC value of 16 mg/liter. In these studies, the experimental duration (10 days), ceftolozane-tazobactam dose ratio (2:1), and dosing interval (every 8 h) were selected to approximate those expected to be used clinically. The ceftolozane-tazobactam doses studied ranged from 125-62.5 to 1,500-750 mg. Negative-and positive-control arms included no treatment and piperacillin-tazobactam at 4.5 g every 6 h, respectively. An inverted-U-shaped function best described the relationship between bacterial drug resistance amplification and drug exposure. The least-and most-intensive ceftolozane-tazobactam dosing regimens, i.e., 125-62.5, 750-375, 1,000-500, and 1,500-750 mg, did not amplify drug resistance, while drug resistance amplification was observed with intermediate-intensity dosing regimens (250-125 and 500-250 mg). For the intermediate-intensity ceftolozane-tazobactam dosing regimens, the drugresistant subpopulation became the dominant population by days 4 to 6. The more-intensive ceftolozane-tazobactam dosing regimens (750-375, 1,000-500, and 1,500-750 mg) not only prevented drug resistance amplification but also virtually sterilized the model system. These data support the selection of ceftolozane-tazobactam dosing regimens that minimize the potential for on-therapy drug resistance amplification.