The importance of pharmacokinetic/pharmacodynamic surrogate markers to outcome. Focus on antibacterial agents.

Pharmacokinetic/pharmacodynamic surrogate relationships have been used to describe the antibacterial activity of various classes of antimicrobial agents. Studies that have evaluated these relationships were reviewed to determine which of these surrogate markers were further dependent on antimicrobial class. The fluoroquinolone and aminoglycoside agents exhibit concentration-dependent killing. Studies have demonstrated that peak serum concentration: minimum inhibitory concentration (MIC) and area under the serum concentration-time curve (AUC): MIC ratios are important predictors of outcome for these antimicrobial agents. Area under the inhibitory concentration-time curve (AUIC24) [i.e. AUC24/MIC] is a useful parameter for describing efficacy for these agents, while an adequate peak concentration: MIC ratio seems necessary to prevent selection of resistant organisms. For beta-lactam antibiotics, the duration of time that the serum concentration exceeds the MIC (T > MIC) was the significant pharmacokinetic/pharmacodynamic surrogate in cases where the bacterial inoculum was low, or where very sensitive organisms were tested. However, in studies using more resistant organisms or larger inoculum sizes there is some concentration-dependence to the observed effect. Studies using reasonable dosage intervals have demonstrated covariance between T > MIC and AUC/MIC ratio for beta-lactam antibiotics. Since glycopeptide antibiotics display relatively slow but concentration-independent killing, and are cell wall active agents similar to beta-lactams, it has been presumed that T > MIC is the important pharmacokinetic surrogate related to efficacy for these agents. Some studies have shown that a concentration multiple of the MIC may be necessary for successful outcome with vancomycin. AUIC24 may prove to be an important pharmacokinetic surrogate if both time and concentration are indeed important parameters. To select an appropriate antimicrobial agent, the clinician must consider many patient-specific as well as organism-specific factors. Utilisation of known pharmacokinetic/pharmacodynamic surrogate relationships should help to optimise treatment outcome.

Temporal assessment of Candida risk factors in the surgical intensive care unit.

HYPOTHESIS: Risk factors for Candida infection in surgical intensive care units (SICUs) change over time. Risk factor progression may influence Candida colonization and infection. DESIGN: Multicenter cohort survey. SETTING: Three urban teaching institutions. PATIENTS: A total of 301 consecutively admitted patients in SICUs for 5 or more days. MAIN OUTCOME MEASURES: Assessment of patients on SICU days 1, 3, 4, 6, and 8 and SICU discharge for risk factors, Candida colonization, and antifungal use. Candida colonization status was categorized as noncolonized (NC), locally colonized (LC) if 1 site was involved, and disseminated infection (DI) if 2 or more sites or candidemia were involved. RESULTS: The most frequent risk factors in the 301 patients enrolled were presence of peripheral and central intravenous catheters, bladder catheters, mechanical ventilation, and lack of enteral or intravenous nutrition. Early risk factors included total parenteral nutrition or central catheter at SICU day 1 and previous SICU admissions or surgical procedures. Peak number of risk factors (mean +/- SD) were as follows: 7.2 +/- 2.6 in NC (n = 229), 9.2 +/- 2.3 in LC (n = 45), and 9.2 +/- 2.6 in DI (n = 27). These numbers were reached at day 8 in the NC and LC groups and day 4 in the DI group. The LC and DI groups had more risk factors on each SICU day than the NC group and longer median SICU length of stay (28 days in the DI group vs 11 and 19 days in the NC and LC groups, respectively). Antifungal therapy, while used most frequently in the DI group, was initiated later for this group than in NC and LC groups. CONCLUSIONS: Risk factors for Candida infection in SICU patients change over time. Patients with DI demonstrate a greater number of and more rapid increase in risk factors than patients in the LC and NC groups. Presence of early risk factors at the time of SICU admission, a high incidence of risk factors, or a rapid increase in risk factors should prompt clinicians to obtain surveillance fungal cultures and consider empirical antifungal therapy.

Efficacy and cost of ampicillin-sulbactam and ticarcillin-clavulanate in the treatment of hospitalized patients with bacterial infections.

STUDY OBJECTIVE: To evaluate the efficacy and cost of treatment with two beta-lactam/beta-lactamase-inhibitor combinations. DESIGN: Retrospective, open-label multicenter study. SETTING: Fifty-four hospitals across the United States. PATIENTS: Eight hundred ninety patients with skin and soft tissue, intraabdominal, gynecologic, respiratory, urinary tract, or other infections that required parenteral antibiotic therapy. INTERVENTION: Patients were administered either ampicillin-sulbactam 1.5 or 3.0 g every 6 hours or ticarcillin-clavulanate 3.1 g every 6 hours. MEASUREMENTS AND MAIN RESULTS: The agents did not differ significantly in efficacy for most infections; although, ampicillin-sulbactam was bacteriologically superior to ticarcillin-clavulanate in the treatment of intraabdominal infections (p=0.0011). Costs of ampicillin-sulbactam, particularly the 1.5-g dose, were lower than those of ticarcillin-clavulanate for skin and soft tissue (p<0.001), intraabdominal (p=0.005), and respiratory tract (p<0.001) infections. CONCLUSION: Ampicillin-sulbactam provides effective coverage for patients with the above infections and is as effective as the broader-spectrum agent.

Pharmacokinetics and pharmacodynamics of ceftizoxime in patients with dosages adjusted for renal function.

STUDY OBJECTIVE: Our institution developed dosing guidelines for patients with renal impairment based on pharmacokinetic data and class-specific pharmacodynamics. Ceftizoxime was chosen as a model agent to evaluate if the modified guidelines achieved similar minimal plasma concentration (Cp(min)) and time above the minimum inhibitory concentration of the infecting organism (T>MIC) in patients with renal impairment versus those with normal renal function. DESIGN: Prospective pharmacokinetic and pharmacodynamic evaluation of ceftizoxime dosages. SETTING: University-affiliated hospital. PATIENTS: Forty-three patients with suspected or documented infection were enrolled and classified into four groups based on creatinine clearance (Cl(cr); ml/min): group 1, above 100; group 2, 61-99; group 3, 31-60; and group 4, 15-30. INTERVENTIONS: Ceftizoxime serum concentrations were obtained at steady state. MEASUREMENTS AND MAIN RESULTS: Pharmacokinetic and pharmacodynamic parameters were calculated. As expected, clearance and elimination rate constant were reduced, and half-life tended to be greater in patients with renal impairment. The Cp(min) and area under the concentration-time curve over 24 hours were similar between groups (p=0.39, p=0.42). The T>MIC was 100% for all patient isolates, and 90% or more versus our clinical strain for all groups. Clinical outcomes were similar among all groups. CONCLUSION: Our dosing guidelines achieved similar Cp(min) among all groups of patients. Our results support that recommendations for dosing adjustments should be based on pharmacokinetic data and must also consider pharmacodynamic parameters.

Pharmacodynamic characterization of nephrotoxicity associated with once-daily aminoglycoside.

STUDY OBJECTIVE: To characterize nephrotoxicity associated with an individualized serum concentration target-specific, once-daily aminoglycoside (ODA) program. DESIGN: Concurrent and retrospective study. SETTING: University-affiliated trauma hospital. PATIENTS: Two hundred patients treated with ODA and 100 treated with individualized traditional dosing (TDA). INTERVENTIONS: Empiric dosing for both groups was based on patient-specific pharmacokinetics and severity of infection. Regimens were modified according to predetermined target maximum and minimum serum concentrations for both groups. MEASUREMENTS AND MAIN RESULTS: Nephrotoxicity occurred in 7.5% patients treated with ODA and 14.7% receiving TDA (p=0.05). Minimum serum concentrations, length of aminoglycoside therapy, and cumulative area under the curve (AUC) were all dependently related to nephrotoxicity, and concomitant vancomycin and other nephrotoxic drugs were independently related to the disorder. The cumulative AUC was greatest in patients receiving TDA (p=0.03), and the modeled probability of becoming toxic at any given cumulative AUC was significantly greater with TDA than with ODA (p<0.01). Clinical and microbiologic outcomes were similar between groups. Maximum concentration:minimum inhibitory concentration ratios were higher (p<0.01) and number of days to organism eradication was shorter in the ODA group (p=0.04). CONCLUSION: The trend was toward decreased nephrotoxicity in patients treated with ODA compared with TDA, and at any given cumulative AUC, the risk of toxicity was lower for ODA.

Epidemiology, resistance, and outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam.

STUDY OBJECTIVE: To evaluate epidemiology, resistance, and treatment outcomes of Acinetobacter baumannii bacteremia treated with imipenem-cilastatin or ampicillin-sulbactam for 72 hours or longer. DESIGN: Retrospective analysis. SETTING: University teaching hospital. PATIENTS: Forty-eight patients with A. baumannii bacteremia. INTERVENTION: Evaluation of susceptibility and clinical data from 48 patients treated with either ampicillin-sulbactam or imipenem-cilastatin from 1987-1999. MEASUREMENTS AND MAIN RESULTS: Comparing ampicillin-sulbactam and imipenem-cilastatin, there were no differences between days of bacteremia (4 vs 2 days, p=0.05), days to resolution of temperature or white blood cell count, success or failure during or at end of treatment, or intensive care unit total or antibiotic-related length of stay (13 vs 10 days, p=0.05). Patients treated with ampicillin-sulbactam had significantly decreased antibiotic treatment costs (1500 dollars vs 500 dollars, p=0.004). CONCLUSION: Ampicillin-sulbactam is at least as effective as imipenem-cilastatin based on clinical response at days 2, 7, and end of treatment and is a cost-effective alternative for treatment of A. baumannii infections.

Once-daily aminoglycoside in the treatment of Enterococcus faecalis endocarditis: case report and review.

Once-daily administration of aminoglycosides (ODA) is effective and safe for many indications. By optimizing pharmacodynamic principles, it enhances bactericidal activity and minimizes toxicity. Its use for the treatment of enterococcal infection is controversial, however, and results of in vitro studies and animal models of endocarditis are conflicting. To date, no case reports or clinical trials have examined its utility in human enterococcal endocarditis. A patient with right-sided endocarditis caused by Enterococcus faecalis was managed by once-daily gentamicin. Clinical and bacteriologic cures of this patient raise questions as to whether enterococcal endocarditis should be regarded as contraindication to ODA. The clinical utility of ODA in this disease deserves further investigation.

Outcome assessment of minimizing vancomycin monitoring and dosing adjustments.

An approach to minimize monitoring of vancomycin therapy was evaluated in 120 patients, and results were compared with data from 120 patients in whom vancomycin therapy was monitored and adjusted based on serum peak and trough concentrations and traditional pharmacokinetic methods. Patients dosed by the nomogram (NM) had regimens adjusted based on actual body weight, estimated creatinine clearance, and a targeted trough concentration of 5-20 microg/ml. A single trough serum concentration was drawn only after 5 or more days of therapy. Overall, the average length of therapy was similar between groups (9.9 +/- 9.4 days NM and 8.6 +/- 7.2 days pharmacokinetic). The most common regimen for both groups was 1 g every 12 hours, although NM patients received significantly fewer grams/day (1.9 +/- 0.7 g/day) than the pharmacokinetic group (2.2 +/- 1.0 g/day, p<0.04). Patients dosed by NM also had significantly fewer regimen changes (0.63 +/- 0.96 vs pharmacokinetic 0.92 +/- 0.97, p=0.02) as well as significantly fewer serum concentrations measured/patient (1.08 +/- 1.9 vs 1.96 +/- 2.0, p=0.001). In addition, serum concentrations for NM patients were drawn later in therapy (5.4 +/- 2.5 vs 3.8 +/- 3.4 days, p=0.004). Of patients dosed by NM guidelines, 77 had trough concentrations drawn; these data were used to validate the nomogram. Seventy-two patients (94%) had trough concentrations in the target range of 5-20 microg/ml. No differences were found between groups with respect to cure, improvement, failure, or days to eradication, or with respect to nephrotoxicity. Finally, total drug cost/patient was not different between groups. A considerable cost savings to our institution was noted for patients dosed by NM compared with pharmacokinetics ($232.5 +/- 50.74 vs $403.75 +/- 70.97/mo, p=0.009) based on levels saved. Caution should be applied when generalizing our results to other patient populations.

Pharmacokinetic and pharmacodynamic issues in the treatment of bacterial infectious diseases.

This review outlines some of the many factors a clinician must consider when selecting an antimicrobial dosing regimen for the treatment of infection. Integration of the principles of antimicrobial pharmacology and the pharmacokinetic parameters of an individual patient provides the most comprehensive assessment of the interactions between pathogen, host, and antibiotic. For each class of agent, appreciation of the different approaches to maximize microbial killing will allow for optimal clinical efficacy and reduction in risk of development of resistance while avoiding excessive exposure and minimizing risk of toxicity. Disease states with special considerations for antimicrobial use are reviewed, as are situations in which pathophysiologic changes may alter the pharmacokinetic handling of antimicrobial agents.

New antibiotics for infections caused by resistant organisms.

A continued increase in the expression of resistance among bacterial pathogens has prompted the development of a variety of new compounds directed against resistant strains of bacteria. Recently, the most dramatic increase in resistance has been among gram-positive organisms, and the predominant areas of development have been within a few classes of agents. Expanded spectrum fluoroquinolones offer advantages against many resistant gram-positive organisms, including S. pneumoniae and S. aureus. Newly developed classes of antimicrobials offer some unique activity against resistant staphylococci and enterococci. The first classes approved for use in the US are the streptogramins, specifically quinupristin/dalfopristin (Synercid), and the oxazolidinone linezolid (Zyvox). Other new classes of agents, including the ketolides, everninomycins, and newer glycopeptides, such as LY-333328, are in the early stages of development.

Cost-effectiveness of ampicillin/sulbactam versus imipenem/cilastatin in the treatment of limb-threatening foot infections in diabetic patients.

A cost-effectiveness analysis was performed following a double-blind, randomized study of ampicillin/sulbactam (A/S) versus imipenem/cilastatin (I/C) for the treatment of limb-threatening foot infections in 90 diabetic patients. There were no significant differences between the treatments in terms of clinical success rate, adverse-event frequency, duration of study antibiotic treatment, or length of hospitalization. Costs of the study antibiotics, treatment of failures and adverse events, and hospitalization were calculated. Mean per-patient treatment cost in the A/S group was $14,084, compared with $17,008 in the I/C group (P = .05), primarily because of lower drug and hospitalization costs and less-severe adverse events in the A/S group. Sensitivity analyses varying drug prices or hospital costs demonstrated that A/S was consistently more cost-effective than I/C. Varying the clinical success rate for each drug revealed that I/C would have to be 30% more effective than A/S to change the economic decisions.