Implementation and outcomes of a clinician-directed intervention to improve antibiotic prescribing for acute respiratory tract infections within the Veterans' Affairs Healthcare System.

OBJECTIVE: To determine whether a clinician-directed acute respiratory tract infection (ARI) intervention was associated with improved antibiotic prescribing and patient outcomes across a large US healthcare system. DESIGN: Multicenter retrospective quasi-experimental analysis of outpatient visits with a diagnosis of uncomplicated ARI over a 7-year period. PARTICIPANTS: Outpatients with ARI diagnoses: sinusitis, pharyngitis, bronchitis, and unspecified upper respiratory tract infection (URI-NOS). Outpatients with concurrent infection or select comorbid conditions were excluded. INTERVENTION(S): Audit and feedback with peer comparison of antibiotic prescribing rates and academic detailing of clinicians with frequent ARI visits. Antimicrobial stewards and academic detailing personnel delivered the intervention; facility and clinician participation were voluntary. MEASURE(S): We calculated the probability to receive antibiotics for an ARI before and after implementation. Secondary outcomes included probability for a return clinic visits or infection-related hospitalization, before and after implementation. Intervention effects were assessed with logistic generalized estimating equation models. Facility participation was tracked, and results were stratified by quartile of facility intervention intensity. RESULTS: We reviewed 1,003,509 and 323,023 uncomplicated ARI visits before and after the implementation of the intervention, respectively. The probability to receive antibiotics for ARI decreased after implementation (odds ratio [OR], 0.82; 95% confidence interval [CI], 0.78-0.86). Facilities with the highest quartile of intervention intensity demonstrated larger reductions in antibiotic prescribing (OR, 0.69; 95% CI, 0.59-0.80) compared to nonparticipating facilities (OR, 0.89; 95% CI, 0.73-1.09). Return visits (OR, 1.00; 95% CI, 0.94-1.07) and infection-related hospitalizations (OR, 1.21; 95% CI, 0.92-1.59) were not different before and after implementation within facilities that performed intensive implementation. CONCLUSIONS: Implementation of a nationwide ARI management intervention (ie, audit and feedback with academic detailing) was associated with improved ARI management in an intervention intensity-dependent manner. No impact on ARI-related clinical outcomes was observed.

Guideline-based antibiotics and mortality in healthcare-associated pneumonia.

BACKGROUND: Guidelines recommend administration of antibiotics with activity against methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa for treatment of healthcare-associated pneumonia (HCAP). It is unclear if this therapy improves outcomes for patients with HCAP. OBJECTIVE: To determine if administration of guideline-similar therapy (GST) was associated with a reduction in 30-day mortality for HCAP. DESIGN: Multi-center retrospective study. PARTICIPANTS: Thirteen hundred and eleven admissions for HCAP in six Veterans Affairs Medical Centers. INTERVENTIONS: Each admission was classified as receiving GST, anti-MRSA or anti-pseudomonal components of GST, or other non-HCAP therapy initiated within 48 hours of hospitalization. Association between 30-day mortality and GST was estimated with a logistic regression model that included GST, propensity to receive GST, probability of recovering an organism from culture resistant to antibiotics traditionally used to treat community-acquired pneumonia (CAP-resistance), and a GST by CAP-resistance probability interaction. MAIN MEASURES: Odds ratios and 95% confidence intervals [OR (95% CI)] of 30-day mortality for patients treated with GST and predicted probability of recovering a CAP-resistant organism, and ratio of odds ratios [ROR (95% CI)] for treatment by CAP-resistance probability interaction. KEY RESULTS: Receipt of GST was associated with increased odds of 30-day mortality [OR = 2.11 (1.11, 4.04), P = 0.02)] as was the predicted probability of recovering a CAP-resistant organism [OR = 1.67 (1.26, 2.20), P < 0.001 for a 25% increase in probability]. An interaction between predicted probability of recovering a CAP-resistant organism and receipt of GST demonstrated lower mortality with GST at high probability of CAP resistance [ROR = 0.71(≤1.00) for a 25% increase in probability, P = 0.05]. CONCLUSIONS: For HCAP patients with high probability of CAP-resistant organisms, GST was associated with lower mortality. Consideration of the magnitude of patient-specific risk for CAP-resistant organisms should be considered when selecting HCAP therapy.

Outpatient treatment and clinical outcomes of bacteriuria in veterans: A retrospective cohort analysis.

Objective: To conduct a contemporary detailed assessment of outpatient antibiotic prescribing and outcomes for positive urine cultures in a mixed-sex cohort. Design: Multicenter retrospective cohort review. Setting: The study was conducted using data from 31 Veterans' Affairs medical centers. Patients: Outpatient adults with positive urine cultures. Methods: From 2016 to 2019, data were extracted through a nationwide database and manual chart review. Positive urine cultures were reviewed at the chart, clinician, and aggregate levels. Cases were classified as cystitis, pyelonephritis, or asymptomatic bacteriuria (ASB) based upon documented signs and symptoms. Preferred therapy definitions were applied for subdiagnoses: ASB (no antibiotics), cystitis (trimethoprim-sulfamethoxazole, nitrofurantoin, ß-lactams), and pyelonephritis (trimethoprim-sulfamethoxazole, fluoroquinolone). Outcomes included 30-day clinical failure or hospitalization. Odds ratios for outcomes between treatments were estimated using logistic regression. Results: Of 3,255 cases reviewed, ASB was identified in 1,628 cases (50%), cystitis was identified in 1,156 cases (36%), and pyelonephritis was identified in 471 cases (15%). Of all 2,831 cases, 1,298 (46%) received preferred therapy selection and duration for cases where it could be defined. The most common antibiotic class prescribed was a fluoroquinolone (34%). Patients prescribed preferred therapy had lower odds of clinical failure: preferred (8%) versus nonpreferred (10%) (unadjusted OR, 0.74; 95% confidence interval [CI], 0.58-0.95; P = .018). They also had lower odds of 30-day hospitalization: preferred therapy (3%) versus nonpreferred therapy (5%) (unadjusted OR, 0.55; 95% CI, 0.37-0.81; P = .002). Odds of clinical treatment failure or hospitalization was higher for ß-lactams relative to ciprofloxacin (unadjusted OR, 1.89; 95% CI, 1.23-2.90; P = .002). Conclusions: Clinicians prescribed preferred therapy 46% of the time. Those prescribed preferred therapy had lower odds of clinical failure and of being hospitalized.

Evaluation of clinicians' knowledge, attitudes, and planned behaviors related to an intervention to improve acute respiratory infection management.

BACKGROUND: Acute respiratory tract infections (ARIs) are commonly diagnosed and major drivers of antibiotic prescribing. Clinician-focused interventions can reduce unnecessary antibiotic prescribing for ARIs. We elicited clinician feedback to design sustainable interventions to improve ARI management by understanding the mental framework of clinicians surrounding antibiotic prescribing within Veterans' Health Administration clinics. METHODS: We conducted one-on-one interviews with clinicians (n = 20) from clinics targeted for intervention at 5 facilities. The theory of planned behavior guided interview questions. Interviews were audio recorded and transcribed for qualitative analysis. An iterative coding approach identified 6 themes. RESULTS: Emergent themes: (1) barriers to appropriate prescribing are multifactorial and include challenges of behavior change; (2) antibiotic prescribing decisions are perceived as autonomous yet, diagnostic uncertainty and perceptions of patient demand can make prescribing decisions difficult; (3) clinicians perceive variation in peer prescribing practices and influences; (4) clinician-focused interventions are valuable if delivered with sensitivity; (5) communication strategies for educating patients are preferred to a shared decisions process; and (6) team standardization of practice and communication are key to facilitate appropriate prescribing. Clinicians perceived audit-and-feedback with peer comparison, academic detailing, and enhanced patient communication strategies as viable approaches to improving appropriate prescribing. CONCLUSION: Implementation strategies that enable clinicians to overcome diagnostic uncertainty, perceived patient demand, and improve patient education are desired. Implementation strategies were welcomed, and some were more readily accepted (eg, audit feedback) than others (eg, shared decision making). Implementation strategies should address clinicians' perceptions of antibiotic prescribing practices and should enhance their patient communication skills.

Identifying patients at risk for medication mismanagement: using cognitive screens to predict a patient's accuracy in filling a pillbox.

OBJECTIVE: To study the relationship between four cognitive screens (Mini-Mental State Examination [MMSE], Mini-Cog, Medication Transfer Screen [MTS], and Medi-Cog [Mini-Cog + MTS]) and pillbox concordance. DESIGN: Prospective cross-sectional pilot study. SETTING: Primary care federal health care system. PARTICIPANTS: English literate inpatients not previously diagnosed or treated for dementia and without physical handicap preventing use of a pillbox. MAIN OUTCOME MEASURE: Correlation between cognitive screens and prospective pill-count scores (PPCS). INTERVENTIONS: Mini-Cog, MTS, and MMSE screening was followed by a 28-compartment pillbox skills assessment. A passing PPCS was defined as correctly loading 80% of the medications in the pillbox. A PPCS of <80% identified patients for pillbox-organization education or supportive intervention. Variables associated with total and passing PPCS were analyzed by multivariate linear and logistic regression, respectively. RESULTS: Fifty-three patients discharged on >1 medication completed all screenings. Other than cognitive screening, only age was associated with total and passing PPCS. After adjustment for age, Medi-Cog had the highest correlation with total PPCS [r2=0.53; P<0.001), whereas Mini-Cog was the single cognitive assessment that remained significantly associated with a passing PPCS (r2=0.23; P=0.023). Age-adjusted models, including MMSE, had relatively poor association with total PPCS (r2=0.23; P=0.046) and no association with passing PPCS (r2=0.15; P=0.46). The Medi-Cog exhibited modest highest overall sensitivity (72%) and specificity (61%) to detect a passing PPCS. CONCLUSION: MMSE is a relatively poor measure of the ability of patients to fill a pillbox. The Medi-Cog and Mini-Cog may have value for assessing pillbox concordance for patients who load their own pillboxes.

A Report of the Efforts of the Veterans Health Administration National Antimicrobial Stewardship Initiative.

OBJECTIVE To detail the activities of the Veterans Health Administration (VHA) Antimicrobial Stewardship Initiative and evaluate outcomes of the program. DESIGN Observational analysis. SETTING The VHA is a large integrated healthcare system serving approximately 6 million individuals annually at more than 140 medical facilities. METHODS Utilization of nationally developed resources, proportional distribution of antibiotics, changes in stewardship practices and patient safety measures were reported. In addition, inpatient antimicrobial use was evaluated before and after implementation of national stewardship activities. RESULTS Nationally developed stewardship resources were well utilized, and many stewardship practices significantly increased, including development of written stewardship policies at 92% of facilities by 2015 (P<.05). While the proportional distribution of antibiotics did not change, inpatient antibiotic use significantly decreased after VHA Antimicrobial Stewardship Initiative activities began (P<.0001). A 12% decrease in antibiotic use was noted overall. The VHA has also noted significantly declining use of antimicrobials prescribed for resistant Gram-negative organisms, including carbapenems, as well as declining hospital readmission and mortality rates. Concurrently, the VHA reported decreasing rates of Clostridium difficile infection. CONCLUSIONS The VHA National Antimicrobial Stewardship Initiative includes continuing education, disease-specific guidelines, and development of example policies in addition to other highly utilized resources. While no specific ideal level of antimicrobial utilization has been established, the VHA has shown that improving antimicrobial usage in a large healthcare system may be achieved through national guidance and resources with local implementation of antimicrobial stewardship programs. Infect Control Hosp Epidemiol 2017;38:513-520.

Evaluation of an intervention designed to decrease the rate of nosocomial methicillin-resistant Staphylococcus aureus infection by encouraging decreased fluoroquinolone use.

OBJECTIVE: Society for Health Care Epidemiology guidelines recommend decreasing the use of fluoroquinolone antibiotics in institutions where methicillin-resistant Staphylococcus aureus (MRSA) is endemic. We evaluated whether an intervention to limit fluoroquinolone use was associated with a lower rate of nosocomial MRSA infection and summarized changes in antibiotic use, changes in other variables potentially correlated with a lower rate of MRSA infection, and rates of nosocomial infections due to other pathogens. DESIGN: Single-center quasi-experimental design. A time series of nosocomial MRSA infections was measured at monthly intervals from July 2001 through June of 2004; there were 80 MRSA infections recorded. Segmented regression analysis (ie, quasi-Poisson generalized linear models) was used to evaluate variables possibly associated with the nosocomial MRSA infection rate. SETTING: An 87-bed Veterans Affairs teaching hospital with an extended-care facility. INTERVENTION: A physician-directed computer-generated intervention designed to limit the use of fluoroquinolone antibiotics was initiated, and institutional changes in antibiotic use and nosocomial MRSA infection rates were tracked. RESULTS: After the intervention, fluoroquinolone use decreased by approximately 34%, and levofloxacin use decreased by approximately 50%. Decreased fluoroquinolone use was offset by increased cephalosporin, piperacillin-tazobactam, and trimethoprim-sulfamethoxazole use. The nosocomial MRSA infection rate decreased from 1.37 to 0.63 episodes per 1,000 patient-days after the study intervention (P=.02). Coagulase-negative Staphylococcus and Enterococcus infection rates also decreased. However, the rate of infection with gram-negative organisms increased. The rate of MRSA infection was positively correlated with levofloxacin use (P=.01) and azithromycin use (P=.08), whereas it was negatively correlated with summer season (P=.05). In a subsequent model, the rate of MRSA infection was negatively correlated with the study intervention (P=.04). CONCLUSION: Reduction in the institutional use of fluoroquinolones may be associated with a lower nosocomial MRSA infection rate.

Experience with a clinical decision support system in community pharmacies to recommend narrow-spectrum antimicrobials, nonantimicrobial prescriptions, and OTC products to decrease broad-spectrum antimicrobial use.

BACKGROUND: Overuse of antibiotics increases the incidence of bacterial resistance and contributes avoidable costs to the health care system. OBJECTIVE: To determine the feasibility of a protocol-driven community pharmacy intervention that was designed to decrease broad-spectrum antimicrobial (BSA) use in patients with upper respiratory tract infections. METHODS: The intervention involved pharmacists who conducted guided interviews regarding patient symptoms in a cohort of patients with BSA prescription visiting 2 rural community pharmacies during peak respiratory illness season. A clinical decision support system was provided to aid in pharmacist diagnosis and assist in determining if the BSA therapy was appropriate. Upon patient consent, pharmacists attempted to contact primary care providers (PCPs) to confirm the diagnosis and recommend appropriate alternative therapy. RESULTS: There were 192 subjects with prescriptions for BSAs and symptoms of respiratory tract infection. Only 3% of the patients who were approached declined to discuss their symptoms and treatment with the pharmacist. A mean of 3 minutes was required to collect symptom and treatment information from the patients. However, when patients were asked if the pharmacist could contact their PCP to recommend alternative therapy, only 7% (n=4) of patients agreed to the intervention. The PCPs who were contacted by pharmacists were receptive to altering the BSA to first-line antimicrobial therapy such as amoxicillin or doxycycline. CONCLUSION: Despite a description of the importance of the intervention, more than 90% of patients prescribed a BSA declined to permit the community pharmacist to contact the prescriber to discuss first-line therapeutic alternatives. This experience in a pilot study to explore the feasibility of pharmacist intervention at the point of dispensing of a BSA made clear that a successful community pharmacy intervention to reduce BSA use would require an alternative method, perhaps via a collaborative practice protocol that does not require patient consent to make the drug substitution to first-line antibiotic therapy.

Total duration of antimicrobial therapy in veterans hospitalized with uncomplicated pneumonia: Results of a national medication utilization evaluation.

OBJECTIVE: Practice guidelines recommend the shortest duration of antimicrobial therapy appropriate to treat uncomplicated pneumonia be prescribed to reduce the emergence of resistant pathogens. A national evaluation was conducted to assess the duration of therapy for pneumonia. DESIGN: Retrospective medication utilization evaluation. SETTING: Thirty Veterans Affairs medical centers. PATIENTS: Inpatients discharged with a diagnosis of pneumonia. MEASUREMENTS: A manual review of electronic medical records of inpatients discharged with uncomplicated community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP) was conducted. Appropriate CAP therapy duration was defined as at least 5 days, and up to 3 additional days beginning the first day the patient achieved clinical stability criteria; the appropriate HCAP therapy duration was defined as 8 days. The duration of antimicrobial therapy for intravenous (IV) and oral (PO) inpatient administration, PO therapy dispensed upon discharge, Clostridium difficile infection (CDI), hospital readmission, and death rates were measured. RESULTS: Of 3881 pneumonia admissions, 1739 met inclusion criteria (CAP [n = 1195]; HCAP [n = 544]). Overall, 13.9% of patients (CAP [6.9%], HCAP [29.0%]) received therapy duration consistent with guideline recommendations. The median (interquartile range) days of therapy were 4 days (3-6 days), 1 day (0-3 days), and 6 days (4-8 days) for inpatient IV, inpatient PO, and outpatient PO antimicrobials, respectively. CDI was rare but more common in patients who received therapy duration consistent with guidelines. Therapy duration was not associated with the readmission or mortality rate. CONCLUSIONS: Antimicrobials were commonly prescribed for a longer duration than guidelines recommend. The majority of excessive therapy was completed upon discharge, identifying the need for strategies to curtail unnecessary use postdischarge. Journal of Hospital Medicine 2015;11:832-839. © 2015 Society of Hospital Medicine.

In vitro pharmacodynamic activity of gatifloxacin, gemifloxacin, moxifloxacin and levofloxacin against Streptococcus pneumoniae containing specific mutations in DNA gyrase and topoisomerase IV.

An in vitro pharmacodynatnic modeling apparatus (PDMA) generated specific bacterial kill profiles for single-dose regimens of gatifloxacin (GT), gemifloxacin (GM), moxifloxacin (MX) and levofloxacin (LV) against isolates of Streptococcus pneumoniae with specific QRDR profiles: SP-WT (no modifications); SP-C (changes in parC); and SP-AC (changes in both parC and gyrA). No differences in 3-log reduction time or total log reduction were observed among the four agents for SP-WT; however, LV failed to achieve a 3-log reduction in SP-C and SP-AC, and total log reduction after 12 hrs was minimal compared to the other agents. GM and MX required less time for 3-log reduction of SP-AC compared to GT, but total log reductions in SP-AC were similar among the three newer quinolone agents (GM > MX > GT). The study isolates with QRDR modifications greatly reduced LV activity. GM and MX maintained the greatest degree of activity against all study isolates and their activity was not adversely influenced by the genetic modifications in SP-C and SP-AC. The dual targeting characteristic of GM was also assessed, but did not offer significant advantages relative to MX and GT.

Predicting antibiotic resistance to community-acquired pneumonia antibiotics in culture-positive patients with healthcare-associated pneumonia.

OBJECTIVE: To develop and validate a model to predict resistance to community-acquired pneumonia antibiotics (CAP-resistance) among patients with healthcare-associated pneumonia (HCAP), and to compare the model's predictive performance to a model including only guideline-defined criteria for HCAP. DESIGN: Retrospective cohort study. SETTING: Six Veterans Affairs Medical Centers in the northwestern United States. PATIENTS: Culture-positive inpatients with HCAP. MEASUREMENTS: Patients were identified based upon guideline-defined criteria for HCAP. Relevant cultures obtained within 48 hours of admission were assessed to determine bacteriology and antibiotic susceptibility. Medical records for the year preceding admission were assessed to develop predictive models of CAP-resistance with logistic regression. The predictive performance of cohort-developed and guideline-defined models was compared. RESULTS: CAP-resistant organisms were identified in 118 of 375 culture-positive patients. Of guideline-defined criteria, CAP-resistance was associated (odds ratio (OR) [95% confidence interval (CI)]) with: admission from nursing home (2.6 [1.6-4.4]); recent antibiotic exposure (1.7 [1.0-2.8]); and prior hospitalization (1.6 [1.0-2.6]). In the cohort-developed model, CAP-resistance was associated with: admission from nursing home or recent nursing home discharge (2.3 [1.4-3.8]); positive methicillin-resistant Staphylococcus aureus (MRSA) history within 90 days of admission (6.4 [2.6-17.8]) or 91-365 days (2.3 [0.9-5.9]); cephalosporin exposure (1.8 [1.1-2.9]); recent infusion therapy (1.9 [1.0-3.5]); diabetes (1.7 [1.0-2.8]); and intensive care unit (ICU) admission (1.6 [1.0-2.6]). Area under the receiver operating characteristic curve (aROC [95% CI]) for the cohort-developed model (0.71 [0.65-0.77]) was significantly higher than for the guideline-defined model (0.63 [0.57-0.69]) (P = 0.01). CONCLUSIONS: Select guideline-defined criteria predicted CAP-resistance. A cohort-developed model based primarily on prior MRSA history, nursing home residence, and specific antibiotic exposures provided improved prediction of CAP-resistant organisms in HCAP.

Efficacy of oral beta-lactam versus non-beta-lactam treatment of uncomplicated cellulitis.

BACKGROUND: Preferred therapy for purulent skin and soft tissue infections is incision and drainage, but many infections cannot be drained. Empiric therapies for these infections are ill-defined in the era of community-acquired methicillin-resistant Staphylococcus aureus. METHODS: A multicenter retrospective cohort study of outpatients treated for cellulitis was conducted to compare clinical failure rates of oral beta-lactam and non-beta-lactam treatments. Exclusion criteria included purulent infection requiring incision and drainage, complicated skin and soft tissue infection, chronic ulceration, and intravenous antibiotics. Failure rates were compared using logistic regression to adjust for both covariates associated with failure and a propensity score for beta-lactam treatment. RESULTS: Of 2977 patients, 861 met inclusion criteria and were classified by treatment: beta-lactam (n = 631) or non-beta-lactam therapy (n = 230). Failure rates were 14.7% versus 17.0% (odds ratio [OR] 0.85, 95% confidence interval [CI], 0.56-1.31) for beta-lactam and non-beta-lactam therapy, respectively. Failure was associated with: age (P = .02), acute symptom severity (P = .03), animal bites (P = .03), Charlson score > 3 (P = .02), and histamine-2 receptor antagonist use (P = .09). Relative efficacy of beta-lactam therapy was greater after adjustment for factors associated with failure but remained statistically insignificant (adjusted OR 0.81, 95% CI, 0.53-1.24); adjusted including propensity score covariate (OR 0.71, 95% CI, 0.45-1.13). Discontinuation due to adverse effects differed between beta-lactam (0.5%) and non-beta-lactam (2.2%) therapies (P = .04). CONCLUSION: There was no significant difference in clinical failure between beta-lactam and non-beta-lactam antibiotics for the treatment of uncomplicated cellulitis. Increased discontinuation due to adverse events with non-beta-lactam therapy was observed.

Clinical outcomes of ambulatory acute exacerbations of chronic bronchitis with older versus newer antimicrobials.

OBJECTIVE: To determine whether the cure rate was similar between traditional and newer antibiotics in the treatment of acute exacerbations of chronic bronchitis (AECB), to determine whether antibiotic selection during the first AECB of the season influences the frequency of subsequent AECB, and to identify variables associated with poor short- and long-term treatment outcome. METHODS: A retrospective analysis of subjects seen for management of their first seasonal AECB was conducted. Subjects were stratified into traditional therapies (n = 95) or newer therapies (n = 101) by antibiotic prescription. RESULTS: There was no difference in initial cure rates between older versus newer antibiotics (93% vs. 95%; p = 0.48). There was no difference in the number of subjects that remained AECB-free for 6 months after initial treatment with older versus newer antibiotic regimens (34% vs. 28%; p = 0.37). Oxygen initiation or increased dose (OR 10.9; 95% CI 1.4 to 84.2; p = 0.02) was the only variable independently associated with lack of AECB resolution. Nonsmoking status trended toward an association with remaining AECB-free at 180 days (OR 0.39; 95% CI 0.15 to 1.01; p = 0.053). CONCLUSIONS: The use of older versus newer antibiotics did not independently predict short-term outcome or future AECB.

Pharmacodynamic characterization of efflux and topoisomerase IV-mediated fluoroquinolone resistance in Streptococcus pneumoniae.

OBJECTIVES: Most in vitro investigations of fluoroquinolone resistance involving Streptococcus pneumoniae have described genotypic changes in quinolone resistance-determining regions (QRDRs) that occur as the result of exposure to fluoroquinolones obtained with static antimicrobial concentrations. The objectives of this study were to determine whether differences exist between moxifloxacin, sparfloxacin and levofloxacin antimicrobial effect (AME) and their ability to select out stepwise mutations with wild-type, efflux-expressing and parC-mediated fluoroquinolone resistance while simulating the in vivo dosing and pharmacokinetics of the respective agents. METHODS: A one-compartment pharmacodynamic model simulated fluoroquinolone dosing regimens. Duplicate 24 h experiments were carried out in Mueller-Hinton broth with 3% horse blood at 1 x 10(8) cfu/mL. Reserpine (10 mg/L) was added to select experiments conducted with efflux-expressing strains. AME was expressed as the area under the time-concentration kill curve (AUEC24). Strains expressing increased MIC post-time-concentration kill curve (TCKC) were evaluated for changes in QRDR. RESULTS: Moxifloxacin exhibited a greater AME against all isolates. Efflux was generally associated with partial loss of AME for all fluoroquinolones, and levofloxacin retained no AME against parC-expressing S. pneumoniae. Increased fluoroquinolone MIC post-TCKC was more common with efflux expression. The addition of reserpine was associated with enhanced AME for levofloxacin and moxifloxacin, but was not associated with altered resistance selection. Isolates recovered post-TCKC from experiments involving efflux- or parC mutation-containing isolates generally exhibited a more than four-fold increase in MIC, which was associated with commonly reported substitutions in both parC and gyrA. CONCLUSION: The results of this study generally indicate that resistance selection under pharmacodynamic conditions is similar to results reported with static fluoroquinolone concentrations. While moxifloxacin AME was greater than levofloxacin and sparfloxacin, the overall selection of resistant isolates did not differ.