Martin H. Adelman

Mathematical Examination of Dual Individualization Principles (I): Relationships between AUC above MIC and Area under the Inhibitory Curve for Cefmenoxime, Ciprofloxacin, and Tobramycin

Traditional antibiotic dosage adjustments target predetermined serum concentrations, whereas a host of in vitro studies and recent clinical trials establish that bacteria vary in their susceptibility. Dual individualization, which considers the variance in both antibiotic pharmacokinetics and bacterial susceptibility, has been employed to describe different rates of bacterial eradication in relation to varying serum concentrations. In patients with nosocomial pneumonia, one of the model compounds studied was cefmenoxime, where a target six-hour area under the serum concentration-time curve (AUC) of 140 μg·h/mL above minimum inhibitory concentration (MIC) was previously associated with bacterial eradication in an average of four days. The target AUC value of 140 μg·h/mL above MIC is unique to cefmenoxime. Ideally, there should be a dual individualized target useful to adjust the dose of any antibiotic. Computer simulations performed to evaluate this hypothesis suggested that each antibiotic had a unique value for target AUC above MIC. These simulations indicated that an optimal AUC above MIC was about 80 percent of the total AUC above the MIC. Predictable rates of bacterial eradication would presumably result from maintaining these relationships across the range of bacterial susceptibility and the range of serum concentration profiles. Each antibiotic has a unique and different 24-hour AUC over MIC value associated with bacterial eradication in 4 days. For cefmenoxime, the target was 540 area units over MIC per 24 hours, tobramycin with 34 area units, and ciprofloxacin with 23 area units per 24 hours. Because it would clearly be desirable to have a target for dosing adjustment that is independent of the particular antibiotic, we then used computer simulations to determine whether the AUIC (area under the inhibitory curve, or integrated AUC above MIC vs. time) could be descriptive of bacterial eradication with the cephalosporin, cefmenoxime; the aminoglycoside, tobramycin; and the fluoroquinolone, ciprofloxacin. Computer simulation revealed that appropriate doses of all three of these antibiotics yield 24-hour AUIC values in the range of 125. On the basis of these simulations, we propose that target AUIC values are likely to be applicable across antibiotic classes, whereas AUC above MIC targets must be unique values to the particular antibiotic. Furthermore, these relationships can be used to make comparisons of antibiotic activity either across different antibiotic classes or within the same class.

Changes in antimicrobial agent usage resulting from interactions among clinical pharmacy, the infectious disease division, and the microbiology laboratory

Rapid reporting of culture and susceptibility data is the first of several important steps in the successful management of infected patients. As has been said many times, rapidly reported data are of little value unless the patient directly benefits. Benefit requires better overall communication and an action plan linked to timely use of these results. In 1989 the Millard Fillmore Hospital Antibiotic Review Committee developed and implemented a prototype approach to hospital wide antimicrobial management. The formulary was revised and the drug use evaluation process modified to enhance effectiveness and to lower the cost of therapy and inventory. Clinical pharmacy antimicrobial agent management specialists were then recruited to individualize patient treatments to the isolated pathogens in conjunction with the Division of Infectious Diseases. To provide the clinical pharmacy specialists with rapid and clinically useful information, a real-time computer link was created between the pharmacy (antibiotic orders) and the microbiology laboratory (culture results). Customized software was implemented to screen all patients automatically for mismatches between pathogens and drugs, or to screen for doses inappropriate to minimum inhibitory concentration or renal function. Special attention was paid to identification of opportunities to target a more appropriate narrow-spectrum regimen after culture results became available. Changes in antimicrobial regimen or dosage were made by contacting the prescribing physician. Over 90% of the recommended changes were made, and virtually all changed regimens had satisfactory clinical outcome. Real dollar expenditures for antimicrobial agents declined by >

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

200,000 per year. Prior to the institution of this computerized clinical management strategy, antimicrobial purchases were rising yearly at the rate of 12%-15%. The combined efforts of clinical pharmacy, microbiology, and infectious disease personnel successfully optimized antimicrobial therapy on a hospital wide basis. Antimicrobial agent optimization improved patient outcome, and the cost savings more than covered the costs of the program personnel and software.

Clinical and economic impact of a diabetes clinical pharmacy service program in a university and primary care–based collaboration model

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.

Effects of enteral and intravenous antimicrobial treatment on survival following intestinal ischemia in rats

OBJECTIVE To provide program methodology and outcomes data identifying the impact of clinical pharmacy services (CPSs) in patients with type 2 diabetes. DESIGN Longitudinal pre-post cohort study. SETTING Regional primary care group in Buffalo, NY, during 2006-2007. PATIENTS Patients with type 2 diabetes identified by their primary care providers were referred to the MedSense program; a pharmacist-led, patient-centered pharmacotherapy management program developed through university collaboration with a regional primary care physician group. INTERVENTIONS Education, clinical assessments, provider recommendations, and longitudinal follow-up of treatment goals provided by MedSense pharmacists. MAIN OUTCOME MEASURES Clinical outcomes were followed for 1 year from the index date for primary diabetes endpoints (glycosylated hemoglobin and fasting plasma glucose) and accompanying metabolic parameters (body mass index, blood pressure, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides). Economic endpoints from the payer perspective were also followed for 1 year from the index date for medical and prescription-related costs. RESULTS Primary diabetes endpoints were significantly reduced versus baseline at the 6-month (-1.1%; P < 0.0001, -39 mg/dL; P = 0.003) and 12-month (-1.1%; P < 0.0001, -35 mg/dL; P = 0.005) assessments. Improvement rates were observed for all accompanying metabolic parameters at each assessment (range 40-64%). Geometric mean costs tended to decrease versus baseline at 6-month (-

Use of ceftaroline after glycopeptide failure to eradicate meticillin-resistant Staphylococcus aureus bacteraemia with elevated vancomycin minimum inhibitory concentrations

84; P = 0.785) and 12-month (-

Kinetics and action of N-methylthiotetrazole in volunteers and patients. Population-based clinical comparisons of antibiotics with and without this moiety.

216; P = 0.414) assessments, despite nominal increases in diabetes and total medication costs. CONCLUSION In this CPS model, there were initial and sustained reductions in the primary diabetes endpoints and a high rate of improvement for accompanying metabolic parameters. Concurrent with clinical improvements, total direct medical costs were reduced despite an increase in antidiabetic medication and total medication costs.

Direct costs in patients hospitalised with community-acquired pneumonia after non-response to outpatient treatment with macrolide antibacterials in the US.

One hundred and twenty rats underwent transection of the superior mesenteric artery. The animals were randomly divided into eight groups of 15 animals. Control group 1 and groups 3, 5, and 7 received intravenous normal saline, gentamicin, metronidazole, and gentamicin plus metronidazole, respectively. Control group 2 and groups 4, 6, and 8 received the same compounds enterally. Small and large bowel sections were taken postmortem and a necrosis score was assigned in blinded fashion. Gentamicin did not prolong survival, indicating that gram-negative microbes were not important in this pathology. Longer survival times for animals given either metronidazole or gentamicin plus metronidazole (P less than 0.01) indicate that anaerobes were a causative factor in mortality. During the first 15 hr after ischemia, antibiotics did not change mortality. After 15 hr, enteral administration was superior to intravenous administration in any regimen including metronidazole (P less than 0.01).

Kinetic mechanism of the Cu(II) enzyme galactose oxidase

Elevated minimum inhibitory concentrations (MICs) of vancomycin against meticillin-resistant Staphylococcus aureus (MRSA) and the emergence of heteroresistant S. aureus strains have led to increased use of anti-MRSA antibiotics other than vancomycin. Ceftaroline fosamil is a novel cephalosporin with activity against MRSA, but there are limited clinical data on its use for MRSA bacteraemia (MRSAB) and against strains exhibiting high vancomycin MICs (2-4 μg/mL). This multicentre, retrospective, case-control study compared the microbiological and clinical effectiveness of ceftaroline used after vancomycin failure with that of vancomycin-treated controls for the treatment of MRSA with vancomycin MICs ≥ 2 μg/mL. In total, 32 patients were matched 1:1 with respect to vancomycin MIC, age and origin of bacteraemia. In the ceftaroline group, patients received prior MRSA therapy for a median of 5 days [interquartile range (IQR), 3-15.8 days] prior to switching to ceftaroline. Median time to eradication of MRSA was significantly less after treatment with ceftaroline compared with vancomycin [4 days (IQR, 3-7.5 days) vs. 8 days (IQR, 5.8-19.5 days); P=0.02]. Both clinical success at the end of treatment and recurrence of MRSA at Day 7 were trending towards being inferior in the vancomycin group, although the results did not attain statistical significance [81% vs. 44% (P=0.06) and 6% vs. 38% (P=0.08), respectively]. Ceftaroline added at the point of vancomycin failure resolves MRSAB more rapidly and with a higher rate of clinical success, therefore ceftaroline should be considered as an alternative for these difficult-to-treat infections.

A disease model descriptive of progression between chronic obstructive pulmonary disease exacerbations and community-acquired pneumonia: roles for underlying lung disease and the pharmacokinetics/pharmacodynamics of the antibiotic

Normal volunteers and patients were studied to determine the relative importance of NMTT and patient risk factors in the production of hypoprothrombinemia. The normal volunteers demonstrated in vivo NMTT production, but the order of magnitude (cefoperazone, moxalactam, and cefotetan in descending order) was different from the usual order of clinical risk. In patients, there was not a NMTT-concentration-versus-effect relationship. Patients who were vitamin K deficient were more sensitive to lower NMTT concentrations than those with normal vitamin K status. In surveillance studies, NMTT-containing antibiotics were nor more frequently associated with hypoprothrombinemia or bleeding than antibiotics that lack this moiety.