Population Pharmacokinetic Analyses for Tebipenem after Oral Administration of Pro-Drug Tebipenem Pivoxil Hydrobromide.

Tebipenem pivoxil hydrobromide (TBP-PI-HBr) is an oral (PO) carbapenem pro-drug that is converted to the active moiety tebipenem in the enterocytes. Tebipenem has activity against multidrug-resistant Gram-negative pathogens, including extended-spectrum beta lactamase-producing Enterobacterales, and is being developed for the treatment of patients with complicated urinary tract infections (cUTI) and acute pyelonephritis (AP). The objectives of these analyses were to develop a population pharmacokinetic (PK) model for tebipenem using data from three phase 1 studies and one phase 3 study and to identify covariates that described the variability in tebipenem PK. Following construction of the base model, a covariate analysis was conducted. The model was then qualified by performing a prediction-corrected visual predictive check and evaluated by using a sampling-importance-resampling procedure. The final population PK data set was composed of data from 746 subjects who provided 3,448 plasma concentrations, including 650 patients (1,985 concentrations) with cUTI/AP. The final population PK model that best described tebipenem PK was found to be a two-compartment model with linear, first-order elimination and two transit compartments to describe the rate of drug absorption after PO administration of TBP-PI-HBr. The relationship between renal clearance (CLR) and creatinine clearance (CLcr), the most clinically significant covariate, was described using a sigmoidal Hill-type function. No dose adjustments are warranted on the basis of age, body size, or sex as none of these covariates were associated with substantial differences in tebipenem exposure in patients with cUTI/AP. The resultant population PK model is expected to be appropriate for model-based simulations and assessment of pharmacokinetic-pharmacodynamic relationships for tebipenem.

Bactericidal activity and mechanism of action of AZD5847, a novel oxazolidinone for treatment of tuberculosis.

Treatment of tuberculosis (TB) is impaired by the long duration and complexity of therapy and the rising incidence of drug resistance. There is an urgent need for new agents with improved efficacy, safety, and compatibility with combination chemotherapies. Oxazolidinones offer a potential new class of TB drugs, and linezolid-the only currently approved oxazolidinone-has proven highly effective against extensively drug-resistant (XDR) TB in experimental trials. However, widespread use of linezolid is prohibited by its significant toxicities. AZD5847, a novel oxazolidinone, demonstrates improved in vitro bactericidal activity against both extracellular and intracellular M. tuberculosis compared to that of linezolid. Killing kinetics in broth media and in macrophages indicate that the rate and extent of kill obtained with AZD5847 are superior to those obtained with linezolid. Moreover, the efficacy of AZD5847 was additive when tested along with a variety of conventional TB agents, indicating that AZD5847 may function well in combination therapies. AZD5847 appears to function similarly to linezolid through impairment of the mycobacterial 50S ribosomal subunit. Future studies should be undertaken to further characterize the pharmacodynamics and pharmacokinetics of AZD5847 in both in vitro and animal models as well is in human clinical trials.

Genetic evidence for dispersal by both sexes in the Central American Squirrel Monkey, Saimiri oerstedii citrinellus.

Sex-biased dispersal (SBD) is common in many vertebrates, including primates. However, dispersal patterns in New World primates may vary among closely related taxa or populations in different local environments. Here, we test for SBD in an endangered New World primate, the Central American Squirrel Monkey (Saimiri oerstedii citrinellus). Previous studies of behavioral ecology suggest predominantly female dispersal in S.o. oerstedii in the Southern Pacific region of Costa Rica. However, our genetic data do not support strongly female-biased dispersal in S.o. citrinellus in the Central Pacific region. Our tests for SBD using microsatellite data including comparisons of isolation-by-distance, AI(c) , and F(ST) values between males and females were not significant. Also, we found greater population genetic structure in mitochondrial markers than in microsatellite markers, indicative of predominantly male dispersal. We conclude that both sexes disperse in S.o. citrinellus, and that males probably disperse over longer distances. We discuss how spatial and temporal variation among local populations should be taken into account when studying dispersal patterns and especially sex bias.

The cryptic seismic potential of the Pichilemu blind fault in Chile revealed by off-fault geomorphology.

The first step towards assessing hazards in seismically active regions involves mapping capable faults and estimating their recurrence times. While the mapping of active faults is commonly based on distinct geologic and geomorphic features evident at the surface, mapping blind seismogenic faults is complicated by the absence of on-fault diagnostic features. Here we investigated the Pichilemu Fault in coastal Chile, unknown until it generated a Mw 7.0 earthquake in 2010. The lack of evident surface faulting suggests activity along a partly-hidden blind fault. We used off-fault deformed marine terraces to estimate a fault-slip rate of 0.52 ± 0.04 m/ka, which, when integrated with satellite geodesy suggests a 2.12 ± 0.2 ka recurrence time for Mw~7.0 normal-faulting earthquakes. We propose that extension in the Pichilemu region is associated with stress changes during megathrust earthquakes and accommodated by sporadic slip during upper-plate earthquakes, which has implications for assessing the seismic potential of cryptic faults along convergent margins and elsewhere.

Penetration of meropenem into epithelial lining fluid of patients with ventilator-associated pneumonia.

Antibiotic penetration to the infection site is critical for obtaining a good clinical outcome in patients with ventilator-associated pneumonia (VAP). Surprisingly few studies have quantified the penetration of ß-lactam agents into the lung, as measured by the ratio of area under the concentration-time curve (AUC) in epithelial lining fluid (ELF) to AUC in plasma (AUC(ELF)/AUC(plasma) ratio). These have typically involved noninfected patients. This study examines the penetration and pharmacodynamics of meropenem in the ELF among patients with VAP. Meropenem plasma and ELF concentration-time data were obtained from patients in a multicenter clinical trial. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer (big nonparametric adaptive grid [BigNPAG]). A Monte Carlo simulation was performed to estimate the range of ELF/plasma penetration ratios one would expect to observe in patients with VAP, as measured by the AUC(ELF)/AUC(plasma) ratio. The range of AUC(ELF)/AUC(plasma) penetration ratios predicted by the Monte Carlo simulation was large. The 10th percentile of lung penetration was 3.7%, while the 90th percentile of penetration was 178%. The variability of ELF penetration is such that if relatively high ELF exposure targets are required to attain multilog kill or resistance suppression for bacteria like Pseudomonas aeruginosa, then even receiving the largest licensed dose of meropenem with an optimal prolonged infusion may not result in target attainment for a substantial fraction of the population.

Meropenem penetration into epithelial lining fluid in mice and humans and delineation of exposure targets.

Pseudomonas aeruginosa pneumonia remains a most-difficult-to-treat nosocomial bacterial infection. We used mathematical modeling to identify drug exposure targets for meropenem in the epithelial lining fluid (ELF) of mice with Pseudomonas pneumonia driving substantial [2 to 3 log(10) (CFU/g)] killing and which suppressed resistant subpopulation amplification. We bridged to humans to estimate the frequency with which the largest licensed meropenem dose would achieve these exposure targets. Cell kills of 2 and 3 log(10) (CFU/g) and resistant subpopulation suppression were mediated by achieving time > MIC in ELF of 32%, 50%, and 50%. Substantial variability in meropenem's ability to penetrate into ELF of both mice and humans was observed. Penetration variability and high exposure targets combined to prevent even the largest licensed meropenem dose from achieving the targets at an acceptable frequency. Even a highly potent agent such as meropenem does not adequately suppress resistant subpopulation amplification as single-agent therapy administered at maximal dose and optimal schedule. Combination chemotherapy is likely required in humans if we are to minimize resistance emergence in Pseudomonas aeruginosa pneumonia. This combination needs evaluation both in the murine pneumonia model and in humans.

Cascading processes in a changing environment: Disturbances on fluvial ecosystems in Chile and implications for hazard and risk management.

The compound hazard effects of multiple process cascades severely affect Chilean river systems and result in a large variety of disturbances on their ecosystems and alterations of their hydromorphologic regimes leading to extreme impacts on society, environment and infrastructure. The acute, neo-tectonically pre-determined susceptibility to seismic hazards, the widespread volcanic activity, the increasing glacier retreat and the continuous exposure to forest fires clearly disturb entire riverine systems and concur to trigger severe floods hazards. With the objective to refine the understanding of such cascading processes and to prospect feasible flood risk management strategies in such a rapidly changing environment we first classify the large river basins according to a set of disturbances (i.e. volcanic eruptions, earthquakes, glacier lake outburst floods, wild fires and mass movements). Then, we describe emblematic cases of process cascades which affected specific Chilean drainage basins and resulted in high losses as tangible examples of how the cascading processes may unfold in other river basins with similar characteristics. As an attempt to enrich the debate among management authorities and academia in Chile, and elsewhere, on how to sustainably manage river systems, we: a) highlight the pivotal need to determine the possible process cascades that may profoundly alter the system and b) we suggest to refine hazard and risk assessments accordingly, accounting for the current and future exposure. We advocate, finally, for the adoption of holistic approaches promoting anticipatory adaptation which may result in resilient system responses.

Clostridium difficile toxin A stimulates intracellular calcium release and chemotactic response in human granulocytes.

Clostridium difficile, a common enteric pathogen, mediates tissue damage and intestinal fluid secretion by release of two protein exotoxins: toxin A, an enterotoxin, and toxin B, a cytotoxin. Because toxin A elicits an intense inflammatory reaction in vivo, we studied the effects of highly purified C. difficile toxins on activation of human granulocytes. Toxin A at concentrations of 10(-7) to 10(-6) M, but not toxin B, elicited a significant chemotactic and chemokinetic response by granulocytes that was comparable with that induced by the chemotactic factor N-FMLP (10(-7) M). Neither toxin stimulated release of superoxide anion from granulocytes. Toxin A produced a rapid, transient rise in cytosolic [Ca2+]i, as measured by quin 2 fluorescence. Pertussis toxin and depletion of intra- and extracellular calcium blocked the toxin A effect on cytosolic [Ca2+]i. These findings suggest that the inflammatory effects of C. difficile toxin A in the intestine may be related to its ability to mobilize intracellular Ca2+ and elicit a chemotactic response by granulocytes.

Phenytoin-salicylate interaction.

Ten healthy adult subjects took a single daily dose of phenytoin for 9 days to achieve a steady-state serum phenytoin concentration in the therapeutic range. While continuing on phenytoin, subjects took increasing doses of salicylate in a step-wise fashion, each dose (325, 650, and 975 mg) given every 4 hr for 48 hr. Serum (total) and salivary (free) phenytoin concentrations and serum salicylate concentrations were measured before and after each dose level of salicylate. Protein binding displacement of phenytoin by salicylate occurred only at the highest salicylate dose. Serum phenytoin control levels fell from 13.5 +/- 1.2 to 10.3 +/- 0.8 micrograms/ml (p less than 0.01), salivary phenytoin levels rose from 0.97 +/- 0.09 to 1.13 +/- 0.12 micrograms/ml (p less than 0.05), and phenytoin free fraction (salivary/serum ratio) increased from 7.14 +/- 0.34% to 10.66 +/- 0.57% (p less than 0.01) in the highest salicylate dose periods. There was no difference in these parameters during low-dose or intermediate-dose salicylate therapy. Linear-regression analysis failed to show a relationship between serum salicylate concentration and serum or salivary phenytoin concentration. Although high-dose salicylate induced protein binding displacement of phenytoin, it is unlikely that this is of clinical importance since the rise (16%) in the free (salivary) phenytoin concentration was small. Serum total phenytoin concentration may fall during salicylate therapy but the dose of phenytoin should not be altered unless there are overt signs of toxicity.

Hybridization and population genetics of two macaque species in Sulawesi, Indonesia.

This study investigates hybridization and population genetics of two species of macaque monkey in Sulawesi, Indonesia, using molecular markers from mitochondrial, autosomal, and Y-chromosome DNA. Hybridization is the interbreeding of individuals from different parental taxa that are distinguishable by one or more heritable characteristics. Because hybridization can affect population structure of the parental taxa, it is an important consideration for conservation management. On the Indonesian island of Sulawesi an explosive diversification of macaques has occurred; seven of 19 species in the genus Macaca live on this island. The contact zone of the subjects of this study, M. maura and M. tonkeana, is located at the base of the southwestern peninsula of Sulawesi. Land conversion in Sulawesi is occurring at an alarming pace; currently two species of Sulawesi macaque, one of which is M. maura, are classified as endangered species. Results of this study indicate that hybridization among M. maura and M. tonkeana has led to different distributions of molecular variation in mitochondrial DNA and nuclear DNA in the contact zone; mitochondrial DNA shows a sharp transition from M. maura to M. tonkeana haplotypes, but nuclear DNA from the parental taxa is homogenized in a narrow hybrid zone. Similarly, within M. maura divergent mitochondrial DNA haplotypes are geographically structured but population subdivision in the nuclear genome is low or absent. In M. tonkeana, mitochondrial DNA haplotypes are geographically structured and a high level of nuclear DNA population subdivision is present in this species. These results are largely consistent with a macaque behavioral paradigm of female philopatry and obligate male dispersal, suggest that introgression between M. maura and M. tonkeana is restricted to the hybrid zone, and delineate one conservation management unit in M. maura and at least two in M. tonkeana.

Nutrition coverage on medical licensing examinations in the United States.

The 1985 National Academy of Sciences report Nutrition Education in US Medical Schools recommended that the National Board of Medical Examiners (NBME), who develops the US Medical Licensing Examination (USMLE), cover basic nutrition knowledge. According to the NBME, the USMLE includes nutrition on their Step 1 and 2 exams; however, this coverage has been questioned. To document whether the NBME adequately addresses nutrition, the 1986 Part I and Part II and the 1993 Step 1 and step 2 exams, which replaced the Part I and II exams, were reviewed by five nutrition professionals. This review identified the nutrition-related areas of the two-part exams and how the extent of nutrition coverage changed from 1986 to 1993. Nutrition items were coded on four dimensions: 1) specific nutrition-related topic area, 2) normal or abnormal scenario, 3) related organ system, and 4) importance in clinical medicine. The percentage of nutrition-related items, as identified by the nutrition professionals, increased from 9% on the 1986 Part I exam to 11% on the 1993 Step 1 exam and from 6% on the 1986 Part II exam to 12% on the 1993 Step 2 exam. The percentage of nutrition items related to vitamin deficiencies increased from 1986 to 1993 on both halves of the exam. Nutrition coverage on the USMLE Step 1 and Step 2 seems adequate in amount, however, the content and appropriateness of the items were not evaluated. The observed increased focus on vitamin deficiencies should be further considered.

Invasive infection with Sarcinosporon inkin in a patient with chronic granulomatous disease.

Sarcinosporon inkin, a rare skin fungus, was found to have caused progressive pneumonia in a young male with chronic granulomatous disease. Histologic sections of right upper lobe lung tissue showed clusters of globose to oblong hyalin-walled, septate, sporangia throughout the necrotic areas within the pyogranulomas. Pure cultures of S. inkin were recovered from the surgical specimen of the lung. Current status of the taxonomy of S. inkin is reviewed and clarified. Treatment of the patient with Amphotericin B and white blood cell transfusions led to clinical and radiographic response. This is the first documented case of systemic infection caused by S. inkin.

An inventory of the personal computers for students' use at 143 U.S. and Canadian medical schools.

The National Board of Medical Examiners (NBME) has been developing new tests to be administered using computers. As these tests near readiness for use, logistical issues of test administration have become important. In 1989-1990, in order to plan for the implementation of computer-based testing in NBME examinations of the future, the authors, under the auspices of the NBME, conducted a telephone survey of knowledgeable individuals at the 143 LCME-accredited medical schools in the United States and Canada to gauge the numbers and types of microcomputers and workstations available for students' use at these schools. The findings, based on the responses of all the schools surveyed, are reported.

Impact of the USMLE step 1 on teaching and learning of the basic biomedical sciences. United States Medical Licensing Examination.

Medical licensure in the United States is in transition. In June 1991, the National Board of Medical Examiners (NBME) made major modifications in the content, format, pass/fail standards, and score reports of the NBME Part I examination. This year, Part I became Step 1, the first of three components of the United States Medical Licensing Examination (USMLE), which will shortly be the sole examination pathway to initial licensure for allopathic physicians. This essay describes Step 1, reviews the phase-in plans for the USMLE, and discusses the potential impact of both on medical schools' teaching and students' learning of the basic biomedical sciences. The authors recommend that medical schools (1) abandon the use of Step 1 as a sole criterion for student promotion to the third year and (2) carefully review other examination-related requirements for promotion and graduation.

Review of the score-reporting policy for the United States Medical Licensing Examination.

In 1998, the authors, acting on behalf of the National Board of Medical Examiners (NBME), undertook a review of the scoring policy for the United States Medical Licensing Examination (USMLE). The main goal was to determine the likely effect of changing from numeric score reporting to reporting pass-fail status. Several groups were surveyed across the nation to learn how they felt they would be affected by such a change, and why: all 54 medical boards; 1,600 randomly selected examinees (including 250 foreign medical graduates) who had recently taken either Step 1, Step 2, or Step 3 of the USMLE; 2,000 residency directors; the deans, education deans, and student affairs deans at all 125 U.S. medical schools accredited by the Liaison Committee on Medical Education; and all 17 members of the Council of Medical Specialty Societies. Responses from the different groups surveyed varied from 80% to a little less than half. The authors describe in detail the various views of the respondents and their reasons. Some members in each group favored each of the reporting formats, but the trend was to favor numeric score reporting. The majority of the responding examinees desired that their USMLE scores be sent to them in numeric form but sent to their schools and to residency directors in pass-fail form. Based on the responses and a thorough discussion of their implications, the Composite Committee (which determines USMLE score-reporting policy) decided that there is no basis at this time for changing the current policy, but that it would review the policy in the future when necessary.

Leukocyte adhesion deficiency: report of a case and review of the literature.

Leukocyte adhesion deficiency (LAD) is a rare inherited immunodeficiency that is characterized by deficiency of the beta 2 integrin leukocyte adhesion molecules Mac-1, LFA-1, and p150,95. We describe a case of the severe form of LAD in an infant with recurrent infections and with a complete deficiency of beta 2 integrin molecules, and review the clinical aspects of the syndrome.

The drug abuse treatment gap: recent estimates.

There is a widely acknowledged problem of drug abuse in the United States, but there is no widely accepted estimate of the number who need treatment for drug abuse. In this article, the authors present new estimates of the numbers of persons in this country who need and receive treatment. These estimates are derived from improved definitions and statistical estimating methods applied to the national Household Survey on Drug Abuse (NHSDS). There are two separate estimates (based on severity) of people needing treatment, yielding a combined total of 7.1 million people. These new estimates are crucial to better resource planning and allocation.

Combined radiofrequency ablation-cooling catheter for reversible cryothermal mapping and ablation.

Reversible cryothermal mapping of cardiac arrhythmias has been performed intraoperatively. However, a steerable cooling catheter for reversible mapping has not yet been developed. We therefore developed and tested a cooling system consisting of a -15 degrees C hypertonic saline reservoir and a 7F steerable catheter also capable of radiofrequency (RF) ablation. Using excised ovine hearts placed in a 37 degrees C circulating saline bath, we measured the temperatures at depths of 0 mm, 1 mm, and 2 mm. The temperature after 90 seconds of cooling was 16.5 +/- 2.1 degrees C at 0 mm compared to 23.9 +/- 4.1 degrees C at 1 mm and 31.1 +/- 3.9 degrees C at 2 mm depth (p < 0.01). These data suggest that a 7F steerable combined RF ablation-cooling catheter may achieve temperatures suitable for mapping arrhythmias such as atrial tachycardias and right ventricular outflow tract tachycardias. Further enhancements to achieve lower temperatures at depth may be needed to reversibly map other arrhythmias such as left ventricular tachycardias.

Meropenem monotherapy for the treatment of hospital-acquired pneumonia: results of a multicenter trial.

The efficacy and tolerability of meropenem as empirical treatment in patients with hospital-acquired pneumonia was determined in a prospective, open-label, non-randomized trial. Patients from 28 centers in the USA received meropenem 1 g every 8 h intravenously. Of 255 patients enrolled, 111 were evaluable for efficacy, including 60 patients with ventilator-associated pneumonia. At end of treatment 74% of patients had a satisfactory clinical response and 64% had this response at follow-up, which could last up to 28 days after treatment. In patients with ventilator-associated pneumonia, a satisfactory clinical response was observed in 68% at the end of treatment and 63% at follow-up. The overall satisfactory response rate for individual pretreatment pathogens ranged from 65% to 100%. This study demonstrates that meropenem monotherapy is effective and well tolerated for patients with hospital-acquired pneumonia, including a subgroup of patients with ventilator-associated pneumonia.