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S H Zinner

Publications and source records attributed to S H Zinner.

At least 37 records · Page 2Linked to original sources
PubMed1998

Inter- and intraquinolone predictors of antimicrobial effect in an in vitro dynamic model: new insight into a widely used concept.

Earlier efforts to search for pharmacokinetic and bacteriological predictors of fluoroquinolone antimicrobial effects (AMEs) have resulted in conflicting findings. To elucidate whether these conflicts are real or apparent, several predictors of the AMEs of two pharmacokinetically different antibiotics, trovafloxacin (TRO) and ciprofloxacin (CIP), as well as different dosing regimens of CIP were examined. The AMEs of TRO given once daily (q.d.) and CIP given q.d. and twice daily (b.i.d.) against Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were studied in an in vitro dynamic model. Different monoexponential pharmacokinetic profiles were simulated with a TRO half-life of 9.2 h and a CIP half-life of 4.0 h to provide similar eightfold ranges of the area under the concentration-time curve (AUC)-to-MIC ratios, from 54 to 432 and from 59 to 473 (microg x h/ml)/(microg/ml), respectively. In each case the observation periods were designed to incorporate full-term regrowth phases in the time-kill curves, and the AME was expressed by its intensity (IE; the area between the control growth and time-kill and regrowth curves up to the point at which the viable counts of regrowing bacteria are close to the maximum values observed without drug). Species-independent linear relationships were established between IE and log AUC/MIC, log AUC above MIC (log AUCeff), and time above the MIC (Teff). Specific and nonsuperimposed IE versus log AUC/MIC or log AUCeff relationships were inherent in each of the treatments: TRO given q.d. (r2 = 0.97 and 0.96), CIP given q.d. (r2 = 0.98 and 0.96), and CIP given b.i.d. (r2 = 0.95 and 0.93). This suggests that in order to combine data sets obtained with individual quinolones to examine potential predictors, one must be sure that these sets may be combined. Unlike AUC/MIC and AUCeff, the IE-Teff relationships plotted for the different quinolones and dosing regimens were nonspecific and virtually superimposed (r2 = 0.95). Hence, AUC/MIC, AUCeff and Teff were equally good predictors of the AME of each of the quinolones and each dosing regimen taken separately, whereas Teff was also a good predictor of the AMEs of the quinolones and their regimens taken together. However, neither the quinolones nor the dosing regimens could be distinguished solely on the basis of Teff whereas they could be distinguished on the basis of AUC/MIC or AUCeff. Thus, two types of predictors of the quinolone AME may be identified: intraquinolone and/or intraregimen predictors (AUC/MIC, AUCeff and Teff) and an interquinolone and interregimen predictor (Teff). Teff may be able to accurately predict the AME of one quinolone on the basis of the data obtained for another quinolone.

Anti-Infective Agents↗
PubMed1997

Net effect of inoculum size on antimicrobial action of ampicillin-sulbactam: studies using an in vitro dynamic model.

To examine the predictable effect of inoculum size on the kinetics of the antimicrobial action of ampicillin-sulbactam, five TEM-1 beta-lactamase-producing Escherichia coli strains were studied in an in vitro dynamic model at two different initial inocula (N0S). All bacteria were exposed to ampicillin-sulbactam in a simulated system reflecting the pharmacokinetic profiles in human tissue after the administration of a single intravenous dose of ampicillin (2 g) plus sulbactam (1 g). Each strain was studied at low (4.0 to 5.2 log CFU/ml) and high (5.0 to 7.1 log CFU/ml) N0S. Despite pronounced differences in susceptibilities, the patterns of the killing curves observed with a given strain at different N0S were similar. As expected, viable bacterial counts increased with inoculum size. Striking visual contrasts in the respective curves for each organism were reflected by the area under the bacterial count-time curve (AUBC) but not by the difference between the N0 and the lowest bacterial counts (Nmin) at the nadir of the killing curve: the N0-associated changes in the AUBC on average were 75%, versus 2.5% for log N0--logNmin. To examine qualitative differences in antimicrobial effects at different N0S (i.e., the net effect of the inoculum), the difference in the high and low N0S was subtracted from each point on the killing curve obtained at the higher N0 for each strain. These adjusted curves were virtually superimposable on the observed killing curves obtained at the lower N0. Moreover, by using adjusted data, the AUBC values were similar at the two inocula, although slight (average, 11%) but systematic increases in the AUBC occurred at high N0S. Thus, there was only a weak net effect of inoculum size on the antibacterial effect of ampicillin-sulbactam. Due to similar slopes of the AUBC-log N0 plots, the antibacterial action at different N0S may be easily predicted by an approximate equation; the predicted AUBCs were unbiased and well correlated with the observed AUBCs (r = 0.997). Compiled data obtained with normalized AUBCs for different strains at different N0S yielded a positive correlation (r = 0.963) between the N0-normalized AUBC and the MIC of ampicillin-sulbactam. The adjustment and normalization procedure described might be a useful tool for revealing the net effect of the inoculum and to predict the inoculum effect if there are no qualitative differences in antimicrobial action at different inocula.

Ampicillin↗
PubMed1997

Sexual behavior and contraceptive use. Changes from 1975 to 1995 in college women.

OBJECTIVE: The objective of this study was to compare the sexual practices and contraceptive use in a sample of college women in 1995 with women surveyed in 1975, 1986 and 1989. STUDY DESIGN: We surveyed 336 college women seen at a university student health service or on campus and compared their responses to those of women surveyed at the university in 1975, 1986 and 1989. RESULTS: The proportions of women who were sexually experienced, number of life-time male sexual partners, number of male sexual partners in the past year and frequencies of specific sexual practices were similar over the four survey times. Condom use was reported as the usual method of contraception in 7% of sexually experienced women in 1975, 14% in 1986, 25% in 1989 and 46% in 1995 (P < .00001, linear trend). CONCLUSION: We found little change in sexual practices in this college population over the four survey years, with the exception of an increase in the self-reported use of condoms. Increased educational efforts should emphasize safe sexual practices (barrier methods) to prevent sexually transmitted diseases and highly efficacious methods of contraception (hormonal contraception) to avoid unintended pregnancy.

Adult↗
PubMed1996

Predictors of effect of ampicillin-sulbactam against TEM-1 beta-lactamase-producing Escherichia coli in an in vitro dynamic model: enzyme activity versus MIC.

The clinical outcome in patients treated with ampicillin-sulbactam may not always be predictable by disc susceptibility testing or with the MIC as determined with a constant level (4 micrograms/ml) of the beta-lactamase inhibitor (MIC1). The enzyme activities (EA) and the MICs estimated at a constant ratio of ampicillin to sulbactam of 2:1 (MIC2) for 15 TEM-1 beta-lactamase-producing strains of Escherichia coli were examined as alternatives to MIC1 as predictors of the antibacterial effects of this combined drug as studied in an in vitro model which simulates ampicillin-sulbactam pharmacokinetic profiles observed in human peripheral tissues. Integral parameters describing the area under the bacterial count-time curve (AUBC), the area between the normal growth curve, and the killing curve of bacteria exposed to antibiotic (ABBC), and the second parameter expressed as a percentage of its maximal hypothetical value (ABBC/ABBCmax) were calculated. All three parameters correlated well with EA (AUBC, r = 0.93; ABBC, r = -0.88; ABBC/ABBCmax, r = -0.91) and with MIC2 (r = 0.94, -0.94, and -0.95, respectively) but not with MIC1. Both EA and MIC2 can be considered reliable predictors of the antibacterial effect of ampicillin-sulbactam in an in vitro model. These correlations suggest that in vitro kinetic-dynamic models might be useful to reexamine established susceptibility breakpoints obtained with data based on the MIC1 (MICs obtained with constant levels of beta-lactamase inhibitors). These data also suggest that quantitative determinations of bacterial beta-lactamase production and MICs based on the component concentration ratio observed in vivo might be useful predictors of the effect of ampicillin-sulbactam and other beta-lactam-inhibitor combinations.

Ampicillin↗
PubMed1996

Monotherapy with meropenem versus combination therapy with ceftazidime plus amikacin as empiric therapy for fever in granulocytopenic patients with cancer. The International Antimicrobial Therapy Cooperative Group of the European Organization for Research and Treatment of Cancer and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto Infection Program.

Combinations of beta-lactams plus aminoglycosides have been standard therapy for suspected infections in granulocytopenic cancer patients, especially those with profound long-lasting granulocytopenia. With the advent of new broad-spectrum bactericidal antibiotics such as extended-spectrum cephalosporins or carbapenems, the need to combine beta-lactams with aminoglycosides became more controversial. The objective of this prospective randomized multicenter study was to compare the efficacy, safety, and tolerance of meropenem monotherapy with those of the combination of ceftazidime plus amikacin for the empirical treatment of fever in granulocytopenic cancer patients. Of 1,034 randomized patients, 958 were assessable in the intent-to-treat analysis for response to antibacterial therapy, including 483 in the meropenem group and 475 in the ceftazidime-plus-amikacin group. The median durations of neutropenia were 16 and 17 days, respectively. A successful outcome was reported in 270 of 483 (56%) patients treated with monotherapy compared with 245 of 475 (52%) patients treated with the combination group (P = 0.20). The success rates in the monotherapy group and the combination group were similar by type of infection (single gram-negative bacteremia, single gram-positive bacteremia, clinically documented infection, and possible infection). The occurrence of further infections assessed in patients for whom the allocated regimen was not modified did not differ between the two groups (12% in both groups). Mortality due to the presenting infection or further infection was relatively low (8 patients treated with the monotherapy compared with 13 patients treated with the combination). A total of 1,027 patients were evaluable for adverse events; the proportion of those who developed adverse effects was similar between the two groups (29% in both groups), and only 19 (4%) patients in the monotherapy group and 31 (6%) in the combination group experienced an adverse event related or probably related to the study drug. Allergic reactions were the only reason for stopping the protocol antibiotic(s) (3 and 5 patients, respectively). This study confirms that monotherapy with meropenem is as effective as the combination of ceftazidime plus amikacin for the empiric treatment of fever in persistently granulocytopenic cancer patients, and both regimens were well tolerated.

Adolescent↗
PubMed1995

New and unusual infections in neutropenic patients.

Infections in immunocompromised patients with cancer are common and the primary risk factor is neutropenia, usually induced by chemotherapeutic agents. The spectrum of bacterial infection is shifting from gram-negative to gram-positive. The array of fungal infections in cancer patients is expanding to include organisms previously unknown as invasive human pathogens. New species are being defined to explain extant pathologies, and free living algae are now emerging as pathogens in immunocompromised patients. Physicians must remain alert to these emerging pathogens and to the need to evaluate optimal treatments for the usual and unusual infections in neutropenic and other compromised patients with cancer and allied diseases.

Bacteria, Anaerobic↗
PubMed1994

Pharmacodynamics of piperacillin alone and in combination with tazobactam against piperacillin-resistant and -susceptible organisms in an in vitro model of infection.

The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.

Bacteria↗
PubMed1993

2',3'-didehydro-3'-deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial.

2',3'-didehydro-3'-deoxythymidine (d4T) is a pyrimidine analogue and inhibitor of reverse transcriptase with potent in vitro activity against human immunodeficiency virus (HIV). A phase I trial of d4T was conducted in 41 HIV-infected patients, 12 with AIDS and 29 with AIDS-related complex (ARC). Thirty-six patients were evaluatable. The maximum tolerated dose was 2 mg/kg/day. The dose-limiting toxicity was sensory peripheral neuropathy, which occurred in 20 patients (55%). Four patients (11%) developed hepatotoxicity. Five (14%) developed anemia requiring a transfusion but not discontinuation of drug. The mean +/- SE plasma elimination half-life at all dose levels was 1.2 +/- 0.09 h. Increased or stable absolute CD4 counts were seen in most patients. The majority of patients with detectable serum p24 antigen levels had a persistent decrease by 6 months. d4T is a promising drug for patients with AIDS or ARC. This clinical trial is continuing to determine the minimal effective dose.

AIDS-Related Complex↗
PubMed1993

Dose ranging and fractionation of intravenous ciprofloxacin against Pseudomonas aeruginosa and Staphylococcus aureus in an in vitro model of infection.

The effect of dose or dose interval on the pharmacodynamics of simulated high-dose intravenous ciprofloxacin therapy on infection due to Pseudomonas aeruginosa and Staphylococcus aureus was studied in an in vitro hollow-fiber model of infection. Simulated doses of 1,200 mg of ciprofloxacin per day as either 400 mg every 8 h or 600 mg every 12 h against P. aeruginosa resulted in selection of ciprofloxacin-resistant bacteria. The results with one test strain that was isolated from a patient prior to administration of intravenous ciprofloxacin demonstrated selection of a gyrA mutant in the model, as had occurred in vivo. A single 1,200-mg dose every 24 h did not select for bacterial resistance; however, breakthrough regrowth of ciprofloxacin-susceptible bacteria occurred. Dosages of 400 or 600 mg of ciprofloxacin every 12 h effectively reduced bacterial counts of one strain each of methicillin-susceptible or -resistant S. aureus, with no bacterial resistance detected at the end of experiment; in contrast, 200 mg every 12 h resulted in bacterial regrowth due to the selection of drug-resistant bacteria. These data show the need for high-dose intravenous ciprofloxacin, particularly with regimens producing high peak levels, for treatment of infections where selection for bacterial resistance is a clinical problem.

Ciprofloxacin↗
PubMed1992

Management of urinary tract infections in pregnancy: a review with comments on single dose therapy.

Most investigators agree that the adverse effects of urinary tract infections in pregnancy can be abrogated by effective early detection and treatment. However, the optimal methods for screening and treatment remain controversial. Although single-dose therapy has not been applied to pregnant women with acute pyelonephritis, most but not all studies which have compared single-dose with longer courses of beta-lactam or other antibiotics in pregnant asymptomatic bacteriuric women have shown no differences in outcome. This paper reviews recent trials of single-dose treatment of bacteriuria in pregnant women.

Anti-Infective Agents, Urinary↗
PubMed1991

Combination therapy with ciprofloxacin plus azlocillin against Pseudomonas aeruginosa: effect of simultaneous versus staggered administration in an in vitro model of infection.

The effect of dose scheduling on the pharmacodynamics of simulated human doses of ciprofloxacin (200 mg intravenously [iv] every 12 h) and azlocillin (4 g iv every 12 h) alone or in combination against Pseudomonas aeruginosa was studied in a two-compartment in vitro kinetic model of infection. Studies with the two drugs in combination were compared using simultaneous or staggered (first doses of each drug were administered 6 h apart) dosing schedules. Bacterial regrowth and resistance were prevented by all combination dosing schedules; however, the simultaneous regimen consistently provided the greatest extent of killing for all strains, particularly in those initially resistant to ciprofloxacin. These enhanced effects of the combination were corroborated by an increase in the peak and duration of bactericidal activity in the analogous "serum" compartment of the model. These data show the potential usefulness of simultaneous dosing of an antipseudomonal beta-lactam with ciprofloxacin against P. aeruginosa.

Azlocillin↗
PubMed1991

Single daily dosing of amikacin in an in-vitro model.

The pharmacodynamics of amikacin given as a single daily dose was compared with standard divided dosing in an in-vitro model of infection. This model allows the exposure of log phase bacteria to changing concentrations of antibiotics that simulate the kinetics of the drugs in human patients. Two strains of Pseudomonas aeruginosa, one sensitive and one resistant to azlocillin were studied (MICs for amikacin were 16 and 8 mg/l respectively). Simulated drug regimens included: amikacin 400 mg q 8 h; amikacin 1.2 g q 24 h; and azlocillin 4 g q 12 h. Each regimen alone and both combinations of amikacin plus azlocillin were studied. With both amikacin regimens initial rapid killing was followed by regrowth of resistant subpopulations. Azlocillin alone produced minimal killing of the resistant strain and moderate killing with ultimate bacteriostasis of the susceptible strain. Bacterial regrowth was prevented with both combination regimens with the single daily dose of amikacin plus azlocillin producing the most rapid and complete killing, especially of the azlocillin resistant strain. These data support further clinical studies of single daily dosing of aminoglycosides.

Amikacin↗