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5039 Background: Standard-of-care (SOC) chemotherapy may contribute to immunosuppression by elevating intratumoral levels of adenosine, activating the A2a and A2b receptors on immune cells. Extracellular adenosine is primarily produced by the enzyme CD73; in prostate cancer, additional adenosine is also produced by the highly expressed protein, prostatic acid phosphatase (PAP). Etrumadenant (etruma) is an orally bioavailable, small-molecule, selective dual adenosine receptor antagonist and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Adenosine axis inhibition combined with SOC regimens and/or immunotherapy may have a synergistic effect on the induction of sustained antitumor immunity against mCRPC. Initial results from the etruma + zimberelimab (zim; anti–PD-1 mAb) + docetaxel (doc) arm are presented herein. Methods: ARC-6 (NCT04381832) is an ongoing, phase 1b/2, open-label, multicohort platform study to evaluate efficacy and safety of etruma combination therapy. All eligible patients (pts) have mCRPC that has progressed on androgen deprivation therapy and are checkpoint inhibitor-naive; additionally, for this arm, pts must be androgen signaling inhibitor (ASI)-experienced and taxane-naive. Study pts receive 150 mg etruma orally once daily + 360 mg zim IV every 3 weeks + SOC doc (EZD). The primary objectives are to evaluate safety and antitumor activity (prostate-specific antigen [PSA], radiographic, and composite response rates) of EZD. PSA levels are assessed every 3 weeks, and radiographic scans are performed every 12 weeks. PSA response-evaluable pts have baseline (BL) + ≥2 consecutive post-BL PSA assessments; radiographic response-evaluable pts have RECIST measurable or non-measurable disease per BL imaging + ≥1 post-BL radiographic assessment. Results: As of 22Jan2021, 17 pts have received EZD in phase 1b; 14 are PSA response-evaluable and 8 are radiographic response-evaluable. 15 (88%) pts reported treatment emergent adverse events (TEAEs); the most common ( > 30%) were lymphocyte count decreased and neutrophil count decreased (7 pts each; 41%), and hyponatremia and alopecia (6 pts each; 35%). Grade ≥3 treatment-related TEAEs were reported by 9 pts (53%). As of 22Jan2021, 16 pts were continuing treatment; median time on EZD for all pts was 9.9 weeks (0.1–27.4+ weeks). In response-evaluable pts, PSA response rate was 36% (5/14), radiographic response rate was 38% (3/8; 1 CR), and the composite response rate was 43% (6/14). Conclusions: Phase 1b results indicate that EZD treatment in pts with mCRPC had a manageable safety profile and was associated with clinical benefit. Having met phase 2 advancement criteria, randomized pt enrollment to EZD vs. doc is ongoing. Clinical trial information: NCT04381832.

TPS272 Background: The tumor microenvironment contains high levels of immunosuppressive adenosine, which binds to and activates the A2a and A2b receptors (R) on immune cells, resulting in an ineffective anti-tumor immune response. Extracellular adenosine is primarily produced by the enzyme CD73. In prostate cancer (PC), the activity of prostatic acid phosphatase produces additional adenosine. AB928 is the first clinical-stage small molecule dual antagonist of both A2aR and A2bR, which is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as a single agent or in combination with chemo/immunotherapy. Targeting the adenosine pathway in combination with standard of care regimens may have a more profound effect on activating and inducing sustained anti-tumor immunity. Methods: This Phase 1b/2, open-label, multi-cohort platform study will evaluate the efficacy and safety of AB928 combination therapy in participants with metastatic castrate resistant PC (mCRPC). Each cohort will independently assess AB928 plus AB122 (anti-PD-1 antibody) in combination with standard of care (SOC; enzalutamide, docetaxel) or AB928 plus AB680 (CD73 inhibitor) with or without AB122. Cohort eligibility is informed by prior treatment history. In Ph1b, up to 15 participants will receive investigational products at the single-agent recommended dose with SOC per label guidance. Provided safety and activity stopping criteria are not met, further accrual will proceed in Ph2 and, depending on treatment cohort, may involve randomization to enzalutamide or docetaxel; crossover to experimental therapy will be allowed following progression on control treatment. Investigator-assessed antitumor response (radiologic, prostate specific antigen) will follow PCWG3 criteria. Conclusions: This Ph1b/2 study is the first to target the adenosine axis using a dual A2aR/A2bR antagonist (AB928) together with a small molecule CD73 inhibitor (AB680), anti-PD-1 antibody (AB122), and SOC for mCRPC. Study enrollment is proceeding in the United States; results will be shared in upcoming scientific conferences.

Background: Increased expression and neomorphic mutations of the histone methyltransferase EZH2 are often observed in cancer, leading to repression of genes associated with apoptosis and differentiation. High EZH2 expression and low expression of EZH2 target genes in mCRPC correlate with poor prognosis. CPI-1205 is a potent, reversible, cofactor-competitive small molecule inhibitor of EZH2. Preclinical studies revealed that prostate cancer models dependent on androgen receptor signaling (ARS) are sensitive to EZH2 inhibition, and that CPI-1205, when combined with novel ARS inhibitors, results in synergistic cell growth inhibition (Bradley 2018). Here we report preliminary results from the Phase Ib component. Methods: In this multicenter Phase Ib/II study, patients (pts) with mCRPC previously treated with a novel ARS inhibitor were enrolled in different cohorts exploring two regimens of oral CPI-1205 on a continuous 28-day cycle: 800 mg TID or 400 mg BID with cobicistat, a CYP3A4 inhibitor, combined with the standard dose of E (160 mg QD) or standard dose of A/P (1000 mg QD/5 mg BID). Prior chemotherapy was allowed. The primary objective in Phase Ib is to determine safety, a recommended Phase II dose, pharmacokinetics (PK), and pharmacodynamics (PD). Results: As of 11/16/2018, 35 pts were enrolled in four cohorts (two cohorts of CPI-1205 + E; two cohorts of CPI-1205 + A/P) and were treated for ≥1 cycle. Age ranged from 55 to 90 years (median 72). 63% were ECOG 0 and 37% ECOG 1. 13 pts (37%) tested positive for ARV7. 21 pts (60%) had unfavorable circulating tumor cells (CTC) counts at baseline. 6 pts (17%) had prior taxane-based chemotherapy for mCRPC. 16 pts received CPI-1205 + E and 19 pts received CPI-1205 + A/P. Only 1 DLT (asymptomatic reversible ALT increase, Grade 4) was reported in the CPI-1205 + A/P + cobicistat. No serious AE related to the study drug was reported in any cohort. Overall, the commonly reported drug-related treatment-emergent adverse events (TEAEs ≥10%) were low-grade diarrhea (n= 11, 31%), fatigue and nausea (n= 9, 26% each), and decreased appetite (n=5, 14%). Grade ≥3 TEAEs were fatigue and elevated ALT (n=2, 6% each), and nausea, pruritus, hypokalemia, and muscular weakness (n=1, 3% each). 16 pts remain on treatment. Cases of PSA >80% reduction, CTC ≥30% reduction, and RECIST response were observed. Both CPI-1205 regimens resulted in significant target engagement (reduced H3K27me3 in PBMCs and CTCs). Patient sample analysis to maximize biomarker identification is ongoing. PK data will be presented. Conclusions: Both CPI-1205 800 mg PO TID and 400 mg PO BID plus cobicistat, combined with full doses of either E or A/P, are well tolerated, with acceptable safety. Encouraging clinical activity has been observed. CPI-1205 800 mg PO TID + E or A/P has been selected for phase 2 expansion, and patient enrollment is ongoing Citation Format: Mary-Ellen Taplin, Arif Hussain, Satish Shah, Neal D. Shore, William Jeffery Edenfield, Oliver A. Sartor, Luke T. Nordquist, Manish Agrawal, William Clark, David R. Wise, William K. Oh, Mark T. Fleming, James E. Butrynski, Gurkamal S. Chatta, Manojkumar Bupathi, Claudia Lebedinsky, Adrian Senderowicz, Jian Li, Gozde Colak, David Nash, Patrick Trojer, William D. Bradley, Jessica Piel, Emmanuel S. Antonarakis. Phase Ib results of ProSTAR: CPI-1205, EZH2 inhibitor, combined with enzalutamide (E) or abiraterone/prednisone (A/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT094.

Background: Percutaneous coronary intervention (PCI) is the most commonly used procedure for coronary revascularization. There are multiple adjuvant anticoagulation strategies available. In this era of cost containment, we performed a comparative effectiveness analysis of clinical outcomes and cost of the major anticoagulant strategies across all types of PCI procedures in a large observational database. Methods: A retrospective, comparative effectiveness analysis of the Premier observational database was conducted to determine the impact of anticoagulant treatment on outcomes. Multiple linear regression and logistic regression models were used to assess the association of initial antithrombotic treatment with outcomes while controlling for other factors. Results: A total of 458,448 inpatient PCI procedures with known antithrombotic regimen from 299 hospitals between January 1, 2004 and March 31, 2008 were identified. Compared to patients treated with heparin plus glycoprotein IIb/IIIa inhibitor (GPI), bivalirudin was associated with a 41% relative risk reduction (RRR) for inpatient mortality, a 44% RRR for clinically apparent bleeding, and a 37% RRR for any transfusion. Furthermore, treatment with bivalirudin alone resulted in a cost savings of $976 per case. Similar results were seen between bivalirudin and heparin in all end-points. Combined use of both bivalirudin and GPI substantially attenuated the cost benefits demonstrated with bivalirudin alone. Conclusion: Bivalirudin use was associated with both improved clinical outcomes and decreased hospital costs in this large "real-world" database. To our knowledge, this study is the first to demonstrate the ideal comparative effectiveness end-point of both improved clinical outcomes with decreased costs in PCI. (J Interven Cardiol 2012;25:278–288)

TPS391 Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.

Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known.To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor.Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs).Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs.Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).

Angiontension-converting enzyme inhibitors (ACEIs) are beneficial in the treatment of diabetic and nondiabetic kidney disease, coronary artery disease and congestive heart failure. One adverse effect of ACEIs use is a rise in serum creatinine and potential renal failure. This paper attempts to quantify this risk and assess the need for pre- and post-ACEI serum creatinine measurements. A computerized search of Kaiser Permanente Northwest's electronic medical record was conducted to find patients over the age of 40 years taking lisinopril between July 1, 2000 and June 30, 2002. Patient demographic information and presence in diabetes and coronary artery disease registries was collected. A subsequent search for pre- and postlisinopril serum creatinine levels within 6 months of initial lisinopril prescription was conducted. Patients with prelisinopril creatinineor = 1.2 mg/dl and postlisinopril creatinine2.5 mg/dl underwent chart review to discern adverse events associated with the rise in serum creatinine. A total of 18,977 patients were prescribed lisinopril between July 1, 2000 and June 30, 2002. In all 13 166 patients had a pre- and postlisinopril creatinine checked. In all, 31 patients had a rise in creatinine fromor = 1.2 mg/dl to2.5 mg/dl (0.2%). Possible contributors to rise in creatinine included congestive heart failure, dehydration and infection. No patients developed end-stage renal disease, although three died. In conclusion, end-stage renal disease is an unlikely outcome among patients prescribed lisinopril and is most likely associated with other events.

Objective: To quantify the relation between community based antibacterial prescribing and antibacterial resistance in community acquired disease. Design: Cross sectional study of antibacterial prescribing and antibacterial resistance of routine isolates within individual practices and primary care groups. Setting: 405 general practices (38 groups) in south west and north west England. Main outcome measures: Correlation between antibacterial prescribing and resistance for urinary coliforms and Streptococcus pneumoniae. Results: Antibacterial resistance in urinary coliform isolates is common but the correlation with prescribing rates was relatively low for individual practices (ampicillin and amoxicillin rs=0.20, P=0.001; trimethoprim rs=0.24, P=0.0001) and primary care groups (ampicillin and amoxicillin rs=0.44, P=0.05; trimethoprim rs=0.31, P=0.09). Regression coefficients were also low; a practice prescribing 20% less ampicillin and amoxicillin than average would have about 1% fewer resistant isolates (0.94/100; 95% confidence interval 0.02 to 1.85). Resistance of S pneumoniae to both penicillin and erythromycin remains uncommon, and no clear relation with prescribing was found. Conclusions: Routine microbiological isolates should not be used for surveillance of antibacterial resistance in the community or for monitoring the outcome of any change in antibacterial prescribing by general practitioners. Trying to reduce the overall level of antibiotic prescribing in UK general practice may not be the most effective strategy for reducing resistance in the community. What is already known on this topic The probability of an individual hosting a resistant organism is increased by recent use of an antibacterial drug Correlation between antibacterial prescribing and coliform resistance in routine microbiological samples from the community has been reported in one study What this study adds In English general practice, there are significant but low correlations between antibacterial prescribing and resistance in routine isolates of urinary coliforms Substantial differences in prescribing between high and low prescribing practices are associated with only small differences in resistance Improved methods of assessing national antimicrobial resistance are required

The in-vitro activity of gemifloxacin, a new fluoroquinolone, against a wide range (c. 700) of recent clinical isolates, was compared with that of three other fluoroquinolones and other relevant agents. Gemifloxacin inhibited 90% of the Enterobacteriaceae strains at 0.5 mg/L or less, exceptions being Serratia spp. (MIC(90) 1 mg/L) and strains possessing a putative mechanism of resistance to fluoroquinolones. Ninety per cent of Pseudomonas aeruginosa were inhibited by 4 mg/L. Gemifloxacin had good activity against respiratory pathogens, with 90% of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis being inhibited by 0.06 mg/L or less. Staphylococcus aureus (MSSA) were highly susceptible (MIC(90) 0.06 mg/L) but MRSA less susceptible (MIC(90) 8 mg/L) to gemifloxacin. Enterococcus spp. were markedly more susceptible to the study agent than to ciprofloxacin. Gemifloxacin showed good activity against Bacteroides fragilis (MIC(90) 0.5 mg/L) and anaerobic cocci. A tentative in-vitro breakpoint of 0.5 mg/L was studied using a 1 microg disc content for all genera except Pseudomonas where a 5 microg disc content was employed. The false sensitivity reporting rate was 0.5% and false resistance rate was 6.0%, which was considered acceptable. In conclusion, gemifloxacin is a highly active fluoroquinolone that should prove clinically useful in the treatment of a wide range of infections. Susceptibility testing criteria have been developed that should prove robust in a clinical laboratory.

In a study involving 15 UK hospitals, sequential respiratory tract isolates of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were studied. The susceptibility of these strains to two fluoroquinolones, ciprofloxacin and levofloxacin were compared to those of currently used macrolides and beta-lactams. The activity of ciprofloxacin and levofloxacin against S. pneumoniae was not statistically significantly different (geometric mean MIC 0.978 and 0.95 mg/L respectively). Beta-lactam resistance did not affect fluoroquinolone susceptibility. H. influenzae and M. catarrhalis were highly susceptible to both fluoroquinolones.

The in-vitro activity of grepafloxacin was compared with that of other antimicrobials against respiratory tract pathogens collected from 15 UK laboratories over the winter of 1995-96. Penicillin-resistant Streptococcus pneumoniae was not encountered, but macrolide resistance was seen in approximately 10% of strains. Grepafloxacin (MIC90 0.25 mg/L) was four- to eight-fold more active than ciprofloxacin. Twelve percent of Haemophilus influenzae were beta-lactamase producers, macrolides were relatively inactive yet fluoroquinolones were highly active. Moraxella catarrhalis were highly susceptible to fluoroquinolones and macrolides. The activity of grepafloxacin against respiratory tract pathogens should make it a useful agent in the treatment of infections at this site.

Objective Preeclampsia is a human pregnancy-specific disorder that presents as maternal hypertension and proteinuria after 20 weeks of gestation. Although the complete pathogenesis of preeclampsia is still unclear, previous studies have shown that placental extracellular vesicles shed from the syncytiotrophoblast into maternal circulation are associated with this disease. These vesicles can be categorised into macro- micro- and nano-vesicles based on their size. Previous studies have also shown that sera from women with preeclampsia changed the nature of placental macro-vesicles to become more dangerous/toxic such that they activated endothelial cells, but whether preeclamptic sera have the same effect on micro and nanovesicles is untested. In this study, we investigated whether preeclamptic sera affect the amount or nature of micro- and nano-vesicles extruded from first trimester placentae. We also investigated whether two drugs commonly used for symptom relief, nifiedipine or labetalol could reverse the activation of endothelial cells induced by these vesicles. Methods 1st trimester placental explants ( n = 8) were treated with 10% preeclamptic or control sera for 24 h. Micro- and nano-vesicles were harvested by sequential centrifugation at 20,000 g or 100,000 g for 1 h, respectively. The number of micro- or nano-vesicles was counted using a Nanosight (NS300) device. Micro- or nano-vesicles were exposed to monolayers of endothelial cells in the presence or absence of nifedipine (50 μg/ml) or labetalol (0.5 μg/ml). Cell-surface intercellular adhesion molecule 1 (ICAM-1) expression was measured by cell-based ELISA as a marker of endothelial cell activation. Results The amount of both micro- and nano-vesicles was significantly ( p p p = 0.004) or labetalol ( p = 0.002). Conclusion Our data demonstrate that an unknown factor(s) in preeclamptic sera causes an increase in the number of both micro- and nano-vesicles released from placentae which is consistent with the known increase in these vesicles in preeclampsia. The vesicles produced after treating placentae with preeclamptic sera were also more dangerous activating endothelial cells but this effect of the vesicles on endothelial cells is reversible by nifedipine or labetalol.

In vitro studies on the activity of cefprozil have been conducted in Europe and North America. Against gram-negative bacilli, cefprozil and cefaclor are at least two to four times more active than cephalexin. Cefixime is more active against these organisms. Against gram-positive cocci, cefprozil is at least two to four times more active than cefaclor and cephalexin; cefixime has limited gram-positive activity, and is particularly inactive against staphylococci (MIC90 32 mg/l). Cefprozil is highly active againstStreptococcus pneumoniae (unlike cefixime). Those strains of this genus that display intermediate resistance to pneumococci are more susceptible to cefprozil than cefaclor.Neisseria species andMoraxella catarrhalis are susceptible to cefprozil (MIC90 0.06 and 1 mg/l). β-lactamase-producing strains ofHaemophilus influenzae appear to be susceptible to cefprozil, as the reported MIC90 is 2–4 mg/I. Enterococci,Pseudomonas aeruginosa, and those strains of theEnterobacteriaceae that commonly possess a chromosomal cephalosporinase (e.g.,Providencia, Morganella andEnterobacter) are generally considered to be resistant to cefprozil as well as to other oral cephalosporins. Cefprozil appears to display enhanced stability to the commonly encountered Tem-1 and SHV-1 plasmid-mediated β-lactamases, as found inHaemophilus influenzae, Neisseria gonorrhoeae and theEnterobacteriaceae. Cefprozil is rapidly absorbed, reaching a maximum concentration 0.9 to 1.2 h post-dose. Following oral doses of 250 and 500 mg, the Cmax is 6.2 and 10.0 mg/l respectively. Serum half-lives are generally reported as between 1.2 and 1.4 h, and urine recovery is high, 57–70 %. Ingestion of food has no significant effect on cefprozil pharmacokinetics, but does reduce the serum levels of cefaclor. Studies in severe renal dysfunction suggest that only when the creatinine clearance is under 30 ml/min (when the half-life exceeds 5 h) is there a need for a reduction in the dosage of cefprozil by 50 % or an increase of the dosage interval. Children (over 2 months of age) have very similar pharmacokinetics, the only difference being a slightly shorter cefprozil half-life (ca. 1.0 h). Studies in the elderly suggest that age, per se, does not need an alteration in dosing. The tissue penetration of cefprozil is similar to that of other β-lactams and the blister-fluid model demonstrates that 80 % penetration is found in an inflammatory exudate.

Background The methacholine challenge test (MCT) is commonly used to assess airway hyperresponsiveness, but the diagnostic characteristics have not been well studied in asthmatic patients receiving controller medications after the use of high-potency inhaled corticosteroids became common. Objectives We investigated the ability of the MCT to differentiate participants with a physician's diagnosis of asthma from nonasthmatic participants. Methods We conducted a cohort-control study in asthmatic participants (n = 126) who were receiving regular controller medications and nonasthmatic control participants (n = 93) to evaluate the sensitivity and specificity of the MCT. Results The overall sensitivity was 77% and the specificity was 96% with a threshold PC 20 (the provocative concentration of methacholine that results in a 20% drop in FEV 1 ) of 8 mg/mL. The sensitivity was significantly lower in white than in African American participants (69% vs 95%, P = .015) and higher in atopic compared with nonatopic (82% vs 52%, P = .005). Increasing the PC 20 threshold from 8 to 16 mg/mL did not noticeably improve the performance characteristics of the test. African American race, presence of atopy, and lower percent predicted FEV 1 were associated with a positive test result. Conclusions The utility of the MCT to rule out a diagnosis of asthma depends on racial and atopic characteristics. Clinicians should take into account the reduced sensitivity of the MCT in white and nonatopic asthmatic patients when using this test for the diagnosis of asthma.

The absolute bioavailability of oral spiramycin varies markedly between individuals (from 10 to 60%), but it is generally within the range of 30 to 40%, and may be reduced in the presence of food. Serum levels are therefore somewhat variable, and after a 1g oral dose Cmax is 0.4 to 1.4 mg/L. As with other macrolides, the tissue distribution of spiramycin is excellent. The volume of distribution is in excess of 300L, and concentrations achieved in bone, muscle, respiratory tract and saliva exceed those found in plasma. Intracellular penetration of spiramycin is also rapid and extensive, concentrations found in alveolar macrophages being 10 to 20 times greater than simultaneous serum concentrations. There is some evidence that spiramycin is less metabolised than some other macrolides. The renal excretion of spiramycin is low but variable, 4 to 20% of a dose being excreted by this route. High concentrations of spiramycin are achieved in bile, which is an important route of elimination. The serum elimination half-life of spiramycin is between 6.2 and 7.7 hours.

The efficacy of the combination of piperacillin plus tazobactam was studied in 142 patients who had a bacteriologically proven bacteraemia. Seventy-three patients were bacteriologically evaluable and, of these, 55 had a follow-up blood culture; there was no follow-up culture in the other 18 patients, so that any cure could only be presumptive. Of the 55 patients who were fully followed up, 32 received only piperacillin and tazobactam and 23 also received an aminoglycoside. Overall, there were 67 cures and six failures out of 73 evaluable cases (three Staphylococcus aureus, two Staphylococcus epidermidis and one Streptococcus bovis). There were 11 deaths, eight of which occurred in neutropenic patients. In no case was death drug related. Side-effects were mild; the commonest adverse events noted were mild elevations of liver enzymes. Piperacillin plus tazobactam appeared efficacious and safe in the therapy of bacteraemia.

The pharmacokinetics of loracarbef in plasma and a mild inflammatory exudate were studied in human volunteers. After a single oral dose of 400 mg, a mean maximum drug concentration (Cmax) of 17.8 mg/L was achieved in the plasma at 1.2 h (mean Tmax). The mean plasma elimination half-life (T1/2) was 1.3 h. In the inflammatory exudate the mean Cmax was 8.9 mg/L at a mean Tmax of 2.0 h and with a mean T1/2 of 1.7 h. The mean penetration into the inflammatory exudate was 90.1%. The in-vitro activity of loracarbef was determined against Haemophilus influenzae and Moraxella catarrhalis (MIC90s of 4 mg/L and 1 mg/L respectively, regardless of beta-lactamase production), as well as Streptococcus pneumoniae (MIC90 of 2 mg/L). Loracarbef was also active against Escherichia coli, Proteus mirabilis and Klebsiella pneumoniae (MIC90s of < or = 2 mg/L). The in-vitro activity and pharmacokinetics of loracarbef suggest that it would be efficative therapy for patients with community-acquired respiratory and urinary tract infections caused by the most frequently-encountered bacterial pathogens.

Capnocytophaga species have been associated with a wide variety of infections in both immunocompetent and immunocompromised patients. On the basis of data from antimicrobial susceptibility studies, beta-lactam antibiotics have been considered efficacious therapy. Six of 19 isolates from primarily clinical sources across Canada demonstrated beta-lactamase production, and agar dilution susceptibility testing showed broad resistance to beta-lactam antibiotics. For the beta-lactamase producing isolates, clavulanate reduced the MIC of amoxicillin for 90% of the strains tested by 64-fold. Isolates were highly susceptible to clindamycin, imipenem, and ciprofloxacin. Characterization of the beta-lactamases produced by two of these isolates (Van1 and Van2) was performed. Isoelectric focusing revealed an identical isoelectric point of 5.6 for both enzymes, but they had markedly different relative hydrolysis efficiencies, and different conditions were required to extract the enzymes. This study demonstrates the production of different types of beta-lactamases by Capnocytophaga spp. and suggests the need to screen all clinical isolates of Capnocytophaga spp. for the presence of beta-lactamases.

The in-vitro activity of cefdinir (FK482), an orally absorbed aminothiazolyl cephalosporin, was compared with that of cefuroxime, cefixime, cephalexin, cefaclor and co-amoxiclav. Cefdinir was highly active against Staphylococcus aureus, inhibiting 90% of strains at 0.03 mg/L. The respiratory pathogens Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis were also susceptible (MIC90 less than or equal to 1 mg/L). The common members of the Enterobacteriaceae were susceptible (MIC90 less than or equal to 1 mg/L), but those possessing chromosomal beta-lactamases were more resistant. Cefdinir appeared highly stable to the TEM-1 and SHV-1 beta-lactamases with only relatively minor degrees of hydrolysis being seen with TEM-3, -5 and -9.

The pharmacokinetics of the older and more recent oral cephalosporins are reviewed. With the exception of cefadroxil the older agents (cephalexin, cephradine and cefaclor) have serum elimination half-lives of less than or equal to 1 h and hence have to be administered three to four times daily. The urinary recovery of these agents is high (greater than 80% of oral dose) with the exception of cefaclor (54%). Cefaclor is also chemically unstable. The newer agents can be divided into those that are prodrugs (cefpodoxime proxetil and cefuroxime axetil) and compounds that are absorbed as such (cefixime, cefprozil and ceftibuten). They all have half-lives greater than 1.25 h and can be given once or twice daily. The penetration of these agents into an inflammatory exudate was studied and found to be cefixime 132%, ceftibuten 113%, cefpodoxime 104%, cefuroxime 92% and cefprozil 79% of the serum concentration. The penetration of cefpodoxime and cefixime into the respiratory tract was also studied; the mean percentage bronchial mucosal penetration was 52% for the former and 38% for cefixime. The urinary recovery of these newer agents (with the exception of ceftibuten) tends to be less than that of the earlier agents. There was a relationship between the serum elimination half-life of these agents and the degree of tissue penetration, those agents with longer half-lives penetrating to a greater extent.

A dense nonaqueous phase liquid (DNAPL) source zone was established within a sheet-pile isolated cell through a controlled release of perchloroethylene (PCE) to evaluate DNAPL remediation by in-situ cosolvent flushing. Ethanol was used as the cosolvent, and the main remedial mechanism was enhanced dissolution based on the phase behavior of the water-ethanol-PCE system. Based on the knowledge of the actual PCE volume introduced into the cell, it was estimated that 83 L of PCE were present at the start of the test. Over a 40-day period, 64% of the PCE was removed by flushing the cell with an alcohol solution of approximately 70% ethanol and 30% water. High removal efficiencies at the end of the test indicated that more PCE could have been removed had it been possible to continue the demonstration. The ethanol solution extracted from the cell was recycled during the test using activated carbon and air stripping treatment. Both of these treatment processes were successful in removing PCE for recycling purposes, with minimal impact on the ethanol content in the treated fluids. Results from pre- and post-flushing partitioning tracer tests overestimated the treatment performance. However, both of these tracer tests missed significant amounts of the PCE present, likely due to inaccessibility of the PCE. The tracer results suggest that some PCE was inaccessible to the ethanol solution which led to the inefficient PCE removal rates observed. The flux-averaged aqueous PCE concentrations measured in the post-flushing tracer test were reduced by a factor of 3 to 4 in the extraction wells that showed the highest PCE removal compared to those concentrations in the pre-flushing tracer test.

Determination de la penetration de cefpirome, cephalosporine semi-synthetique, dans le tissu prostatique. Etude faite chez des volontaires apres administration i.v. unique. Le medicament possede une bonne diffusion, un large spectre d'action et une faible toxicite. Il peut donc etre utile dans le traitement de la prostatite aigue ou en prophylaxie avant une prostatectomie

There are a number of potential sites of infection in the lower respiratory tract. This review summaries the nature of these sites and the ways in which antibiotic penetration can be studied. The results of a single-dose and a multiple-dose study of the penetration of sparfloxacin into the respiratory tract are also provided. After a single oral dose of sparfloxacin 400 mg or a 400 mg loading dose on day 1 followed by 200 mg daily for 2 days, sparfloxacin concentrations in the bronchial mucosa, epithelial lining fluid and alveolar macrophages were higher than the corresponding concentrations in serum. Compared with other fluoroquinolones, sparfloxacin achieves higher concentrations at these sites. Sparfloxacin diffusion into maxillary sinus mucosa has been studied in patients with chronic maxillary sinusitis undergoing surgery. High concentrations of sparfloxacin were detected in sinus mucosa 2 to 5 h after administration of a single dose of sparfloxacin 200 or 400 mg.

A single 200-mg oral dose of trovafloxacin (CP-99,219) was given to each of eight healthy male volunteers, and the concentrations of the drug were measured in plasma, cantharides-induced inflammatory fluid, and urine over the subsequent 36 h. The mean maximum concentration observed in plasma was 2.9 micrograms/ml at a mean time of 0.75 h postdose. The mean maximum concentration observed in inflammatory fluid was 1.2 micrograms/ml at 4.0 h postdose. The mean elimination half-life in plasma was 7.8 h. The overall penetration into inflammatory fluid was 64%, as assessed by determining the ratio of the area under the concentration-time curves. Recovery of the dose in urine within the first 36 h postdose was 5.0% of the administered dose. Our results indicate that trovafloxacin, at a dosage of 200 mg once or twice daily, should be adequate for the treatment of systemic infections caused by most common bacterial pathogens.

The in vitro activities of two glycylcyclines, CL 329,998 and CL 331,002 (two new semisynthetic tetracyclines), were evaluated in comparison with those of tetracycline and other available oral antimicrobial agents. A total of 523 recent clinical isolates were studied, including strains resistant to tetracycline. Members of the family Enterobacteriaceae were generally > or = 16-fold more susceptible to the glycylcyclines than to tetracycline (although less difference was seen with Proteus spp.). Pseudomonas aeruginosa was modestly susceptible to both new compounds (MIC for 90% of strains tested [MIC90], 16 micrograms/ml). Tetracycline- and methicillin-susceptible and -resistant strains of Staphylococcus aureus were all susceptible to the glycylcyclines (MIC90 < or = 1 microgram/ml). Streptococci (including Streptococcus pneumoniae) and Enterococcus faecalis and Enterococcus faecium displayed a bimodal distribution of susceptibility to tetracycline yet were uniformly susceptible to the glycylcyclines (MIC90 < or = 0.25 microgram/ml). The glycylcyclines were highly potent against Neisseria, Moraxella, Haemophilus, and Bacteroides spp. (MIC90 < or = 0.5 microgram/ml). Strains of Chlamydia spp. (three C. trachomatis strains and one C. pneumoniae strain) were inhibited by < or = 0.25 microgram of CL 329,998 or CL 331,002 per ml. Two strains of Mycoplasma pneumoniae were inhibited by < or = 0.12 microgram of CL 331,002 per ml and by 1 microgram of CL 329,998 per ml. Mycobacterium tuberculosis and Mycobacterium avium were resistant to the two glycylcyclines (MIC > or = 8 micrograms/ml). These results indicate that the two glycylcyclines have potent in vitro activities against a wide range of clinically important pathogenic bacteria.

Each of 12 patients undergoing routine diagnostic upper gastrointestinal endoscopy received a single iv infusion of clindamycin phosphate 300 mg over 10 min. During the endoscopy, mucosal biopsies of the gastric antrum and fundus were obtained at varying times following the infusion. The clindamycin concentrations in the biopsies and in serum samples also taken after the infusion were determined. In addition, six healthy volunteers participated in a cross-over study on two different days. On both days, each subject received a single iv infusion of clindamycin phosphate 300 mg, immediately after which, gastric secretion was stimulated by iv pentagastrin (2 micrograms/kg/h) which was infused continuously over 150 min. On one of the study days, acid secretion by the stomach was inhibited by a slow iv infusion of ranitidine 50 mg. Clindamycin concentrations in gastric aspirates and serum samples collected after the infusion were determined. Concentrations of clindamycin in the fundal mucosa were significantly higher than the simultaneous serum concentrations (median ratio of tissue concentration to serum concentration, 2.0; P < 0.005) while concentrations in the antral mucosa were similar to those in serum (median ratio, 1.2; P = 0.65). Ranitidine significantly inhibited pentagastrin-stimulated acid secretion as demonstrated by a decrease in the volume of gastric aspirate when ranitidine was administered compared with when it was not administered (P < 0.01). Clindamycin concentrations in gastric juice were approximately one and one-half times higher than those in serum samples obtained simultaneously, both during stimulation of gastric acid secretion with pentagastrin and during inhibition of pentagastrin-stimulated acid secretion with ranitidine. Gastric juice concentrations of clindamycin were significantly higher following administration of ranitidine than after stimulation of gastric secretion by pentagastrin alone. Fundal mucosal and gastric juice concentrations of clindamycin exceeded the hypothetical maximum serum concentrations, indicating that accumulation in the stomach occurred against a concentration gradient.

The in vitro activity of ceftibuten was studied in 572 bacterial strains and was compared with the activity of other orally administered beta-lactams. Ceftibuten displayed high activity against the Enterobacteriaceae, generally being 16-fold more active than cefuroxime, cefaclor, cephalexin, or amoxicillin-clavulanic acid. Its activity was comparable to cefixime. There was little ceftibuten or cefixime activity against staphylococci (MIC90s greater than or equal to 64 micrograms/ml) and reduced activity against Streptococcus pneumoniae (MIC90, 16 micrograms/ml). Haemophilus influenzae and Neisseria spp. were highly susceptible to ceftibuten and cefixime. The protein binding of ceftibuten was 77%, and the primary target site was PBP 3. A high degree of stability to beta-lactamase hydrolysis was observed.

The inhibition of supercoiling activity of reconstituted Escherichia coli DNA gyrase by lomefloxacin, ciprofloxacin, and norfloxacin was determined. The concentrations of quinolones needed to inhibit DNA synthesis in Escherichia coli, Enterobacter cloacae, Serratia marcescens, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Staphylococcus aureus were also measured. The kinetics of uptake of [14C]lomefloxacin and unlabeled lomefloxacin into whole cells of E. coli KL-16 and S. aureus NCTC 8532 and the induction of RecA in E. coli GC2241 were assayed. All strains had wild-type susceptibilities to quinolones. The concentration of quinolones needed to inhibit DNA synthesis by 50% correlated with the MIC for members of the family Enterobacteriaceae and P. aeruginosa. The concentration of quinolones needed to inhibit DNA synthesis by 50% for late-logarithmic-phase S. aureus also correlated with the MIC, unlike the data from early-logarithmic-phase cultures. E. coli and S. aureus showed a similar pattern of uptake kinetics of [14C]lomefloxacin and unlabeled lomefloxacin, indicating that the difference in the susceptibilities of the two species is probably due to different target site affinities. Essentially, lomefloxacin was less active than ciprofloxacin and ofloxacin and had activity similar to those of norfloxacin and enoxacin.

A single preoperative dose of imipenem/cilastatin was compared with metronidazole for the prevention of infectious sequelae following emergency appendicectomy. Patients with established sepsis received in addition 72 h of either intravenous imipenem or ampicillin, gentamicin and metronidazole postoperatively. Two hundred and sixty-eight patients were studied. Wound infection rate in low-risk patients was 9% for metronidazole and 8% for imipenem. When sepsis was already established intraperitoneally the wound infection rate was 24% for the triple therapy regimen and 8% for imipenem. There was no statistically significant difference between the infection rates in the two groups of treatment whatever the state of the appendix, but there was a trend in favour of imipenem in those patients with a perforated appendix.

Antimicrobial resistance in pneumococci is well established. Of major concern is the development of resistance to penicillin; however, reduced susceptibility to other commonly used agents such as chloramphenicol, erythromycin, and tetracycline has also been observed with increasing frequency.1,2 We wish to report the isolation of a clinical strain of Streptococcus pneumoniae with intermediate susceptibility to penicillin (minimum inhibitory concentration, 1 mg/L), which was also resistant to numerous other antimicrobial agents.

1 Child J, Andrews J, Boswell F, Brenwald NP, Wise R. The in vitro activity of CP 99,219, a new naphthyridone antimicrobial agent. J Antimicrob Chemother 1995; 35: 869–76. 2 Petersen U, Bremm KD, Dalhoff A, et al. Synthesis in BAY 12-8039, a new 8-methoxy-quinolone. Abst no F1. 36th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans. Sept 15–18, 1996. 3 Report of the Working Party on Antimicrobial Sensitivity Testing of the British Society for Chemotherapy. London: Academic Press, 1991. 4 Pan X-S, Ambler J, Mehtar S, Fisher LM. Involvement of topoisomerase IV and DNA gyrase as ciprofloxacin targets in Streptococcus pneumoniae. Antimicrob Agents Chemother 1996; 40: 2321–26. financial burdens and may ultimately hamper access to effective antimalarial treatment rather than improve access. It is equally important, therefore, that when policy changes are made, they are made in favour of a drug that will have a reasonably long useful lifespan. Clearly, chloroquine’s reign is ending in much of Africa. However, no country will choose to replace chloroquine as long as it remains effective. By definition, resistance rates to chloroquine will already be high when a change is contemplated. Thus, with crossresistance between chloroquine and amodiaquine, the efficacy of amodiaquine will be severely impaired from the beginning. Increased usage after a policy change would raise drug pressure on an already resistant population of parasites and might rapidly increase resistance to even higher levels. How long would amodiaquine really remain effective? By the time a country fully implemented a change from chloroquine to amodiaquine, the efficacy of amodiaquine might already be in jeopardy. The country would then be left with an even more difficult decision: to start the policy change process all over again or to accept—as has been done with chloroquine—an inadequate treatment for a very common disease.

The in vitro activity of fludalanine ( MK641 ) combined with pentizidone ( MK642 ) so as to give a fludalanine /D-cycloserine ratio of 1:1 was compared with the activities of ampicillin, ticarcillin, cefuroxime, ceftazidime, and trimethoprim against 452 recent isolates and known beta-lactam- and trimethoprim-resistant strains. In addition, the in vitro activity of fludalanine - pentizidone on four different media, including a defined medium ( DFN -2), was studied. The MIC of fludalanine - pentizidone against 90% of Escherichia coli, Klebsiella spp., Enterobacter spp., Providencia stuartii, Haemophilus influenzae, Neisseria gonorrhoeae, Staphylococcus aureus, and fecal streptococci was 4 micrograms or less per ml on DFN -2, and activity was somewhat reduced on the other media. Proteus spp. and Pseudomonas aeruginosa (90% MIC, less than or equal to 64 micrograms/ml) and Bacteroides spp. (90% MIC, 16 micrograms/ml) were less susceptible. Generally, fludalanine - pentizidone was less active than ceftazidime and comparable in activity to cefuroxime. beta-Lactamase-producing and trimethoprim-resistant strains tended to be susceptible to fludalanine - pentidizone . In the absence of human serum, the MBC of fludalanine - pentizidone was similar to the MIC. In the presence of increasing concentrations of human serum, there tended to be a greater difference between the MIC and MBC.

Temocillin is a new penicillin combining activity against Gram-positive organisms, beta-lactamase stability and an exceptionally long half-life. In patients with normal renal function the half-life was approximately 4-6 h and this increased to 30 h in patients with severe renal failure. It is suggested that unlike other penicillins this compound may give adequate antibacterial concentration with once daily dosing in subjects with normal renal function; this will certainly require reduction in subjects with severely impaired renal function.

Forty strains of Bacteroides sp. were tested against three nitroimidazole compounds, metronidazole, tinidazole and nimorazole and the aminoglycosidic antibiotic spectinomycin. The effect of altering the inoculum and the presence of serum upon the minimum inhibitory concentration (MIC) was also noted. The three nitroimidazole compounds were all very active (average MIC = circa 0.25 mg/l. Tinidazole was twofold more active. The MIC of spectinomycin was 32 mg/l