Ron E. Polk

Antimicrobial Stewardship Programs in Health Care Systems

SUMMARY Antimicrobial stewardship programs in hospitals seek to optimize antimicrobial prescribing in order to improve individual patient care as well as reduce hospital costs and slow the spread of antimicrobial resistance. With antimicrobial resistance on the rise worldwide and few new agents in development, antimicrobial stewardship programs are more important than ever in ensuring the continued efficacy of available antimicrobials. The design of antimicrobial management programs should be based on the best current understanding of the relationship between antimicrobial use and resistance. Such programs should be administered by multidisciplinary teams composed of infectious diseases physicians, clinical pharmacists, clinical microbiologists, and infection control practitioners and should be actively supported by hospital administrators. Strategies for changing antimicrobial prescribing behavior include education of prescribers regarding proper antimicrobial usage, creation of an antimicrobial formulary with restricted prescribing of targeted agents, and review of antimicrobial prescribing with feedback to prescribers. Clinical computer systems can aid in the implementation of each of these strategies, especially as expert systems able to provide patient-specific data and suggestions at the point of care. Antibiotic rotation strategies control the prescribing process by scheduled changes of antimicrobial classes used for empirical therapy. When instituting an antimicrobial stewardship program, a hospital should tailor its choice of strategies to its needs and available resources.

Measurement of Adult Antibacterial Drug Use in 130 US Hospitals: Comparison of Defined Daily Dose and Days of Therapy

BACKGROUND Hospitals are advised to measure antibiotic use and monitor its relationship to resistance. The World Health Organizations recommended metric is the defined daily dose (DDD). An alternative measure is the number of days of therapy (DOT). The purpose of this study was to contrast these measures. METHODS We measured the use of 50 antibacterial drugs that were administered to adults who were discharged from 130 US hospitals during 1 August 2002-31 July 2003. RESULTS Of 1,795,504 patients, 1,074,174 received at least 1 dose of an antibacterial drug (59.8%). The mean (+/- standard deviation) of total antibacterial drug use measured by the number of DDDs per 1000 patient-days and the number of DOTs per 1000 patient-days were not significantly different (792+/-147 and 776+/-120, respectively; P=.137), although the correlation was poor (r=0.603). For some individual drugs, such as levofloxacin and linezolid, there was no significant difference between DDDs per 1000 patient-days and DOTs per 1000 patient-days, because the administered daily dosage was nearly equivalent to the DDD. When the administered dosage exceeded the DDD, such as for ampicillin-sulbactam and cefepime, estimates of use based on DDDs per 1000 patient-days significantly exceeded those based on DOTs per 1000 patient-days (P<.001). When the administered dosage was less than the DDD, such as for piperacillin-tazobactam and ceftriaxone, estimates of use based on DDDs per 1000 patient-days were significantly lower than those based on DOTs per 1000 patient-days (P<.001). CONCLUSION The measurement of aggregate hospital antibiotic use by DDDs per 1000 patient-days and DOTs per 1000 patient-days is discordant for many frequently used antibacterial drugs, because the administered dose is dissimilar from the DDD recommended by the World Health Organization. DDD methods are useful for benchmarking purposes but cannot be used to make inferences about the number of DOTs or relative use for many antibacterial drugs.

Antimicrobial use and bacterial resistance.

The current epidemic of bacterial resistance is attributed, in part, to the overuse of antibiotics. Recent studies have documented increases in resistance with over-use of particular antibiotics and improvements in susceptibility when antibiotic use is controlled. The most effective means of improving use of antibiotics is unknown. Comprehensive management programs directed by multi-disciplinary teams, computer-assisted decision-making, and antibiotic cycling have been beneficial in controlling antibiotic use, decreasing costs without impacting patient outcomes, and possibly decreasing resistance.

Pharmacokinetic drug interactions with antimicrobial agents.

SummaryAs new classes of antimicrobial drugs have become available, and new uses found for older drugs, pharmacokinetic drug interactions with antimicrobials have become more common. Macrolides, fluoroquinolones, rifamycins, azoles and other agents can interact adversely with commonly used drugs, usually by altering their hepatic metabolism. The mechanisms by which antimicrobial agents alter the biotransformation of other drugs is increasingly understood to reflect inhibition or induction of specific cytochrome P450 enzymes.Macrolides inhibit cytochrome P450IIIA4 (CYP3A4), which appears to be the most common metabolic enzyme in the human liver and is involved in the metabolism of many drugs, including cyclosporin, warfarin and terfenadine. Some quinolones preferentially inhibit CYP1A2, which is partially responsible for methylxanthine metabolism. Azoles appear to be broad spectrum inhibitors of cytochromes P450. Within each of these antibiotic classes, there is a rank order of inhibitory potency towards specific cytochrome P450 enzymes. By contrast, rifampicin (rifampin) and rifabutin induce several cytochromes P450, including CYP3A4, and hence can enhance the metabolism of many other drugs.By using in vitro preparations of human enzymes it is increasingly possible to predict those antibiotics that will adversely affect the metabolism of other drugs. In addition, between-patient variability in frequency of interaction may relate to differences in the activities of these enzymes. Although the mechanisms and scope of these interactions are becoming well characterised, the remaining challenge is how to best inform the clinician so that the undesirable consequences of interactions may be prevented.

Trends in Antibacterial Use in US Academic Health Centers: 2002 to 2006

BACKGROUND Antibacterial drug use is a major risk factor for bacterial resistance, but little is known about antibacterial use in US hospitals. The objectives of this study were to characterize trends in antibacterial use in a sample of US hospitals and to identify predictors of use. METHODS We measured systemic antibacterial use from validated claims data at 22 university teaching hospitals from January 1, 2002, through December 31, 2006, and we examined potential predictors of use in 2006, including hospital and patient demographics and antibacterial stewardship policies. RESULTS A total of 775,731 adult patients were discharged in 35 hospitals during 2006, and 492,721 (63.5%) received an antibacterial drug. The mean (SD) total antibacterial use increased from 798 (113) days of therapy per 1000 patient days in 2002 to 855 (153) in 2006 (P < .001). Fluoroquinolones were the most commonly used antibacterial class from 2002 through 2006, and use remained stable. Piperacillin sodium-tazobactam sodium and carbapenem use increased significantly, and aminoglycoside use declined. Cefazolin sodium was the most commonly used antibacterial drug in 2002 and 2003 but was eclipsed by vancomycin hydrochloride in 2004. The strongest predictor of broad-spectrum antibacterial use was explained by differences across hospitals in the mean durations of therapy. CONCLUSIONS Total antibacterial use in adults increased significantly from 2002 through 2006 in this sample of academic health centers, driven by increases in the use of broad-spectrum agents and vancomycin. These developments have important implications for acquired resistance among nosocomial pathogens, particularly for methicillin-resistant Staphylococcus aureus (MRSA).

Drug-drug interactions with ciprofloxacin and other fluoroquinolones

Early investigational trials with new quinolone antibiotics revealed two important drug-drug interactions: decreased fluoroquinolone absorption when co-administered with magnesium-aluminum antacids and inhibition of theophylline metabolism. Subsequent studies have investigated the mechanisms of these interactions. With respect to the effect of antacids, the absorption of all quinolones appears to be significantly reduced by antacids containing magnesium and/or aluminum, and concomitant administration must be avoided. Other cations, such as calcium, iron, and probably zinc, appear to interact in a similar manner. Chelation between the quinolone and cation is the most likely mechanism. With respect to the effect on theophylline metabolism, quinolones inhibit specific cytochrome P-450 isozymes responsible for metabolism of methylxanthines, although there are major differences between the quinolones. Enoxacin is the most potent inhibitor, followed by ciprofloxacin, pefloxacin, norfloxacin, and ofloxacin. Caffeine metabolism is also inhibited, although the clinical significance is uncertain. Case reports describe renal failure associated with concomitant administration of cyclosporine and ciprofloxacin, although controlled trials have not demonstrated an interaction. Enoxacin has little effect on warfarin metabolism, suggesting that other quinolones may not affect warfarin disposition. Case reports of central nervous system toxicity from administration of nonsteroidal anti-inflammatory agents and quinolones need confirmation. Patients should be monitored closely when potential interacting agents are used; it is probable that not all interactions have been identified.

Hospital and Community Fluoroquinolone Use and Resistance in Staphylococcus aureus and Escherichia coli in 17 US Hospitals

BACKGROUND Fluoroquinolones are widely prescribed in hospitals and the community. Previous studies have shown associations between fluoroquinolone use and isolation of fluoroquinolone-resistant Escherichia coli and methicillin-resistant Staphylococcus aureus (MRSA). We performed an ecologic-level study to determine whether variability in hospital percentages of fluoroquinolone-resistant E. coli and MRSA were associated with fluoroquinolone use in hospitals and their surrounding communities. METHODS We measured fluoroquinolone use in 17 US hospitals and their surrounding communities in the year 2000. Data on fluoroquinolone use in hospitals was electronically extracted from billing data. Data on fluoroquinolone use in communities was obtained from IMS health data for all prescriptions filled in pharmacies within a 16-km radius of each hospital. We used hospital antibiograms to determine the percentage of isolates that were fluoroquinolone-resistant E. coli and MRSA, and we performed linear regression to determine the relationship between percentage of resistant isolates and fluoroquinolone use in hospitals and their surrounding communities. RESULTS There was a significant association between total fluoroquinolone use within hospitals and percentage of S. aureus isolates that were MRSA (r=0.77; P=.0003) and between total fluoroquinolone use in the community and percentage of E. coli isolates that were fluoroquinolone-resistant E. coli (r=0.68; P=.003). Population density within the 16-km radius also correlated with MRSA percentage (r=0.57; P=.015) and fluoroquinolone-resistant E. coli percentage (r=0.85; P=.002), but associations between total fluoroquinolone use and resistance remained significant after adjustment for population density. CONCLUSIONS In this ecologic analysis, we found associations between fluoroquinolone use in hospitals and methicillin resistance in S. aureus and between fluoroquinolone use in communities and fluoroquinolone resistance in E. coli in hospitals. Antimicrobial use in hospitals and communities may have different relative importance with regard to resistance in different pathogens encountered in hospitals.

Effect of ferrous sulfate and multivitamins with zinc on absorption of ciprofloxacin in normal volunteers.

Cations such as magnesium and aluminum significantly impair the absorption of ciprofloxacin. Twelve healthy adult male volunteers participated in this four-way crossover study to investigate the effects of ferrous sulfate and multivitamins with zinc on the absorption of ciprofloxacin. Doses of ciprofloxacin (500 mg) were given 7 days apart and after an overnight fast. Dose 1 was administered alone (regimen A). The subjects then received either a ferrous sulfate tablet (325 mg three times a day; regimen B) or a once-daily multivitamin with zinc (regimen C) for 7 days; dose 2 of ciprofloxacin was then given with the last dose of regimen B or C. Subjects were crossed over to the alternate regimen for 7 days, and dose 3 of ciprofloxacin was again administered with the last dose of regimen B or C. After a 7-day washout, dose 4 of ciprofloxacin was given (regimen D). Ciprofloxacin concentrations were determined by high-pressure liquid chromatography. The areas under the concentration-time curve (AUCs) of ciprofloxacin for regimens A and D were not significantly different (14.5 +/- 2.3 versus 15.7 +/- 2.8 micrograms.h/ml, mean +/- standard deviation). The AUCs for regimen B (5.4 +/- 1.7 micrograms.h/ml) and regimen C (11.3 +/- 2.4 micrograms.h/ml) were significantly different from the AUCs for regimens A and D. Peak concentrations of ciprofloxacin with regimen B were below the MIC for 90% of strains of many organisms normally considered susceptible. Ferrous sulfate and multivitamins with zinc significantly impaired the absorption of ciprofloxacin. The effect of ferrous sulfate is likely to be clinically significant; the responsible component of multivitamins with zinc requires additional study.

Predicting hospital rates of fluoroquinolone-resistant Pseudomonas aeruginosa from fluoroquinolone use in US hospitals and their surrounding communities.

Rates of fluoroquinolone resistance among Pseudomonas aeruginosa in hospitals are increasing, but interhospital variability is great. We sought to determine whether this variability correlated to fluoroquinolone use in hospitals and in the surrounding community. Hospital quinolone use in 1999 (24 hospitals) through 2001 (35 hospitals) was determined from billing records. The number of fluoroquinolone prescriptions within a 10-mile (approximately 16-km) radius of each hospital was determined for 1999 and 2000. Hospital fluoroquinolone use increased from 1999 through 2001, from 137 to 163 defined daily doses (DDD)/1000 patient-days (P=.01). The rate of community fluoroquinolone use also increased, from 2.3 to 2.8 DDD/1000 inhabitant-days (P<.001). Rates of fluoroquinolone-resistant P. aeruginosa increased from 29% in 1999 to 36% in 2001 (P=.003). Both community and hospital fluoroquinolone use were predictive of rates of fluoroquinolone-resistant P. aeruginosa. Levofloxacin was associated with resistance, but ciprofloxacin was not. Most of the variability in resistance rates is explained by volume of fluoroquinolone use, both in the hospital and the surrounding community.

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.