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Biomedical subjects

A Forrest

Publications and source records attributed to A Forrest.

At least 19 recordsLinked to original sources

Containment of heart failure hospitalizations and cost by angiotensin-converting enzyme inhibitor dosage optimization.

Using our model relating angiotensin-converting enzyme (ACE) inhibitor dosing and outcomes in heart failure (HF), we designed a prospective intervention trial for patients with systolic dysfunction. A clinical pharmacist initiated or titrated ACE inhibitor therapy or adjusted other medications within an HF management program based on Agency for Healthcare Policy and Research guidelines. Entry into the protocol required the approval of the attending physician. All patients received dietary, nursing, rehabilitation, social service, and clinical pharmacy consultations. Treatment conformed to Agency for Healthcare Policy and Research guidelines in 25% of patients (group A). Suboptimal therapy (75% of patients) was usually due to failure to administer an ACE inhibitor (48%) or inadequate dosing of an ACE inhibitor (46%). In 62% of suboptimal cases, the attending physician agreed to follow the clinical pharmacist's recommendations (group B). Patients of physicians who declined pharmacist intervention served as a negative control (group C). On admission, mean enalapril-equivalent daily doses in groups A, B, and C were 30, 4, and 6 mg, respectively, and at discharge, 36, 18, and 6 mg, respectively. At 180 days, rehospitalization frequency and total charges were lower in groups A (31% and $5,600) and B (35% and $3,800) than in group C (63% [p <0.004] and $9,800 [p <0.04]). Thus, optimization of ACE inhibitor doses by a clinical pharmacist can greatly improve rehospitalization rates and significantly lower cost of care in an HF management program.

Angiotensin-Converting Enzyme Inhibitors↗

Regulation of CDC25B phosphatases subcellular localization.

The CDC25B dual specificity phosphatase is involved in the control of the G2/M transition of the cell cycle. Subcellular localization might represent an important aspect of the regulation of its activity. We have examined in transiently transfected asynchronous HeLa cells the localization of HA-tagged CDC25B proteins and found that they are nuclear or cytoplasmic suggesting the existence of an active shuttling. Accordingly, localization analysis of deletion and truncation proteins indicates that CDC25B contains a putative nuclear localization signal located between residues 335 and 354. We also demonstrated that a short 58 residues deletion of the amino-terminus end of CDC25B is sufficient to retain it to the nucleus. Mutational analysis indicates that a nuclear export sequence is located between residues 28 and 40. In addition, treatment of the cells with the exportin inhibitor, Leptomycin B, has the same effect. The mutation of Ser-323, a residue that is essential for the interaction with 14-3-3 proteins, also abolishes cytoplasmic staining. The subcellular localization of CDC25B is therefore dependent on the combined effects of a nuclear localization signal, a nuclear export signal and on the interaction with 14-3-3 proteins.

14-3-3 Proteins↗

A nationwide, multicenter, case-control study comparing risk factors, treatment, and outcome for vancomycin-resistant and -susceptible enterococcal bacteremia.

National Nosocomial Resistance Surveillance Group participants from 22 hospitals across the United States reviewed medical records for hospitalized patients with vancomycin-resistant enterococcal (VRE) or vancomycin-susceptible enterococcal (VSE) bacteremia to identify risk factors associated with the acquisition of VRE bacteremia, describe genetic traits of VRE strains, and identify factors predictive of clinical outcome. VRE cases were matched to VSE controls within each institution. Multiple logistic regression (LR) and classification and regression tree (CART) analysis were used to probe for factors associated with VRE bacteremia and clinical outcome. A total of 150 matched-pairs of VRE cases and VSE controls were collected from 1995 to 1997. Using LR, the following were found to be highly associated with VRE bacteremia: history of AIDS, positive HIV status, or drug abuse (OR 9.58); prior exposure with parenteral vancomycin (OR 8.37); and liver transplant history (OR 6. 75). CART analysis revealed that isolation of Enterococcus faecium, prior vancomycin exposure, and serum creatinine values > or = 1.1 mg/dl were predictors of VRE bacteremia. Greater proportions of clinical failure (60% versus 40%, P < 0.001) and all-cause mortality (52% versus 27%, P < 0.001) were seen in patients with VRE versus VSE bacteremia. Results from both LR and CART indicated that patients with persisting enterococcal bacteremia, intubation at baseline, higher APACHE II scores, and VRE bacteremia were at greater risk for poor outcome.

APACHE↗

Comparison of the abilities of grepafloxacin and clarithromycin to eradicate potential bacterial pathogens from the sputa of patients with chronic bronchitis: influence of pharmacokinetic and pharmacodynamic variables.

A randomized open-label study was conducted to compare the pharmacokinetics and pharmacodynamics of grepafloxacin with those of clarithromycin in patients with chronic bronchitis whose sputa were colonized with potential bacterial pathogens. Patients received oral grepafloxacin 400 mg od for 10 days (n = 15) or oral clarithromycin 500 mg bd for 10 days (n = 10). Sputum samples were collected before the first dose, 1, 4 and 8 h after a dose on day 1 and then before a dose on days 2, 3, 5, 7 and 10 to determine the time to eradication (T(erad)) of the potential bacterial pathogens. Blood samples for measurement of grepafloxacin or clarithromycin and 14-hydroxyclarithromycin concentrations were obtained before a dose and 1, 2, 4, 8 and 12 h after doses on days 1 and 5. The area under the inhibitory serum concentration-time curve over 24 h (AUIC(24)), peak serum concentration:MIC ratio (C(max):MIC) and the percentage of the dosing interval during which the serum concentration exceeded the MIC (%tau >MIC) were calculated and serum inhibitory titres (SITs) were determined. Haemophilus spp. were the predominant potential bacterial pathogens and were recovered from the sputa of 24 patients. Strains of Streptococcus pneumoniae were isolated from two patients in the grepafloxacin group and a strain of Moraxella catarrhalis was isolated from one patient in the clarithromycin group. Haemophilus spp. isolates were eradicated from the sputa of 13 of 14 (93%) patients given grepafloxacin, but from only two of 10 (20%) patients given clarithromycin (P < 0.05). In the other eight (80%) patients who received clarithromycin, the sputum cultures remained positive throughout the 10 day course. Grepafloxacin eliminated potential bacterial pathogens more quickly than clarithromycin (median T(erad) 4 h versus 76 h). The S. pneumoniae strains were eradicated by grepafloxacin within 4 h and the single M. catarrhalis strain was eradicated by clarithromycin within 1 h. The greater efficacy of grepafloxacin, compared with that of clarithromycin, in terms of the incidence and speed of eradication of the Haemophilus spp. isolates, was associated with higher median values of AUIC(24) (169 SIT(-1)*h versus 8.1 SIT(-1)*h), C(max):MIC ratio (23.6 versus 0.7) and %tau >MIC (100% versus 0%). A Hill-type model adequately described the relationship between the percentage probability of eradicating potential bacterial pathogens from sputa and the plasma grepafloxacin concentration.

Adolescent↗

Safety, tolerability, and pharmacokinetics of single oral doses of BCH-10652 in healthy adult males.

Racemic dOTC (BCH-10652) is a novel nucleoside reverse transcriptase inhibitor consisting of two enantiomers of 2'-deoxy-3'-oxa-4'-thiocytidine, (-)dOTC and (+)dOTC, that have both shown activity against human immunodeficiency virus type 1. The objectives of this study were to characterize the safety, tolerability, and stereospecific pharmacokinetics of single oral doses of racemic dOTC in healthy, nonsmoking adult male volunteers. Subjects received single oral doses of 100, 200, 400, 800, and 1,600 mg of racemic dOTC in a placebo-controlled, dose-rising, incomplete crossover study design, and the pharmacokinetics of both (+)dOTC and (-)dOTC were determined. At least six subjects were studied at each dose level, with each subject studied in three of five periods, receiving two different doses of racemic dOTC and one placebo dose. Plasma and urine drug concentrations were measured for 24 to 48 h after each dose. Pharmacokinetic models were fitted to the plasma concentrations of (+)dOTC and (-)dOTC using maximum likelihood and maximum a posteriori Bayesian procedures. Statistical hypothesis testing was by nonparametric analysis of variance (where possible) and, when tests with dose as a covariate were performed, by linear mixed-effects modeling. The mean terminal elimination half-lives for (+)dOTC and (-)dOTC were 15.3 h (coefficient of variation [CV], 28%) and 11.3 h (CV, 43%), respectively (P<0.05). The mean CV for total oral clearance (liter/h/65 kg) was 17.5 (25%) for (+)dOTC and 21.5 (24%) for (-)dOTC; for oral steady-state volume of distribution (liter/65 kg), values were 61.8 (24%) for (+)dOTC and 34.1 (33%) for (-)dOTC (P<0.05). The mean CV for renal clearance (liter/h/65 kg) of (+)dOTC was 10.4 (19%) and for (-)dOTC was 13.6 (20%) (P<0.05). There was no significant effect of dose size on the pharmacokinetics of racemic dOTC. All doses were well tolerated, and no serious adverse events or laboratory abnormalities were observed.

Adolescent↗

Absolute bioavailability and disposition of (-) and (+) 2'-deoxy- 3'-oxa-4'-thiocytidine (dOTC) following single intravenous and oral doses of racemic dOTC in humans.

The purpose of this study was to characterize the pharmacokinetics and determine the absolute bioavailability of 2'-deoxy-3'-oxa-4'-thiocytidine (dOTC) (BCH-10652), a novel nucleoside analogue reverse transcriptase inhibitor, in humans. dOTC belongs to the 4'-thio heterosubstituted class of compounds and is a 1:1 mixture of its two enantiomers, (-) and (+) dOTC. Twelve healthy adult male volunteers each received oral (800-mg) and intravenous (100-mg) doses of dOTC in two study periods separated by at least 7 days. Sixteen plasma samples were obtained over 72 h and assayed for (-) and (+) dOTC, and the resultant data fit by candidate pharmacokinetic models. Data were weighted by the fitted inverse of the observation variance; model discrimination was by AIC. The pharmacokinetic model was a linear, three compartment model, with absorption occurring during one to three first-order input phases, each following a fitted lag time. The model goodness-of-fit was excellent; r(2) ranged from 0.995 to 1.0. The mean absolute bioavailabilities of (+) and (-) dOTC were 77.2% (coefficient of variation [given as a percentage] [CV%], 14) and 80.7% (CV%, 15), respectively. The median steady-state volume of distribution for (+) dOTC, 74.7 (CV%, 19.2) liters/65 kg, was greater than that for (-) dOTC, 51.7 (CV%, 16.7) liters/65 kg (P<0.05). The median total clearance of (+) dOTC was less than that of (-) dOTC, 11.7 (CV%, 17.3) versus 15.4 (CV%, 18.6) liters/h/65 kg, respectively (P< 0.05). The intersubject variability of these parameters was very low. The median terminal half-life of (+) dOTC was 18.0 (CV%, 31.5) h, significantly longer than the 6.8 (CV%, 69.9) h observed for (-) dOTC (P<0.01). No serious adverse events were reported during the study. These results suggest that dOTC is well absorbed, widely distributed, and well tolerated. The terminal half-lives indicate that dosing intervals of 12 to 24 h would be reasonable.

Administration, Oral↗

Gender-related effects on metoprolol pharmacokinetics and pharmacodynamics in healthy volunteers.

OBJECTIVE: To determine whether there are gender-specific differences in the pharmacokinetics and pharmacodynamics of metoprolol enantiomers. METHODS: Twenty normal volunteers (10 men and 10 women) received 100 mg oral metoprolol tartrate twice daily for a total of nine doses. Pharmacokinetics and pharmacodynamics were studied after the last dose. Subjects also completed a control pharmacodynamic study; the order of drug and control studies was randomized. Measurements of heart rate and systolic blood pressure were obtained during peak submaximal bicycle exercise testing. (R)-Metoprolol and (S)-metoprolol concentrations were determined by stereospecific HPLC. The percentage difference in exercise heart rate and systolic blood pressure (metoprolol versus control), and (R)- and (S)-metoprolol plasma concentrations were comodeled. RESULTS: Men and women showed stereoselective pharmacokinetics; (S)-metoprolol concentrations were significantly greater than those for (R)-metoprolol for both groups. Women had greater drug exposure than men (higher maximum concentration and area under the plasma concentration-time curve). No differences were observed between genders with respect to elimination half-life. Females had a greater reduction in exercise heart rate and systolic blood pressure; however, the area under the effect curve was significantly greater for heart rate only. Pharmacodynamic data were best fitted by the Hill equation with the effect site in the central compartment. The fitted maximum effect and the concentration at one-half of the maximum effect for heart rate and systolic blood pressure did not differ between men and women (P > .20). CONCLUSIONS: Gender-related differences exist in the pharmacokinetics of metoprolol enantiomers, resulting in greater drug exposure in female subjects. However, concentration-effect relationships did not differ between men and women. Therefore the observed differences in drug effects were the result of gender-specific differences in metoprolol pharmacokinetics.

Adrenergic beta-Antagonists↗

Antibiotic dosing issues in lower respiratory tract infection: population-derived area under inhibitory curve is predictive of efficacy.

Several lower respiratory tract infection (LRTI) trials have documented a correlation between clinical response and area under the inhibitory curve (24 h AUC/MIC; AUIC). The AUIC values in these studies were based on measured MICs and measured serum concentrations. This study evaluates AUIC estimates made using population pharmacokinetic parameters, and MICs from an automated microbiological susceptibility testing system. A computer database review over 2 years yielded 81 patients at Millard Fillmore Hospital with a culture-documented gram-negative LRTI who had been treated with piperacillin and an aminoglycoside, ceftazidime, ciprofloxacin or imipenem. Their AUIC values were estimated using renal function, drug dosages and MIC values. Outcome groups (clinical and microbiological cures and failures) were related to the AUIC values using Kruskal-Wallis ANOVA, linear regression and classification and regression tree (CART) analysis. A significant breakpoint for clinical cures was an AUIC value at least 72 SIT(-1) x 24 h (inverse serum inhibitory titre integrated over time). All antibiotics performed significantly better above this value than below it. Clinical cure was well described by a Hill-type equation. Within the piperacillin/aminoglycoside regimen, most of the activity came from the piperacillin, which had a higher overall AUIC value than the aminoglycoside. AUIC estimations based upon MIC values derived from the automated susceptibility testing method differed from NCCLS breakpoint data and from tube dilution derived values in this hospital by as much as three tube dilutions. These automated methods probably overestimated the MIC values of extremely susceptible organisms. The lack of precise MIC estimates in automated clinical microbiology methods impairs the use of AUIC to prospectively optimize microbiological outcome. Even ignoring this limitation and using the values as they are reported, the results of this analysis suggest that AUIC targets between 72 and 275 SIT(-1) x 24 h are useful in predicting clinical outcome.

Aged↗

The population pharmacokinetics of amphotericin B colloidal dispersion in patients receiving bone marrow transplants.

The purpose of this study was to identify the pharmacokinetics of Amphotericin B Colloidal Dispersion in patients undergoing bone marrow transplantations with systemic fungal infections and to assess the influence of ABCD on renal function. Seventy-five patients (42 females, 33 males) with a median age of 34.5 years and median weight of 70.0 kg were enrolled in the study. The plasma concentration data was available in 51/75 patients and was best described by a two-compartment model; both plasma clearance and volume of distribution increased with escalating doses; the overall average terminal elimination half-life was 29 h. Serum creatinine values over the duration of therapy were available in 59/75 patients. Overall, there was no net change in renal function over the duration of therapy.

Adolescent↗

The pharmacodynamics of sumatriptan in nitroglycerin-induced headache.

Migraine is a common disorder that causes significant morbidity in those afflicted. Many novel antimigraine compounds are in clinical development, yet full characterization of each one's pharmacodynamic behavior is a formidable task due to the difficulty in studying a migraineur during an attack. Nitroglycerin (NTG) administration commonly causes a headache with some features similar to those of a migraine. As such, NTG has been used as a model of vascular headaches, including migraine. The pharmacodynamic effects of nitroglycerin and sumatriptan on middle cerebral artery blood flow velocity (MCAv) and headache scores were studied in 10 healthy male volunteers. An intravenous infusion of NTG titrated to 0.5 mcg/kg/min over 30 minutes resulted in a median reduction from baseline in MCAv of 27% (range: 16.4%-37.3%). Nine of the subjects developed a headache with a median verbal score of 3.5 of 10 (range: 0-5). Subjects received sumatriptan either 2 mg intravenously or 6 mg subcutaneously, which abated clinical headache in 9 of the 10 subjects (p = 0.030). A median sumatriptan-induced increase in MCAv of 21% (p = 0.054) suggested a constricting effect on the NTG-induced dilated MCA. A two-compartment pharmacokinetic/indirect-effects pharmacodynamic model was fit to the sumatriptan concentration and MCAv data using iterative two-stage analysis. This model was unbiased and fit the concentration (r2 = 0.98) and the MCAv (r2 = 0.79) data well. These results suggest that NTG-induced headache and the development of pharmacokinetic/pharmacodynamic models could serve as a useful method for exploring the mechanisms of abortive migraine drugs.

Adult↗

Relationship of dose intensity to the induction of palmar-plantar erythrodysesthia by pegylated liposomal doxorubicin in dogs.

The multiple dose pharmacokinetics of pegylated liposomal doxorubicin (PL-DOX), known as DOXIL (US) and CAELYX (EU), was characterized in dogs and a pharmacokinetic/pharmacodynamic model to identify a relationship between drug exposure and the probability of observing treatment-related palmar-plantar erythrodysesthesia (PPE) was developed. Twenty dogs were assigned to PL-DOX groups (2/sex/ group) that received intravenous PL-DOX doses of 0.5 mg/kg ql, 2, or 4 weeks; 1.0 mg/kg q2weeks; or 1.5 mg/kg q4weeks for 12 weeks. Blood was collected for HPLC analysis of doxorubicin concentration pre-dose and periodically up to 120 h after dosing three times during treatment. Plasma drug concentration was modeled using iterative 2-stage analysis. Dermal lesions (PPE) were scored twice weekly for six regions of each dog using a 0-6 severity scale; maximum severity was 36. PPE score data were modeled using an approach in which the % probability of PPE was related to a hypothetical effect site by a series of Hill-type functions. Pharmacokinetics were best modeled as a one-compartment open model. Vss (ml/kg), CLt (ml/hr/kg) and half-life (h) were 44.1, 1.39 and 23.1, respectively. Cmax increased linearly with dose. CLt decreased with repeated doses. 5 A two-compartment pharmacodynamic model, which correctly predicted 97% of the observed lesion severity, was developed to establish the relationship of lesion severity to dose intensity (a measure of drug exposure incorporating the effect of both dose level and dosing frequency, which can be expressed in units of mg/kg/week). The model demonstrated that maximal PPE was positively correlated with dose intensity, the major factor that affects the incidence and severity of dermal lesions. 6 The model can be used to predict acceptable dose intensities in humans utilizing body surface area conversion factors and comparative AUCs for dogs and humans. It predicts that a dose intensity of 10-12.5 mg/m2 of PL-DOX will be well tolerated in patients. The results of recent clinical studies are consistent with this prediction.

Animals↗

Patterns of prescribing ACE inhibitors after myocardial infarction.

We attempted to determine physician prescribing patterns of angiotensin-converting enzyme (ACE) inhibitors in patients who experienced a myocardial infarction, stratified by left ventricular function. We retrospectively reviewed drug therapy at discharge in 534 patients to assess prescription of ACE inhibitor therapy, including dosage. Thirty-four percent of patients were discharged taking an ACE inhibitor, of whom only 11% received recommended dosages. The drugs were prescribed more often for patients who had an ejection fraction below 40% than for those with an ejection fraction of 40% or above (54% vs 28%, p<0.05). We conclude that ACE inhibitors are underprescribed for patients who experienced a myocardial infarction, illustrating the gap between clinical research and clinical practice, and the need for programs to ensure optimal medical management.

Aged↗

Impact of angiotensin-converting enzyme inhibitor underdosing on rehospitalization rates in congestive heart failure.

In a retrospective, cohort design, clinical usage of digoxin, diuretic, and angiotensin-converting enzyme (ACE) inhibitor was assessed in all patients readmitted over a 36-month period for congestive heart failure (CHF) diagnostic-related group (DRG) 127. ACE inhibitor dose-response analysis used the discharge dose of ACE inhibitor, converted to enalapril-equivalent doses and adjusted for renal function. Principal end points were time-to-readmission and 90-day readmission rate. Of 314 total patients, digoxin was used in 72%, diuretic in 86%, and 67% received an ACE inhibitor. Only 22% of those on an ACE inhibitor received currently recommended doses of enalapril > or = 20 mg/day or equivalent, whereas 41% received enalapril < or = 5 mg/day. Time-to-readmission was increased by an ACE inhibitor (p = 0.002) but not digoxin or diuretic. An ACE inhibitor was the principal covariate of 90-day readmission rate (p <0.05). The readmission rate was not reduced with daily ACE inhibitor doses of < or = 5 mg enalapril, whereas daily doses of > or = 10 mg enalapril reduced 90-day readmission rates by 28% compared to those receiving diuretic or digoxin therapy (p <0.05). Using a dynamic model, the dose required to achieve 90% to 95% of the theoretical maximum ACE inhibitor effect exceeded 100 mg enalapril daily. Thus, CHF readmission rates are lower when daily ACE inhibitor doses exceed 5 mg enalapril or the equivalent daily, but are unaffected by digoxin or diuretic. Modeled maximum ACE inhibitor benefits require doses 8- to 10-fold higher than current usage patterns.

Aged↗

Vasoreactivity in pre- and postmenopausal women: evaluation by pharmacodynamic modeling.

Postmenopausal women experience an increase in cardiovascular mortality and morbidity compared with their premenopausal counterparts. This study was undertaken to develop a pharmacodynamic model to determine whether vascular reactivity in postmenopausal women differed from that in premenopausal women. Eleven subjects in each group were recruited. Graded doses of norepinephrine and insulin were infused via the dorsal hand vein. Venous diameter was measured by ultrasound. Dosage and venous diameter were fit to a Hill-type pharmacodynamic model in which norepinephrine acts as a vasoconstrictor and insulin counteracts varying fractions of norepinephrine constriction. Fitted pharmacodynamic parameters for norepinephrine did not differ uniformly between groups, but at norepinephrine infusion rates between 14 and 46 ng/mL, postmenopausal women demonstrated increased norepinephrine-induced vasoconstriction. Also, the modeled maximal response to insulin (Emaxi) was greater in premenopausal women. By stepwise linear regression, maximal response to insulin was found to be related to menopausal status and diastolic blood pressure. Postmenopausal women showed differences in vasoreactivity that may have important implications in the pathogenesis of hypertension.

Aged↗

Eprosartan does not affect the pharmacodynamics of warfarin.

Eprosartan is an angiotensin II receptor antagonist being developed for the treatment of hypertension and heart failure. The effect of eprosartan on the steady-state anticoagulant activity of warfarin was evaluated in 18 healthy male volunteers. Each subject's daily warfarin dose was titrated over 9 days to achieve a stable international normalized ratio (INR) of 1.3 to 1.6 by day 14. After the 14-day warfarin titration phase, subjects were randomized to receive either eprosartan 300 mg or matching placebo twice a day for 7 days. All subjects continued to take the warfarin dose established during the 14-day titration phase. The anticoagulant activity of warfarin was statistically equivalent when coadministered with eprosartan or with placebo. No serious or unexpected adverse events suggestive of abnormal bleeding occurred during coadministration of eprosartan and warfarin. As measured by the INR, there is no apparent effect of eprosartan on the anticoagulant effect of warfarin.

Acrylates↗

Pharmacokinetic modeling of recombinant interleukin-2 in patients with human immunodeficiency virus infection.

A novel model was developed to characterize the time-varying clearance of recombinant interleukin-2 (IL-2). Sixty-eight patients with human immunodeficiency virus infection received 83 cycles of IL-2 either by continuous infusion or by subcutaneous injection for 5 days. IL-2 concentrations after intravenous infusions peaked at 24 hours and then declined by 55% to 78% during the remainder of the infusion. Soluble IL-2 receptors increased greater than 10-fold before gradually returning to baseline. Subcutaneous administration showed a dose-dependent decrease in area under the concentration-time curve (AUC) between days 1 and 5. A model was developed in 9 patients who had IL-2 concentrations and soluble IL-2 receptors determined by ELISA. Concentrations were fitted by an indirect stimulatory pharmacodynamic model. An additional 59 patients with only IL-2 concentrations were fitted to a simplified empiric model. Both models provided an overall r2 of 0.99 for the plot of observed versus fitted concentrations. The time-dependent increase in IL-2 clearance, likely receptor-mediated, was well described with use of an indirect-effects pharmacokinetic-pharmacodynamic model.

Adult↗

Pharmacodynamic interactions of antibiotics alone and in combination.

Clinical trials show that the area under the inhibitory curve (AUIC) is predictive of antibacterial killing rates in patients with nosocomial pneumonia and is useful for predicting clinical or microbiological outcomes and making dosage adjustments with beta-lactams, quinolones, aminoglycosides, and vancomycin. The AUIC values of two antibiotics are additive, and since antibiotics are often given in combination, determining the AUIC for antibiotic combinations could potentially predict the microbiological outcomes for patients given these combinations. To further address this question, mathematical modeling was used to study in vitro pharmacokinetic and pharmacodynamic interactions of the antimicrobials piperacillin and ciprofloxacin. These agents were also studied in vivo in healthy volunteers. Blood samples were obtained for analysis of serum drug concentrations, and serum inhibitory titers were determined against eight common bacterial pathogens, chosen to reflect the range of MIC values to ciprofloxacin and piperacillin. Additive AUIC relationships predictive of bacterial killing rates were typical in patients given these antibiotics in combination.

Anti-Bacterial Agents↗

Pharmacodynamic evaluation of factors associated with the development of bacterial resistance in acutely ill patients during therapy.

The selection of bacterial resistance was examined in relationship to antibiotic pharmacokinetics (PK) and organism MICs in the patients from four nosocomial lower respiratory tract infection clinical trials. The evaluable database included 107 acutely ill patients, 128 pathogens, and five antimicrobial regimens. Antimicrobial pharmacokinetics were characterized by using serum concentrations, and culture and sensitivity tests were performed daily on tracheal aspirates to examine resistance. Pharmacodynamic (PD) models were developed to identify factors associated with the probability of developing bacterial resistance. Overall, in 32 of 128 (25%) initially susceptible cases resistance developed during therapy. An initial univariate screen and a classification and regression tree analysis identified the ratio of the area under the concentration-time curve from 0 to 24 h to the MIC (AUC[0-24]/MIC) as a significant predictor of the development of resistance (P < 0.001). The final PK/PD model, a variant of the Hill equation, demonstrated that the probability of developing resistance during therapy increased significantly when antimicrobial exposure was at an AUC[0-24]/MIC ratio of less than 100. This relationship was observed across all treatments and within all organism groupings, with the exception of beta-lactamase-producing gram-negative organisms (consistent with type I beta-lactamase producers) treated with beta-lactam monotherapy. Combination therapy resulted in much lower rates of resistance than monotherapy, probably because all of the combination regimens examined had an AUC[0-24]/MIC ratio in excess of 100. In summary, the selection of antimicrobial resistance appears to be strongly associated with suboptimal antimicrobial exposure, defined as an AUC[0-24]MIC ratio of less than 100.

Acute Disease↗