Assessment of Antimicrobial Activity of Dehydrated Amniotic Membrane in Infectious Keratitis: A Small Retrospective Case Series and In Vitro Study.

PURPOSE: To describe a small case series of infectious keratitis with poor visual outcomes after amniotic membrane (AM) placement and to prospectively evaluate whether AM demonstrates antibacterial activity in vitro against pathogens commonly isolated from infectious corneal ulcers. METHODS: A retrospective case series and in vitro study of antibacterial activity of dehydrated AM using disk diffusion and measurement of inhibitory zones for bacterial assessment and inverted microscopy analysis for Acanthamoeba sp. growth. RESULTS: Three cases of known etiology infectious keratitis are described where the clinical presentation worsened after treatment with AM. In vitro analysis of dehydrated AM, with and without a soft contact lens, demonstrated no inhibition of growth against Pseudomonas aeruginosa or Streptococcus pneumoniae. There was minimal growth inhibition of Staphylococcus aureus, although these zones of inhibition were much smaller than that surrounding the positive control. For Acanthamoeba sp., solubilized, dehydrated AM did not alter cyst density. CONCLUSIONS: In an in vitro analysis, dehydrated AM did not provide evidence for a potentially clinically meaningful antibacterial effect against organisms commonly isolated from corneal ulcers.

The impact and cost-effectiveness of introducing the 10-valent pneumococcal conjugate vaccine into the paediatric immunisation programme in Iceland-A population-based time series analysis.

INTRODUCTION: Streptococcus pneumoniae is a cause of infections that range in severity from acute otitis media (AOM) to pneumonia and invasive pneumococcal disease (IPD). The 10-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic paediatric immunisation programme in 2011. The aim was to estimate the population impact and cost-effectiveness of PHiD-CV10 introduction. METHODS: Data on primary care visits from 2005-2015 and hospitalisations from 2005-2017 were obtained from population-based registries. A Bayesian time series analysis with synthetic controls was employed to estimate the number of cases of AOM, pneumonia and IPD that would have occurred between 2013-2017, had PHiD-CV10 not been introduced. Prevented cases were calculated by subtracting the observed number of cases from this estimate. The cost of the programme was calculated accounting for cost-savings due to prevented cases. RESULTS: The introduction of PHiD-CV10 prevented 13,767 (95% credible interval [CI] 2,511-29,410) visits for AOM from 2013-2015, and prevented 1,814 (95%CI -523-4,512) hospitalisations for pneumonia and 53 (95%CI -17-177) admissions for IPD from 2013-2017. Visits for AOM decreased both among young children and among children 4-19 years of age, with rate ratios between 0.72-0.89. Decreases were observed in both pneumonia hospitalisations (rate ratios between 0.67-0.92) and IPD (rate ratios between 0.27-0.94). The total cost of implementing PHiD-CV10 in Iceland was -7,463,176 United States Dollars (USD) (95%CI -16,159,551-582,135) with 2.1 USD (95%CI 0.2-4.7) saved for every 1 USD spent. CONCLUSIONS: The introduction of PHiD-CV10 was associated with large decreases in visits and hospitalisations for infections commonly caused by pneumococcus and was cost-saving during the first five years of the immunisation programme.

Serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae associated with invasive pneumococcal disease among adults in Japan.

OBJECTIVES: This study evaluated the serotype distribution and antimicrobial susceptibility of Streptococcus pneumoniae isolates from adults (aged ≥20 years) with invasive pneumococcal disease (IPD) in Japan. METHODS: This prospective observational study was conducted in 49 participating Japanese hospitals. S. pneumoniae isolates were serotyped and tested for antimicrobial susceptibility at a central laboratory. Information regarding patient characteristics, underlying disease, IPD clinical syndromes, and treatment was collected through medical chart review. RESULTS: The final analysis included 177 patients enrolled from 45 hospitals between September 2016 and April 2018 (bacteraemic pneumonia, 110; bacteraemia without identified focus, 29; meningitis, 19). Most patients (70.1%) were aged ≥65 years and most had underlying disease (79.1%). The proportion of isolates from serotypes contained in the pneumococcal polysaccharide vaccine (PPV) 23 was 61.0%, while those in the pneumococcal conjugate vaccine (PCV) 7 and PCV13 were 2.8% and 28.2%, respectively. Non-vaccine serotypes accounted for 37.9% of all isolates and 50.8% of isolates from immunosuppressed patients. Serotype 12F was the most common vaccine serotype, followed by serotype 3. CONCLUSIONS: The continued disease burden of IPD in adults in Japan warrants improved vaccination rates and development of next-generation vaccines that include serotypes not currently covered. CLINICAL TRIAL REGISTRATION: Clinical trial summary registration number 160,822,918,146; JapicCTI-163352.

Pneumococcal disease in Thailand.

This review examines the epidemiology of pneumococcal disease, serotype prevalence, antibiotic resistance, and national vaccination recommendations in Thailand. The incidence of invasive pneumococcal disease (IPD) and annualized hospitalization rates for pneumococcal bacteremia in Thailand were highest in children aged <5years and the elderly. The most prevalent serotype is serotype 6B, which is included in both the 10- and 13-valent pneumococcal conjugate vaccines (PCV10 [also known as PHiD-CV] and PCV13, respectively) registered in Thailand. Other common serotypes are 14, 18C, 19F, and 23F (included in both PCVs) and 6A and 19A (only included in PCV13). PCV10/PHiD-CV and PCV13 should cover 48.8%-74% and 73.2%-92% of isolates among children aged ≤5 years, respectively, and 40.0%-47.9% and 58.3%-60.9% of isolates among adults aged ≥65 years. Only PCV13 is licensed for adults in Thailand. Pneumococcal isolates were most commonly resistant to erythromycin, cefuroxime, and penicillin. Despite their demonstrated cost effectiveness and efficacy in reducing nasopharyngeal carriage and IPD, PCVs are not included in the Thai national immunization program. The serotype-specific IPD incidence in Thailand suggests that PCVs will reduce the disease burden in all age groups, but particularly in children and older adults.

Identification of biomarkers for the accurate and sensitive diagnosis of three bacterial pneumonia pathogens using in silico approaches.

BACKGROUND: Pneumonia ranks as one of the main infectious sources of mortality among kids under 5 years of age, killing 2500 a day; late research has additionally demonstrated that mortality is higher in the elderly. A few biomarkers, which up to this point have been distinguished for its determination lack specificity, as these biomarkers fail to build up a differentiation between pneumonia and other related diseases, for example, pulmonary tuberculosis and Human Immunodeficiency Infection (HIV). There is an inclusive global consensus of an improved comprehension of the utilization of new biomarkers, which are delivered in light of pneumonia infection for precision identification to defeat these previously mentioned constraints. Antimicrobial peptides (AMPs) have been demonstrated to be promising remedial specialists against numerous illnesses. This research work sought to identify AMPs as biomarkers for three bacterial pneumonia pathogens such as Streptococcus pneumoniae, Klebsiella pneumoniae, Acinetobacter baumannii using in silico technology. Hidden Markov Models (HMMER) was used to identify putative anti-bacterial pneumonia AMPs against the identified receptor proteins of Streptococcus pneumoniae, Klebsiella pneumoniae, and Acinetobacter baumannii. The physicochemical parameters of these putative AMPs were computed and their 3-D structures were predicted using I-TASSER. These AMPs were subsequently subjected to docking interaction analysis against the identified bacterial pneumonia pathogen proteins using PATCHDOCK. RESULTS: The in silico results showed 18 antibacterial AMPs which were ranked based on their E values with significant physicochemical parameters in conformity with known experimentally validated AMPs. The AMPs also bound the pneumonia receptors of their respective pathogens sensitively at the extracellular regions. CONCLUSIONS: The propensity of these AMPs to bind pneumonia pathogens proteins justifies that they would be potential applicant biomarkers for the recognizable detection of these bacterial pathogens in a point-of-care POC pneumonia diagnostics. The high sensitivity, accuracy, and specificity of the AMPs likewise justify the utilization of HMMER in the design and discovery of AMPs for disease diagnostics and therapeutics.

In Vivo Pharmacodynamic Target Assessment of Antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in a Neutropenic Murine Pneumonia Model.

We determined in vivo efficacy and target PK/PD exposures of antofloxacin against Streptococcus pneumoniae and Staphylococcus aureus in the murine pneumonia model. The mean plasma free drug area under the concentration-time curve/MIC (fAUC/MIC) targets associated with stasis and 1-log10 and 2-log10 kill effects were 8.93, 19.2, and 48.1, respectively, for S. pneumoniae, whereas they were 30.5, 55.4, and 115.8, respectively, for S. aureus The fAUC/MIC targets in murine lung epithelial lining fluids (ELF) for the same endpoints were nearly 2-fold higher than those in plasma.

Cefuroxime pharmacokinetics and pharmacodynamics for intravenous dosage regimens with 750 mg or 1500 mg doses in healthy young volunteers.

Introduction. Cefuroxime is an important antibiotic to treat several serious infections. Rapid elimination through the kidneys and the variation in MICs of various susceptible pathogens such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus and Streptococcus pneumoniae give rise to dosing issues, especially in otherwise healthy patients.Aim. To investigate the probability of target attainment (PTA) for obtaining the optimal dosage regimens for cefuroxime in healthy young people.Methodology. Two weeks apart 750 and 1500 mg cefuroxime were administered as an intravenous bolus to 20 healthy volunteers (mean age: 27 years). Population modelling and simulation studies were done based on the obtained data for cefuroxime plasma concentration.Results. With a target value of time above MIC (T >MIC) greater than 50 % the simulations revealed that a PTA of >99 % is obtained for S. pneumoniae with a dosage regimen of 750 mg q12h. For E. coli and K. pneumoniae the PTA was <90 % even with the highest, simulated dosage of 1500 mg q6h. For S. aureus a dosage of 1500 mg q8h gave a PTA above 97 %.Conclusions. S. pneumoniae is most likely treatable with a two-daily dose of 750 mg cefuroxime. Not treatable are K. pneumoniae and E. coli. For S. aureus 1500 mg q8h constitutes an optimal dosing schedule.

International prevalence and risk factors evaluation for drug-resistant Streptococcus pneumoniae pneumonia.

OBJECTIVE: Streptococcus pneumoniae is the most frequent bacterial pathogen isolated in subjects with Community-acquired pneumonia (CAP) worldwide. Limited data are available regarding the current global burden and risk factors associated with drug-resistant Streptococcus pneumoniae (DRSP) in CAP subjects. We assessed the multinational prevalence and risk factors for DRSP-CAP in a multinational point-prevalence study. DESIGN: The prevalence of DRSP-CAP was assessed by identification of DRSP in blood or respiratory samples among adults hospitalized with CAP in 54 countries. Prevalence and risk factors were compared among subjects that had microbiological testing and antibiotic susceptibility data. Multivariate logistic regressions were used to identify risk factors independently associated with DRSP-CAP. RESULTS: 3,193 subjects were included in the study. The global prevalence of DRSP-CAP was 1.3% and continental prevalence rates were 7.0% in Africa, 1.2% in Asia, and 1.0% in South America, Europe, and North America, respectively. Macrolide resistance was most frequently identified in subjects with DRSP-CAP (0.6%) followed by penicillin resistance (0.5%). Subjects in Africa were more likely to have DRSP-CAP (OR: 7.6; 95%CI: 3.34-15.35, p<0.001) when compared to centres representing other continents. CONCLUSIONS: This multinational point-prevalence study found a low global prevalence of DRSP-CAP that may impact guideline development and antimicrobial policies.

Resistance proportions for eight priority antibiotic-bacterium combinations in OECD, EU/EEA and G20 countries 2000 to 2030: a modelling study.

BackgroundAntimicrobial resistance is widely considered an urgent global health issue due to associated mortality and disability, societal and healthcare costs.AimTo estimate the past, current and projected future proportion of infections resistant to treatment for eight priority antibiotic-bacterium combinations from 2000 to 2030 for 52 countries.MethodsWe collated data from a variety of sources including ResistanceMap and World Bank. Feature selection algorithms and multiple imputation were used to produce a complete historical dataset. Forecasts were derived from an ensemble of three models: exponential smoothing, linear regression and random forest. The latter two were informed by projections of antibiotic consumption, out-of-pocket medical spending, populations aged 64 years and older and under 15 years and real gross domestic product. We incorporated three types of uncertainty, producing 150 estimates for each country-antibiotic-bacterium-year.ResultsAverage resistance proportions across antibiotic-bacterium combinations could grow moderately from 17% to 18% within the Organisation for Economic Co-operation and Development (OECD; growth in 64% of uncertainty sets), from 18% to 19% in the European Union/European Economic Area (EU/EEA; growth in 87% of uncertainty sets) and from 29% to 31% in Group of Twenty (G20) countries (growth in 62% of uncertainty sets) between 2015 and 2030. There is broad heterogeneity in levels and rates of change across countries and antibiotic-bacterium combinations from 2000 to 2030.ConclusionIf current trends continue, resistance proportions are projected to marginally increase in the coming years. The estimates indicate there is significant heterogeneity in resistance proportions across countries and antibiotic-bacterium combinations.

Population Pharmacokinetics of Doripenem in Pediatric Patients and Monte-Carlo Pharmacokinetic-Pharmacodynamic Simulations for Dosing Regimen Assessment.

The aims of this study were to evaluate the pharmacokinetics of doripenem (Finibax®, Doribax®, S-4661), a parenteral carbapenem antibiotic, in pediatric patients based on concentrations of doripenem in plasma after administration of 20 mg/kg 2 or 3 times daily and to evaluate the dosing regimens by using Monte-Carlo pharmacokinetic-pharmacodynamic simulations. Population pharmacokinetic analysis was performed by using 190 plasma concentrations of doripenem from 99 patients (2 months-13 years old). The two-compartment model well described the doripenem plasma concentrations in pediatric patients. Body weight was found to be the most significant influential factor. Gender was also found to be a significant covariate although the effect was relatively small. Monte-Carlo simulations indicated that 20 mg/kg over 1 h infusion would give 90% probability of target attainment for 40% of time above minimum inhibitory concentration against Haemophilus influenzae and Streptococcus pneumoniae, major causative pathogens in pediatric infections, and that 40 mg/kg, the highest approved dose for Japanese pediatric patients, administered over 3 h infusion achieved 98.6% against 8 µg/mL. The developed population pharmacokinetic model of doripenem and Monte-Carlo simulations for pediatric patients should provide useful information for understanding the pharmacokinetic and pharmacokinetic-pharmacodynamic characteristics of doripenem and for optimal treatment of pediatric patients.

Pharmacokinetic/pharmacodynamic target attainment analyses to support intravenous and oral lefamulin dose selection for the treatment of patients with community-acquired bacterial pneumonia.

OBJECTIVES: Lefamulin is a semi-synthetic intravenous (iv) and oral pleuromutilin antibiotic active against community-acquired bacterial pneumonia (CABP) pathogens. Pharmacokinetic/pharmacodynamic (PK/PD) target attainment analyses were carried out to evaluate lefamulin 150 mg iv q12h and 600 mg orally q12h under fed and fasted conditions for the treatment of patients with CABP. METHODS: The analyses undertaken used a population PK model based on Phase 1 PK data, non-clinical PK/PD targets for efficacy and in vitro surveillance data for Streptococcus pneumoniae (SP) and Staphylococcus aureus (SA), and Monte Carlo simulation. Percentage probabilities of PK/PD target attainment by MIC on day 1 were determined using median total-drug epithelial lining fluid (ELF) and free-drug plasma AUC:MIC ratio targets associated with 1 and 2 log10 cfu reductions from baseline. RESULTS: Percentage probabilities of attaining the total-drug ELF AUC:MIC ratio target for a 1 log10 cfu reduction from baseline for SP were ≥99.2% at the MIC90 of 0.12 mg/L and 96.7%, 82.1% and 96.3% for iv and oral dosing regimens under fed and fasted conditions, respectively, at the MIC99 of 0.25 mg/L. Percentage probabilities of attaining the free-drug plasma AUC:MIC target for the same endpoint at the SP MIC99 were 100% for each regimen. For the SA MIC90 of 0.12 mg/L and AUC:MIC ratio targets for the same endpoint, percentage probabilities were 92.7%-100% for iv and oral dosing regimens. CONCLUSIONS: These data provide support for lefamulin 150 mg iv q12h and 600 mg orally q12h for the treatment of patients with CABP and suggest that doses may not need to be taken under fasted conditions.

Application of pharmacokinetic/pharmacodynamic analysis to evaluate the adequacy of antimicrobial therapy for pediatric acute otitis media in Spain before and after the introduction of the PCV7 vaccine.

OBJECTIVE: To evaluate, by applying pharmacokinetic/pharmacodynamic (PK/PD) analysis, if the change in antibiotic susceptibility after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in Spain had any influence on the usefulness of the antimicrobials more frequently used as empirical treatment of pediatric acute otitis media (AOM). METHODS: PK parameters and susceptibility of Streptococcus pneumoniae and Haemophilus influenzae were obtained from bibliography. Monte Carlo simulation was used to estimate the cumulative fraction of response (CFR), understood as the expected probability of therapy success. For amoxicillin and amoxicillin/clavulanate, the target was free antibiotic concentration remaining above the minimum inhibitory concentration (MIC) for ≥50% of the dosing interval (fT>MIC≥50%), whereas for cefuroxime axetil and cefotaxime, the target was fT>MIC≥60%. CFR values ≥90% were considered successful. RESULTS: When all serotypes of S. pneumoniae are considered, amoxicillin and cefotaxime turned out to reach a high probability of success, and difference before and after vaccination was scarce. For H. influenzae, CFR values were higher with amoxicillin/clavulanate than with amoxicillin. For both microorganisms, cefuroxime axetil resulted in low probability of success in the two periods of study. CONCLUSIONS: We have shown that the introduction of the PCV7 vaccination did not lead to changes in the probability of success of the current empiric treatments of the AOM. Integrated PK/PD analysis has demonstrated to be a useful tool to identify changes in antimicrobial activity after the implantation of a vaccination program, providing complementary information to the simple assessment of MIC values.

Investigating the impact of poverty on colonization and infection with drug-resistant organisms in humans: a systematic review.

BACKGROUND: Poverty increases the risk of contracting infectious diseases and therefore exposure to antibiotics. Yet there is lacking evidence on the relationship between income and non-income dimensions of poverty and antimicrobial resistance. Investigating such relationship would strengthen antimicrobial stewardship interventions. METHODS: A systematic review was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Ovid, MEDLINE, EMBASE, Scopus, CINAHL, PsychINFO, EBSCO, HMIC, and Web of Science databases were searched in October 2016. Prospective and retrospective studies reporting on income or non-income dimensions of poverty and their influence on colonisation or infection with antimicrobial-resistant organisms were retrieved. Study quality was assessed with the Integrated quality criteria for review of multiple study designs (ICROMS) tool. RESULTS: Nineteen articles were reviewed. Crowding and homelessness were associated with antimicrobial resistance in community and hospital patients. In high-income countries, low income was associated with Streptococcus pneumoniae and Acinetobacter baumannii resistance and a seven-fold higher infection rate. In low-income countries the findings on this relation were contradictory. Lack of education was linked to resistant S. pneumoniae and Escherichia coli. Two papers explored the relation between water and sanitation and antimicrobial resistance in low-income settings. CONCLUSIONS: Despite methodological limitations, the results suggest that addressing social determinants of poverty worldwide remains a crucial yet neglected step towards preventing antimicrobial resistance.

Introduction to the SAVE study (2011-15): Streptococcus pneumoniae serotyping and antimicrobial susceptibility: Assessment for Vaccine Efficacy in Canada after the introduction of PCV-13.

Streptococcus pneumoniae continues to be an important bacterial pathogen associated with invasive (e.g. bacteraemia) and non-invasive (e.g. community-acquired respiratory tract) infections worldwide. Surveillance studies conducted nationally and globally can assist in determining trends across geographical areas and allow comparisons between countries. SAVE is an ongoing, annual, national study focused on characterizing invasive isolates of S. pneumoniae obtained across Canada. This Supplement documents the initial 5 years of the SAVE study (2011-15) during which 6207 invasive isolates of S. pneumoniae were evaluated. The three manuscripts in this Supplement provide a comprehensive examination of the changing patterns of invasive S. pneumoniae obtained across Canada over a 5 year period. The data highlight the evolution of S. pneumoniae antimicrobial resistance and multidrug resistance, serotype distribution, genotypic relatedness and virulence under pressure by vaccination and antimicrobial usage. This allows both clinicians and researchers nationally and globally to view the current status of invasive pneumococcal infections in Canada.

The tigecycline evaluation and surveillance trial; assessment of the activity of tigecycline and other selected antibiotics against gram-positive and gram-negative pathogens from France collected between 2004 and 2016.

Background: A high level of antibiotic consumption in France means antimicrobial resistance requires rigorous monitoring. The Tigecycline Evaluation and Surveillance Trial (T.E.S.T.) is a global surveillance study that monitors the in vitro activities of tigecycline and a panel of marketed antimicrobials against clinically important Gram-positive and Gram-negative isolates. Methods: Annually clinically relevant strains were prospectively included in the survey through a national network of hospital-based laboratories. MICs were determined locally by broth microdilution using CLSI guidelines. Antimicrobial susceptibility was assessed using European Committee on Antimicrobial Susceptibility Testing breakpoints. Results: Thirty-three centres in France collected 26,486 isolates between 2004 and 2016. Enterococcus species were highly susceptible (≥94.4%) to linezolid, tigecycline and vancomycin. Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA), were susceptible (≥99.9%) to tigecycline, vancomycin and linezolid. Between 2004 and 2016, 27.7% of S. aureus isolates were MRSA, decreasing from 28.0% in 2013 to 23.5% in 2016. Susceptibility of Streptococcus pneumoniae isolates was 100% to vancomycin, and > 99.0% to levofloxacin, linezolid and meropenem; 3.0% were penicillin-resistant S. pneumoniae (100% susceptibility to vancomycin and linezolid). Escherichia coli isolates were highly susceptible (> 98.0%) to meropenem, tigecycline and amikacin. The rate of extended-spectrum ß-lactamase (ESBL) positive E. coli increased from 2004 (3.0%), but was stable from 2012 (23.1%) to 2016 (19.8%). Susceptibility of Klebsiella pneumoniae isolates was 99.4% to meropenem and 96.5% to amikacin. The proportion of ESBL-positive K. pneumoniae isolates increased from 2004 (7.5%) to 2012 (33.3%) and was highest in 2016 (43.6%). A. baumannii was susceptible to meropenem (81.0%) and amikacin (74.9%); none of the 6.2% of isolates identified as multidrug-resistant (MDR) was susceptible to any agents with breakpoints. P. aeruginosa isolates were most susceptible to amikacin (88.5%), and MDR rates were 13.6% in 2013 to 4.0% in 2016; susceptibility of MDR isolates was no higher than 31.4% to amikacin. Conclusions: Rates of MRSA decreased slowly, while rates of ESBL-positive E. coli and K. pneumoniae increased from 2004 to 2016. Susceptibility of Gram-positive isolates to vancomycin, tigecycline, meropenem and linezolid was well conserved, as was susceptibility of Gram-negative isolates to tigecycline and meropenem. The spread of MDR non-fermentative isolates must be carefully monitored.

Epidemiology of Otitis Media With Otorrhea Among Bangladeshi Children: Baseline Study for Future Assessment of Pneumococcal Conjugate Vaccine Impact.

BACKGROUND: Otitis media (OM) poses a high disease burden on Bangladeshi children, but little is known about its etiologies. We conducted a surveillance study in the largest pediatric hospital to characterize pathogens responsible for OM. METHODS: In the outpatient ear-nose-throat department of Dhaka Shishu Hospital, which serves 0 to 18-year-old children, we collected ear swabs from OM children with otorrhea from April 2014 to March 2015. We cultured all specimens for bacterial pathogens and assessed serotype and antimicrobial susceptibility of Streptococcus pneumoniae (Spn) and Haemophilus influenzae (Hi) isolates. RESULTS: We recorded 1111 OM episodes; 88% (981/1111) involved otorrhea, and we collected samples from 91% (891/981) of these children. Fifty-one percent (452/891) were culture positive (contaminants excluded), with Hi (21%, 187/891) and Spn (18%, 164/891) most commonly detected. Overall, 45 distinct single and mixed pathogens were revealed. Dominant pneumococcal serotypes were 19A, 19F, 3 and 14; 98% of Hi isolates were nontypeable. Pneumococcal conjugate vaccine (PCV)10 and PCV10 + 6A serotypes accounted for 8% and 9% of all OM and 46% and 49% of pneumococcus-positive cases, respectively, and were more likely to be nonsusceptible to at least 1 antibiotic (erythromycin and/or trimethoprim-sulfamethoxazole) than nonvaccine serotypes (91% vs. 77%). Staphylococcus aureus (9%, 83/891) and Pseudomonas aeruginosa (4%, 38/891) were also found. CONCLUSIONS: Nontypeable Hi (NTHi) and Spn are predominant causes of OM in Bangladesh. PCV10, introduced in March 2015, is likely to reduce pneumococcal and overall OM burden. Data collected post-PCV10 will provide comprehensive insight into the effects of this vaccine on these pathogens.

Pharmacokinetics and Pharmacodynamic Target Attainment of Benzylpenicillin in an Adult Severely Ill Sub-Saharan African Patient Population.

Background: In intensive care (ICU) patients, systemic exposure of ß-lactam antibiotics can be altered, and positive clinical outcome is associated with increasing fT > MIC ratios. In sub-Saharan African hospitals, benzylpenicillin (PEN) is frequently used for the empiric treatment of severe pneumococcal infections. Pharmacokinetic data for non-ICU hospitalized populations are lacking. Methods: We performed a population pharmacokinetic (PPK) study in an adult Mozambican hospital population treated intravenously with PEN from October 2014 through November 2015. Four blood samples/patient were collected for total PEN (PENt) and unbound PEN (PENu) concentration measurement. We developed a PPK model through nonlinear mixed-effects analysis and performed simulations for different patient variable, dosing, and pharmacodynamic target scenarios. Results: One hundred twelve participants yielded 387 PENt and 53 PENu concentrations. The median body mass index was 18.3 (range, 10.5-31.3) kg/m2 and the median albumin concentration and creatinine clearance (CrCl) were 29 (range, 12-44) g/L and 80 (range, 3-195) mL/minute, respectively. In a 1-compartment model, CrCl was positively correlated with PENt clearance. For infections with a microorganism with a minimum inhibitory concentration (MIC) of 1 mg/L, simulations demonstrated that with 3 million IU (1.8 g) every 6 hours, 74.1% would have a PENu concentration greater than the MIC during half of the dosing interval (fT > MIC = 50%), whereas this was 24.8% for the fT > MIC = 100% target. For pathogens with an MIC of 0.06 mg/L, these percentages were 98.2% and 72.3%, respectively. Conclusions: Severely ill adult sub-Saharan African patients may be at high risk for underexposure to PENu during routine intermittent bolus dosing, especially when their renal function is intact and when infected with pathogens with intermediate susceptibility.

Pharmacokinetic and Pharmacodynamic Analyses To Determine the Optimal Fixed Dosing Regimen of Iclaprim for Treatment of Patients with Serious Infections Caused by Gram-Positive Pathogens.

Iclaprim is a bacterial dihydrofolate reductase inhibitor that is currently being evaluated in two phase 3 trials for the treatment of patients with acute bacterial skin and skin structure infections (ABSSSI). Prior animal infection model studies suggest that the pharmacokinetic/pharmacodynamic (PK/PD) drivers for efficacy are area under the concentration-time curve from 0 to 24 h at steady state (AUC0-24ss), AUC/MIC, and time above the MIC during the dosing interval (T > MIC), while QTc prolongation was associated with the maximal concentration at steady state (Cmaxss) in a thorough QTc phase 1 study. Using PK data collected from 470 patients from the previously conducted phase 3 complicated skin and skin structure infection (cSSSI) trials, population PK modeling and Monte Carlo simulation (MCS) were used to identify a fixed iclaprim dosage regimen for the ongoing phase 3 ABSSSI studies that maximizes AUC0-24ss, AUC/MIC, and T > MIC while minimizing the probability of a Cmaxss of ≥800 ng/ml relative to the values for the previously employed cSSSI regimen of 0.8 mg/kg of body weight infused intravenously over 0.5 h every 12 h. The MCS analyses indicated that administration of 80 mg as a 2-h infusion every 12 h provides 28%, 28%, and 32% increases in AUC0-24ss, AUC/MIC, and T > MIC, respectively, compared to values for the 0.8-mg/kg cSSSI regimen, while decreasing the probability of a Cmaxss of ≥800 ng/ml, by 9%. Based on PK/PD analyses, 80 mg iclaprim administered over 2 h every 12 h was selected as the dosing scheme for subsequent phase 3 clinical trials.

The full benefits of adult pneumococcal vaccination: A systematic review.

BACKGROUND: Pneumococcal disease causes substantial morbidity and mortality, including among adults. Adult pneumococcal vaccines help to prevent these burdens, but they are underused. Accounting for the full benefits of adult pneumococcal vaccination may promote more rational resource allocation decisions with respect to adult pneumococcal vaccines. OBJECTIVES: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review to assess the extent to which the literature has empirically captured (e.g., through measurement or modeling) the full benefits of adult pneumococcal vaccination. METHODS: We systematically searched PubMed and Embase to identify studies published between January 1, 2010 and April 10, 2016 that examine adult pneumococcal vaccination. We included articles if they captured any health or economic benefit of an adult pneumococcal vaccine administered to adults age ≥ 50 or ≥ 18 in risk groups. Finally, we summarized the literature by categorizing the types of benefits captured, the perspective taken, and the strength of the evidence presented. Our protocol is number 42016038335 in the PROSPERO International prospective register of systematic reviews. RESULTS: We identified 5,857 papers and included 150 studies for analysis. While most capture health gains and healthcare cost savings, far fewer studies consider additional benefit categories, such as productivity gains. However, the studies with a broader approach still exhibit significant limitations; for example, many present only abstracts, while others offer no new measurements. Studies that examine the 13-valent pneumococcal conjugate vaccine focus more on broad economic benefits, but still have limitations. CONCLUSIONS: This review highlights the need for more robust empirical accounting of the full benefits of adult pneumococcal vaccination. Literature outside this realm indicates that these broad benefits may be substantial. Failing to investigate the full benefits may lead society to undervalue vaccines' contributions and therefore underinvest in their development and adoption.

A Population-Based Assessment of the Impact of 7- and 13-Valent Pneumococcal Conjugate Vaccines on Macrolide-Resistant Invasive Pneumococcal Disease: Emergence and Decline of Streptococcus pneumoniae Serotype 19A (CC320) With Dual Macrolide Resistance Mechanisms.

BACKGROUND: Macrolide efflux encoded by mef(E)/mel and ribosomal methylation encoded by erm(B) confer most macrolide resistance in Streptococcus pneumoniae. Introduction of the heptavalent pneumococcal conjugate vaccine (PCV7) in 2000 reduced macrolide-resistant invasive pneumococcal disease (MR-IPD) due to PCV7 serotypes (6B, 9V, 14, 19F, and 23F). METHODS: In this study, the impact of PCV7 and PCV13 on MR-IPD was prospectively assessed. A 20-year study of IPD performed in metropolitan Atlanta, Georgia, using active, population-based surveillance formed the basis for this study. Genetic determinants of macrolide resistance were evaluated using established techniques. RESULTS: During the decade of PCV7 use (2000-2009), MR-IPD decreased rapidly until 2002 and subsequently stabilized until the introduction of PCV13 in 2010 when MR-IPD incidence decreased further from 3.71 to 2.45/100000 population. In 2003, serotype 19A CC320 isolates containing both mef(E)/mel and erm(B) were observed and rapidly expanded in 2005-2009, peaking in 2010 (incidence 1.38/100000 population), accounting for 36.1% of MR-IPD and 11.7% of all IPD isolates. Following PCV13 introduction, dual macrolide-resistant IPD decreased 74.1% (incidence 0.32/100000 in 2013). However, other macrolide-resistant serotypes (eg, 15A and 35B) not currently represented in PCV formulations increased modestly. CONCLUSIONS: The selective pressures of widespread macrolide use and PCV7 and PCV13 introductions on S. pneumoniae were associated with changes in macrolide resistance and the molecular basis over time in our population. Durable surveillance and programs that emphasize the judicious use of antibiotics need to continue to be a focus of public health strategies directed at S. pneumoniae.