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J C Rotschafer

Publications and source records attributed to J C Rotschafer.

At least 19 recordsLinked to original sources
PubMed2002

Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model.

An in vitro pharmacodynamic investigation was conducted to explore whether the area under the concentration time curve from 0 to 24 h (AUC(0-24))/MIC ratio could predict fluoroquinolone performance against Bacteroides fragilis. An in vitro model was used to generate kill curves for trovafloxacin (TVA) and levofloxacin (LVX) at AUC(0-24)/MIC ratios of 1 to 406 against three strains of B. fragilis (ATCC 25285, ATCC 23745, and clinical isolate M97-117). TVA and LVX were bolused prior to the start of experiments to achieve the corresponding AUC(0-24)/MIC ratio. Experiments were performed in duplicate over 24 h and in an anaerobic environment. Analyses of antimicrobial performance were conducted by comparing the rates of bacterial kill (K) using nonlinear regression analysis with 95% confidence intervals. Statistical significance was defined as a lack of overlap in the 95% confidence limits generated from the slope of each kill curve. For both TVA and LVX, K was maximized once an AUC(0-24)/MIC ratio of > or =40 was achieved and was not further increased despite a 10-fold increase in AUC(0-24)/MIC from approximately 40 to 400 against all three strains of B. fragilis. No significant differences were found in K between AUC(0-24)/MIC ratios of approximately 40 to 200. In experiments where AUC(0-24)/MIC ratios that were > or = 5 and < or = 44 were conducted, 64% demonstrated regrowth at 24 h. Resistant strains were selected in 50% of those experiments, demonstrating regrowth, which resulted in increased MICs of two- to 16-fold for both TVA and LVX. Regrowth did not occur, nor were resistant strains selected in any studies with an AUC/MIC that was > 44. Our findings suggest that fluoroquinolones provide antibacterial effects against B. fragilis in a concentration-independent manner associated with an AUC(0-24)/MIC ratio of > or =40. Also, the potential for the selection of resistant strains of B. fragilis may increase with an AUC(0-24)/MIC ratio of < or =44.

Anti-Infective Agents↗
PubMed2001

Intensive care unit antimicrobial resistance and the role of the pharmacist.

Over the past 20 yrs, pharmacists have successfully integrated their services and expertise to gain acceptance as full members of pediatric, surgical, medical, and intensive care unit (ICU) patient care teams. The pharmacists' training in pharmacology, pharmacokinetics, pharmacodynamics, and pharmacoeconomics complements the expertise of other members of the patient care team. Generally, a strong background in infectious diseases and critical care also provides a focal point for clinical pharmacy service intervention. Although practitioners often focus on issues exclusively related to their specific hospital or ICU, the issues surrounding antibiotic resistance are more global and societal in nature. Medical, surgical, and pharmaceutical practices inside the hospital and ICU extend their influence into the community. Customs and practices of daily living in our society coupled with use of agents capable of altering microbial flora impact our hospital and ICU when patients from the community are admitted. The misuse of antibiotics and the lack of effective infection control programs are often identified as key components in the perpetuation of these phenomena. The focus for the pharmacist and the ICU team must be on the optimization of antibiotic use and infection control guidelines. This review will address the many issues that surround the appropriate use of antibiotics and what role the pharmacist can play in ensuring the optimal use of infection control measures in the ICU and hospital.

Anti-Bacterial Agents↗
PubMed2001

Comparison of once-daily versus twice-daily administration of cefdinir against typical bacterial respiratory tract pathogens.

In an in vitro pharmacodynamic model, a twice-daily cefdinir dosing regimen was more effective than a once-daily regimen against common bacterial respiratory pathogens in producing 3-log(10) killing and preventing the occurrence of regrowth at 24 h. Twice-daily administration is likely the more appropriate cefdinir dosing strategy for the treatment of community-acquired pneumonia.

Anti-Bacterial Agents↗
PubMed2001

Fluoroquinolone resistance in anaerobic bacteria following exposure to levofloxacin, trovafloxacin, and sparfloxacin in an in vitro pharmacodynamic model.

This investigation explored pharmacodynamic characteristics of fluoroquinolones against Bacteroides thetaiotamicron and the potential for development of resistance. An in vitro model was used to generate kill curves with three fluoroquinolones at various area under the concentration-time curve (AUC)/MIC ratios. Concentration-independent killing was observed. Increases in MICs were noted following exposure to fluoroquinolones at AUC/MIC ratios of 6 to 14.

Anti-Infective Agents↗
PubMed2001

What do we really know about antibiotic pharmacodynamics?

Antibiotic pharmacodynamics is an evolving science that focuses on the relationship between drug concentration and pharmacologic effect, which is an antibiotic-induced bacterial death that also can manifest as an adverse drug reaction. The pharmacologic action of antibiotics usually can be described as concentration dependent or independent, although such classifications are highly reliant on the specific antibiotic and bacterial pathogen being studied. Quantitative pharmacodynamic parameters, such as ratio of the area under the concentration-time curve during a 24-hour dosing period to minimum inhibitory concentration (AUC0-24:MIC), ratio of maximum serum antibiotic concentration to MIC (Cmax:MIC), and duration of time that antibiotic concentrations exceed MIC (T>MIC), have been proposed as likely predictors of clinical and microbiologic success or failure for different pairings of antibiotic and bacteria. Thus far, most pharmacodynamic data reported have focused on fluoroquinolones, but work has been conducted on vancomycin, beta-lactams, macrolides, aminoglycosides, and other antibiotics. Despite the development of a number of different pharmacodynamic modeling systems, remarkable agreement exists between in vitro, animal, and limited human data. Although still somewhat premature and requiring additional clinical validation, antibiotic pharmacodynamics will likely advance on four fronts: the science should prove to be extremely useful and represent a cost-effective and efficient method to help develop new antibiotics; formulary committees will likely use pharmacodynamic parameters to assist in differentiating antibiotics of the same chemical class in making antibiotic formulary selections; pharmacodynamic principles will likely be used to design optimal antibiotic strategies for patients with severe infections; and limited data to date suggest that the application of pharmacodynamic concepts may limit or prevent the development of antibiotic resistance. The study of antibiotic pharmacodynamics appears to hold great promise and will likely become a routine part of our daily clinical practices.

Animals↗
PubMed2001

In vitro pharmacodynamic analysis of single daily dosing versus conventional dosing of gentamicin administered with penicillin against Enterococcus faecalis.

STUDY OBJECTIVE: To compare the effectiveness of single daily dosing (SDD) versus conventional dosing of gentamicin when administered with penicillin to treat enterococcal infections. DESIGN: In vitro pharmacodynamic model. SETTING: Hospital laboratory. MEASUREMENTS AND MAIN RESULTS: A 24-hour in vitro pharmacodynamic model was employed to simulate SDD and 3 times/day dosing of gentamicin, in conjunction with continuously infused penicillin, against Enterococcus faecalis. Duplicate 24-hour kill curves were generated with varying concentrations of penicillin and gentamicin alone and in combination. No difference in the rate of kill was seen between any combination of penicillin and gentamicin. Regrowth occurred only with drug combinations in which penicillin was administered continuously at the minimum inhibitory concentration. Variations in the gentamicin dosing regimen did not affect regrowth. CONCLUSION: In the treatment of enterococcal infections, an SDD regimen for gentamicin shows no efficacy benefit compared with conventional dosing.

Anti-Bacterial Agents↗
PubMed2000

Application of fluoroquinolone pharmacodynamics.

Pharmacodynamics provides a rational basis for optimizing dosing regimens by describing the relationship between drug, host and antimicrobial effect. The successful identification of meaningful pharmacodynamic outcome parameters can, therefore, greatly assist clinicians in making objective prescribing decisions rather than relying on static in vitro MIC data. While pharmacodynamic outcome parameters have been proposed for select antimicrobial agents, their clinical application remains to be defined fully. Quinolone antibiotics are generally considered to have concentration-dependent bactericidal activity and peak/MIC and AUC/MIC ratios have been identified as possible pharmacodynamic predictors of clinical and microbiological outcome as well as the development of bacterial resistance. Investigators have suggested that AUC/MIC ratios of 100-125 or peak/MIC ratios of >10 are required to predict clinical and microbiological success and to limit the development of bacterial resistance. These conclusions are derived primarily from studies of Gram-negative bacteria, and recent data suggest that these ratios may not be applicable for Streptococcus pneumoniae, where an AUC/MIC ratio of <40 appears to be a more accurate predictor. There is considerable variation in pharmacodynamic calculations and outcome parameters appear to be quinolone- and pathogen-specific. Additional prospective clinical research is needed to characterize quinolone pharmacodynamic parameters and answer unresolved questions regarding optimal pharmacodynamic outcome predictors for Gram-positive bacteria, anaerobes and atypical respiratory pathogens.

Animals↗
PubMed1999

Gram-positive infections: pharmacy issues and strategy for quinupristin/dalfopristin.

The development of the first streptogramin antibiotic, quinupristin/dalfopristin represents an attempt to bring new antimicrobial strategies on line to combat the menacing problem of Gram-positive-resistant bacteria. With introduction to the medical center formulary, the pharmacy will need to be aware of several practical issues surrounding the use of quinupristin/dalfopristin. Cost and unit size will be important issues. Initially, this drug will only be available in 500-mg vials which may not always accommodate the suggested dose of 7.5 mg/kg of actual body weight. In addition, the drug can only be reconstituted with D5W or sterile water, and it can not be mixed with normal saline, heparin, or other drugs. Institutions adding this drug to their formularies must address the expected logistical concerns with their medical, nursing, and pharmacy staffs prior to patient usage.

Anti-Bacterial Agents↗
PubMed1999

Fluoroquinolone resistance in Bacteroides fragilis following sparfloxacin exposure.

In vitro pharmacodynamic studies investigating the antimicrobial properties of five fluoroquinolones, (trovafloxacin, sparfloxacin, clinafloxacin, levofloxacin, and ciprofloxacin) against Bacteroides fragilis ATCC 23745 were conducted. The times required to reduce the viable counts by 3 log units were as follows: clinafloxacin, 2.9 h; levofloxacin, 4.6 h; trovafloxacin, 6 h; and sparfloxacin, 10 h. Exposure to ciprofloxacin did not achieve a 3-log decrease in viable counts. The susceptibility of B. fragilis was determined both prior to exposure and following 24 h of exposure to each of the five fluoroquinolones tested. The MICs of clinafloxacin, levofloxacin, trovafloxacin, sparfloxacin, ciprofloxacin, metronidazole, cefoxitin, chloramphenicol, and clindamycin were determined by the broth microdilution method. The MICs for B. fragilis preexposure were as follows: clinafloxacin, 0.25 microg/ml; trovafloxacin, 0.5 microg/ml; sparfloxacin, 2 microg /ml; levofloxacin, 2 microg/ml; and ciprofloxacin, 8 microg/ml. Similar pre- and postexposure MICs were obtained for cultures exposed to trovafloxacin, clinafloxacin, levofloxacin, and ciprofloxacin. However, following 24 h of exposure to sparfloxacin, a fluoroquinolone-resistant strain emerged. The MICs for this strain were as follows: clinafloxacin, 1 microg/ml; trovafloxacin, 4 microg/ml; sparfloxacin, 16 microg/ml; levofloxacin, 16 microg/ml; and ciprofloxacin, 32 microg/ml. No changes in the susceptibility of B. fragilis pre- and postexposure to sparfloxacin were noted for metronidazole (MIC, 1 microg/ml), cefoxitin (MIC, 4 microg /ml), chloramphenicol (MIC, 4 microg/ml), and clindamycin (MIC, 0.06 microg/ml). Resistance remained stable as the organism was passaged on antibiotic-free agar for 10 consecutive days. Mutant B. fragilis strains with decreased susceptibility to clinafloxacin, trovafloxacin, sparfloxacin, levofloxacin, and ciprofloxacin were selected on brucella blood agar containing 8x the MIC of levofloxacin at a frequencies of 6.4 x 10(-9), 4x the MICs of trovafloxacin and sparfloxacin at frequencies of 2.2 x 10(-9) and 3. 3 x 10(-10), respectively, and 2x the MIC of clinafloxacin at a frequency of 5.5 x 10(-11); no mutants were selected with ciprofloxacin. The susceptibilities of strains to trovafloxacin, levofloxacin, clinafloxacin, sparfloxacin, and ciprofloxacin before and after exposure to sparfloxacin were modestly affected by the presence of reserpine (20 microg/ml), an inhibitor of antibiotic efflux. The mechanism of fluoroquinolone resistance is being explored, but it is unlikely to be efflux due to a lack of cross-resistance to unrelated antimicrobial agents and to the fact that the MICs for strains before and after exposure to sparfloxacin are minimally affected by reserpine.

Anti-Infective Agents↗
PubMed1999

Cyclospora: review of an emerging parasite.

Cyclospora is a parasite traditionally associated with diarrhea in travelers to endemic countries. Recently, several cases of cyclosporiasis were reported in nontravelers in the United States and Canada, implicating various fruits and vegetables as vehicles of infection. The life cycle of cyclospora is not fully known, but is believed to involve both asexual and sexual stages of proliferation. Food- and water-borne transmission of infection have been implicated. Patients infected with Cyclospora cayetanensis have protracted watery diarrhea. Various generalized symptoms are also present, making cyclosporiasis indistinguishable from infectious diarrhea caused by other microorganisms. Diagnosis depends on identifying the organism by microbiologic examination of stool samples. Treatment consists of supportive care, maintenance of fluid and electrolyte status, symptomatic relief, and antibiotic therapy. Trimethoprim-sulfamethoxazole is the only antibiotic available that is effective in eradicating the organism.

Anti-Infective Agents↗
PubMed1999

Bacillus anthracis: medical issues of biologic warfare.

Recent world events refocused attention on the possibility of nations engaging in biologic warfare, including an attack with Bacillus anthracis. The single available anthrax vaccine in the United States for human use, formerly known as MDPH-PA, has decreased ability to protect laboratory animals against virulent B. anthracis strains, especially compared with new vaccines being developed. Studies with these vaccines, however, have several shortcomings. The pathogenesis, diagnosis, treatment, and prophylaxis of anthrax are discussed, as well as the implications that an attack with B. anthracis would place on the health care system.

Anthrax↗
PubMed1999

Implications of vancomycin degradation products on therapeutic drug monitoring in patients with end-stage renal disease.

In renally impaired patients, vancomycin concentrations typically are maintained at body temperature for extended periods of time due to the drug's prolonged half-life. Both time and increased temperature potentiate production of vancomycin crystalline degradation products (CDP-1). Commercially available vancomycin assays, such as fluorescence polarization immunoassay (FPI) and radioimmunoassay, cross-react with CDP-1 isomers. Overestimation of vancomycin concentrations by 40-53% due to cross-reactivity of CDP-1 with active factor B vancomycin occurs with FPI. As FPI is the most common method of analyzing serum vancomycin, clinicians must be aware of its potential shortcomings and be prepared to alter vancomycin dosages in renally impaired patients. The possibility of adverse affects due to elevated concentrations of CDP-1 or therapeutic failures due to subtherapeutic levels of factor B vancomycin cannot be excluded.

Anti-Bacterial Agents↗
PubMed1998

Determination of quinolone antibiotics in growth media by reversed-phase high-performance liquid chromatography.

A simple, accurate, precise, and versatile high-performance liquid chromatographic (HPLC) method was developed and validated for the determination of three quinolone antibodies in Mueller-Hinton broth. The fluoroquinolone agents studied were ciprofloxacin, ofloxacin, and sparfloxacin; other quinolone agents have been identified using this method but not validated in this matrix (levofloxacin, clinafloxacin, temafloxacin, and trovafloxacin). In addition, several other biological growth mediums have been investigated (human serum, human urine, Todd-Hewitt growth media, Ensure enteral feeding solution, and Haemophilus growth media). This method uses UV detection (280 nm), a simple, one-step protein precipitation extraction, and separation using a C18 column with an isocratic, ion-pairing mobile phase. An appropriate internal standard was obtained by using another quinolone antibiotic of differing retention time. The calibration curves were linear (r2> or =0.999) over a concentration range of 0.0625-20.0 microg/ml with a lower limit of quantification of 0.1 microg/ml. The intra-day and inter-day coefficients of variation were less than 15%.

Calibration↗
PubMed1996

A pharmacodynamic evaluation of ciprofloxacin and ofloxacin against two strains of Pseudomonas aeruginosa.

The greater potency of ciprofloxacin in vitro to that of ofloxacin against Pseudomonas aeruginosa may be potentially offset by the more favorable pharmacokinetic profile of the latter drug. In order to test this hypothesis, we generated time concentration kill curves for P. aeruginosa ATCC 27853 and a clinical isolate P. aeruginosa PSA 9258 using an in-vitro model to simulate the pharmacokinetic characteristics found in vivo for ciprofloxacin at a peak concentration (CPmax) of 5 mg/L and an elimination T1/2 of 4.5 h, and ofloxacin at a CPmax of 5 mg/L and a T1/2 of both 4.5 h and 6 h, and at a CPmax of 8.0 mg/L and a T1/2 of 6 h. A 3 log10 kill (T3 kill) of P. aeruginosa ATCC 27853 was achieved in 0.15 h by ciprofloxacin and of P. aeruginosa PSA 9258 in 0.09 h. Ofloxacin at a CPmax of 8 mg/L and T1/2 of 6 h achieved a T3 kill of P. aeruginosa ATCC 27853 in 0.74 h and of P. aeruginosa PSA 9258 in 0.16 h. The area under the kill curve (AUKC) was 1.10 x 10(4)and 1.96 x 10(3) mL-h/cfu for ciprofloxacin against P. aeruginosa ATCC 27853 and P. aeruginosa PSA 9258, respectively and that of ofloxacin at CPmax 8 mg/L and a T1/2 of 6 h was 9.78 x 10(4)and 2.20 x 10(4) mL-h/cfu respectively. Significant differences (P > or = 0.05) were evident between ciprofloxacin and all ofloxacin regimens against P. aeruginosa ATCC 27853 but not against P. aeruginosa PSA 9258. There was a poor correlation (r = 0.22) between the AUKC and area under the time concentration curve (AUC) for P. aeruginosa ATCC 27853 but a strong correlation (r = 0.96) between the AUKC and area under the inhibitory curve (AUIC). Similar results were obtained for P. aeruginosa PSA 9258 for which the correlation between AUKC and AUC was weak (r = 0.10) whereas that between the AUKC and AUIC was strong (r = 0.93). When the data for both P. aeruginosa were combined, a correlation coefficient of r = 0.04 for AUC and r = 0.80 for AUIC was found. These limited data suggest that fluoroquinolones can be compared using the AUIC for specific bacterial isolates. In addition, the larger AUC, higher CP, and longer T1/2 of ofloxacin in vivo did not fully compensate for the intrinsic differences in the antibiotic susceptibility against P. aeruginosa.

Analysis of Variance↗
PubMed1996

The concentration-independent effect of monoexponential and biexponential decay in vancomycin concentrations on the killing of Staphylococcus aureus under aerobic and anaerobic conditions.

An in-vitro pharmacodynamic system was used to generate time-kill curves to demonstrate the concentration-independent pharmacodynamics of vancomycin against Staphylococcus aureus ATCC 29213. Initial vancomycin concentrations of 5, 10, 20 and 40 mg/L were studied monoexponentially while simulating a 6 h half-life. One parallel experiment was performed in duplicate using an initial peak concentration of 40 mg/L where both a distribution alpha-phase half-life of 0.66 h for 1 h and an elimination beta-phase half-life of 6 h for 11 h were simulated to determine if the transient distribution phase concentrations of vancomycin have any impact on bacterial killing beyond that provided by the elimination phase concentrations. Additionally, two monoexponential experiments with peak concentrations of 40 and 20 mg/L and a half-life of 6 h were repeated in an anaerobic chamber to determine if killing of S. aureus was affected. The time to achieve a 3 log10 kill was calculated from the linear portion of the regression line and averaged (mean +/- S.D.) 9.0 +/- 1.4 h for all aerobic monoexponential experiments and was 8.4 and 8.6 h for the aerobic biexponential experiments (P > 0.05). For the anaerobic studies, the times to reach 3 log10 kill were significantly greater averaging 18.9 +/- 1.7 h. The slopes of the bacterial kill curves were virtually identical for both monoexponential and biexponential aerobic experiments averaging -0.34 +/- 0.04, yet significantly different from the anaerobic bacterial kill curve slopes of -0.16 +/- 0.015 (P < 0.05). Time-kill curve analyses suggest that varying the concentration of vancomycin does not affect the rate or extent of bacterial killing aerobically or anaerobically against S. aureus and more efficient killing was achieved under aerobic conditions. The simulated distribution phase concentrations did not contribute to more effective killing of this strain of S. aureus.

Aerobiosis↗