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1.  Recurrent Urinary Tract Infections Among Women: Comparative Effectiveness of 5 Prevention and Management Strategies Using a Markov Chain Monte Carlo Model 
In our Monte Carlo model comparing management strategies for recurrent urinary tract infections in women, we found that nitrofurantoin prophylaxis was most effective, but most expensive to the payer. Other strategies resulted in payer savings but were less efficacious.
Background. Recurrent urinary tract infections (UTIs) are a common problem among women. However, comparative effectiveness strategies for managing recurrent UTIs are lacking.
Methods. We performed a systematic literature review of management of women experiencing ≥3 UTIs per year. We then developed a Markov chain Monte Carlo model of recurrent UTI for each management strategy with ≥2 adequate trials published. We simulated a cohort that experienced 3 UTIs/year and a secondary cohort that experienced 8 UTIs/year. Model outcomes were treatment efficacy, patient and payer cost, and health-related quality of life.
Results. Five strategies had ≥2 clinical trials published: (1) daily antibiotic (nitrofurantoin) prophylaxis; (2) daily estrogen prophylaxis; (3) daily cranberry prophylaxis; (4) acupuncture prophylaxis; and (5) symptomatic self-treatment. In the 3 UTIs/year model, nitrofurantoin prophylaxis was most effective, reducing the UTI rate to 0.4 UTIs/year, and the most expensive to the payer ($821/year). All other strategies resulted in payer cost savings but were less efficacious. Symptomatic self-treatment was the only strategy that resulted in patient cost savings, and was the most favorable strategy in term of cost per quality-adjusted life-year (QALY) gained.
Conclusions. Daily antibiotic use is the most effective strategy for recurrent UTI prevention compared to daily cranberry pills, daily estrogen therapy, and acupuncture. Cost savings to payers and patients were seen for most regimens, and improvement in QALYs were seen with all. Our findings provide clinically meaningful data to guide the physician–patient partnership in determining a preferred method of prevention for this common clinical problem.
PMCID: PMC3871790  PMID: 24065333
urinary tract infection; recurrent; management
2.  A Systematic Literature Review and Meta-analysis of Factors Associated with MRSA Colonization at Time of Hospital or ICU Admission 
Screening for methicillin-resistant Staphylococcus aureus (MRSA) in high-risk patients is a legislative mandate in nine U.S. states and has been adopted by many hospitals. Definitions of “high-risk” differ among hospitals and state laws. A systematic evaluation of factors associated with colonization is lacking. We performed a systematic review of the literature to assess factors associated with MRSA colonization at hospital admission.
We searched MEDLINE from 1966–2012 for articles comparing MRSA colonized and non-colonized patients on hospital or ICU admission. Data were extracted using a standardized instrument. Meta-analyses were performed to identify factors associated with MRSA colonization.
We reviewed 4,381 abstracts; twenty-nine manuscripts met inclusion criteria (n=76,913 patients). MRSA colonization at hospital admission was associated with recent prior hospitalization (OR=2.4 95%-CI=1.3–4.7;p<0.01), nursing home exposure (OR=3.8 95%-CI=2.3–6.3;p<0.01) and history of exposure to healthcare-associated pathogens (MRSA carriage OR=8.0 95%-CI =4.2–15.1, C. difficile infection OR=3.4 95%-CI=2.2–5.3, vancomycin-resistant Enterococci carriage OR=3.1 95%-CI=2.5–4.0;p<0.01 for all). Select comorbidities were associated with MRSA colonization (congestive heart failure, diabetes, pulmonary disease, immunosuppression and renal failure; p<0.01 for all), while others were not (HIV, cirrhosis, and malignancy). ICU admission was not associated with an increased risk of MRSA colonization (OR=1.1 95%-CI =0.6–1.8;p=0.87).
MRSA colonization on hospital admission was associated with healthcare contact, previous healthcare-associated pathogens, and select comorbid conditions. ICU admission was not associated with MRSA colonization although this is commonly used in state mandates for MRSA screening. Infection prevention programs utilizing targeted MRSA screening may consider our results to define patients likely to have MRSA colonization.
PMCID: PMC3883507  PMID: 24018925
3.  Systematic Review and Meta-Analysis of Linezolid and Daptomycin for Treatment of Vancomycin-Resistant Enterococcal Bloodstream Infections 
Antimicrobial Agents and Chemotherapy  2013;57(10):5013-5018.
Bloodstream infections due to vancomycin-resistant enterococci (VRE-BSI) result in substantial patient mortality and cost. Daptomycin and linezolid are commonly prescribed for VRE-BSI, but there are no clinical trials to determine optimal antibiotic selection. We conducted a systematic review for investigations that compared daptomycin and linezolid for VRE-BSI. We searched Medline from 1966 through 2012 for comparisons of linezolid and daptomycin for VRE-BSI. We included searches of EMBASE,, and national meetings. Data were extracted using a standardized instrument. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using a fixed-effects model. Our search yielded 4,243 publications, of which 482 contained data on VRE treatment. Most studies (452/482) did not present data on BSI or did not provide information on linezolid or daptomycin. Among the remaining 30 studies, 9 offered comparative data between the two agents. None were randomized clinical trials. There was no difference in microbiologic (n = 5 studies, 517 patients; OR, 1.0; 95% CI, 0.4 to 1.7; P = 0.95) and clinical (n = 3 studies, 357 patients; OR, 1.2; 95% CI, 0.7 to 2.0; P = 0.7) cures between the two antibiotics. There was a trend toward increased survival with linezolid compared to daptomycin treatment (n = 9 studies, 1,074 patients; OR, 1.3; 95% CI, 1.1 to 1.8; I2 = 0 [where I2 is a measure of inconsistency]), but this did not reach statistical significance (P = 0.054). There are limited data to inform clinicians on optimal antibiotic selection for VRE-BSI. Available studies are limited by small sample size, lack of patient-level data, and inconsistent outcome definitions. Additional research, including randomized clinical trials, is needed before conclusions can be drawn about treatment options for VRE therapy.
PMCID: PMC3811395  PMID: 23896468
4.  Quantifying The Impact of Extra-Nasal Testing Body Sites for MRSA Colonization at the Time of Hospital or Intensive Care Unit Admission 
Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of healthcare-associated infections. Recent legislative mandates require nares screening for MRSA at hospital and ICU admission in many states. However, MRSA colonization at extra-nasal sites is increasingly recognized. We conducted a systematic review of the literature to identify the yield of extra-nasal testing for MRSA.
We searched MEDLINE from January 1966 through January 2012 for articles comparing nasal and extra-nasal screening for MRSA colonization. Studies were categorized by population tested, specifically those admitted to ICUs, and those admitted to hospitals with a high prevalence (≥6%) or low prevalence (<6%) of MRSA carriers. Data were extracted using a standardized instrument.
We reviewed 4,381 abstracts and 735 manuscripts. Twenty-three manuscripts met criteria for analysis (n=39,479 patients). Extra-nasal MRSA screening increased yield by approximately one-third over nares alone. The yield was similar upon ICU admission (weighted average 33%, range 9%–69%), and hospital admission in high (weighted average 37%, range 9–86%) and low prevalence (weighted average 50%, range 0–150%) populations. Comparing individual extra nasal sites, testing the oropharynx increased MRSA detection by 21% over nares alone; rectum by 20%; wounds by 17%; and axilla by 7%.
Extra-nasal MRSA screening at hospital or ICU admission in adults will increase MRSA detection by one-third compared to nares screening alone. Findings were consistent among subpopulations examined. Extra-nasal testing may be a valuable strategy for outbreak control or in settings of persistent disease, particularly when combined with decolonization or enhanced infection prevention protocols.
PMCID: PMC3894230  PMID: 23295562
5.  Pneumocystis Pneumonia in Hospitalized Patients; A Detailed Examination of Symptoms, Management, and Outcomes in HIV-infected and HIV-uninfected Persons 
Pneumocystis jiroveci pneumonia is a life-threatening infection for immunocompromised individuals. There are robust data and clear guidelines for prophylaxis and treatment of HIV-related Pneumocystis jiroveci pneumonia (HIV-PCP), yet few data and no guidelines for non-HIV related Pneumocystis pneumonia (NH-PCP). We postulated that prevention and inpatient management of HIV-PCP differed from NH-PCP.
We performed a retrospective case review of all pathologically confirmed cases of PCP seen at the University of Alabama Medical Center from 1996 to 2008. Data on clinical presentation, hospital course, and outcome were collected using a standardized data collection instrument. Bivariate analysis compared prophylaxis, adjunctive corticosteroids, and clinical outcomes between patients with HIV-PCP and NH-PCP.
Our analysis of the cohort included 97 cases of PCP; 65 HIV and 32 non-HIV cases. Non-HIV cases rarely received primary prophylaxis (4% vs. 38%, p=0.01) and received appropriate antibiotics later in the course of hospitalization (5.2 vs 1.1 days, P<0.005). Among transplant patients, NH-PCP was diagnosed a mean of 1,066 days after transplantation and most patients were on low-dose corticosteroids (87%) at the time of disease onset. No significant differences in adjunctive corticosteroid use (69% vs. 77%, p=0.39) and 90-day mortality (41% vs. 28%, p=0.20) were detected.
Patients who have undergone organ or stem cell transplant remain at risk for PCP for many years after transplantation. In our cohort, patients who developed NH-PCP were rarely given prophylaxis and initiation of appropriate antibiotics was significantly delayed compared to cases of HIV-PCP. Medical providers should be aware of the ongoing risk for NH-PCP, even late after transplantation, and consider more aggressive approaches to both prophylaxis and earlier empiric therapy for PCP.
PMCID: PMC3889465  PMID: 22548840
Pneumocystis Pneumonia; Transplant; Infectious Complications
6.  Association of Vancomycin-Resistant Enterococcus Bacteremia and Ceftriaxone Usage 
Vancomycin-resistant Enterococci (VRE) have become a public health concern with implications for patient mortality and costs. Hospital antibiotic usage may impact VRE incidence, but the relationship is poorly understood. Animal investigations suggest ceftriaxone may be associated with VRE proliferation. We measured antimicrobial usage and VRE bloodstream infection (BSI) incidence to test our hypothesis that increased ceftriaxone use would be associated with a higher incidence of VRE-BSI.
The University of Alabama at Birmingham Medical Center is a 900-bed urban tertiary-care hospital
Retrospective analysis of antimicrobial usage and VRE-BSI from 2005 to 2008 (43 months). Antimicrobial usage quantified as days of therapy/1,000 patient-days (DOT). VRE-BSI incidence calculated as cases/1,000 patient-days. Negative binomial regression with adjustment for correlation between consecutive observations measured the association between antimicrobial usage and VRE-BSI incidence at the hospital- and care-unit levels.
VRE-BSI incidence increased from 0.06 to 0.17 infections/1,000 patient-days. Hospital VRE-BSI incidence was associated with prior-month ceftriaxone DOT (Incidence Rate Ratio 1.38 per 10 DOT; p=0.005). After controlling for ceftriaxone, prior-month cephalosporin use (class) was not predictive of VRE-BSI (p=0.70). Similarly, prior-month use of piperacillin-tazobactam, ceftazidime, cefepime, cefazolin, or vancomycin was not predictive of VRE-BSI when considered individually (p≥0.4 for all comparisons). The final model suggests that type of intensive care unit was related to VRE-BSI incidence.
Ceftriaxone use in the prior month, but not cephalosporin (class) or vancomycin use, was related to VRE-BSI incidence. These findings suggest that an antimicrobial stewardship program that limits ceftriaxone may reduce nosocomial VRE-BSI incidence.
PMCID: PMC3879097  PMID: 22669234
7.  In vitro Endothelial Cell Damage is Positively Correlated with Enhanced Virulence and Poor Vancomycin Responsiveness in Experimental Endocarditis due to Methicillin Resistant Staphylococcus aureus 
Cellular microbiology  2011;13(10):1530-1541.
The pathogenesis of Staphylococcus aureus infective endocarditis (IE) is postulated to involve invasion and damage of endothelial cells (ECs). However, the precise relationships between S. aureus – EC interactions in vitro and IE virulence and treatment outcomes in vivo are poorly defined. Ten methicillin-resistant S. aureus (MRSA) clinical isolates previously tested for their virulence and vancomycin responsiveness in an experimental IE model were assessed in vitro for their hemolytic activity, protease production, and capacity to invade and damage ECs. There was a significant positive correlation between the in vitro EC damage caused by these MRSA strains and their virulence during experimental IE (in terms of bacterial densities in target tissues; P < 0.02). Importantly, higher EC damage was also significantly correlated with poor microbiologic response to vancomycin in the IE model (P < 0.001). Interestingly, the extent of EC damage was unrelated to a strain's ability to invade ECs, hemolytic activity and protease production, or β-toxin gene transcription. Inactivation of the agr locus in two MRSA strains caused ∼20% less damage as compared to the corresponding parental strains, indicating that a functional agr is required for maximal EC damage induction. Thus, MRSA-induced EC damage in vitro is a unique virulence phenotype that is independent of many other prototypical MRSA virulence factors, and may be a key biomarker for predicting MRSA virulence potential and antibiotic outcomes during endovascular infections.
PMCID: PMC3173605  PMID: 21777408
10.  In Vitro Cross-Resistance to Daptomycin and Host Defense Cationic Antimicrobial Peptides in Clinical Methicillin-Resistant Staphylococcus aureus Isolates▿ 
We investigated the hypothesis that methicillin-resistant Staphylococcus aureus (MRSA) isolates developing reduced susceptibilities to daptomycin (DAP; a calcium-dependent molecule acting as a cationic antimicrobial peptide [CAP]) may also coevolve reduced in vitro susceptibilities to host defense cationic antimicrobial peptides (HDPs). Ten isogenic pairs of clinical MRSA DAP-susceptible/DAP-resistant (DAPs/DAPr) strains were tested against two distinct HDPs differing in structure, mechanism of action, and origin (thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide-1 [hNP-1]) and one bacterium-derived CAP, polymyxin B (PMB). Seven of 10 DAPr strains had point mutations in the mprF locus (with or without yyc operon mutations), while three DAPr strains had neither mutation. Several phenotypic parameters previously associated with DAPr were also examined: cell membrane order (fluidity), surface charge, and cell wall thickness profiles. Compared to the 10 DAPs parental strains, their respective DAPr strains exhibited (i) significantly reduced susceptibility to killing by all three peptides (P < 0.05), (ii) increased cell membrane fluidity, and (iii) significantly thicker cell walls (P < 0.0001). There was no consistent pattern of surface charge profiles distinguishing DAPs and DAPr strain pairs. Reduced in vitro susceptibility to two HDPs and one bacterium-derived CAP tracked closely with DAPr in these 10 recent MRSA clinical isolates. These results suggest that adaptive mechanisms involved in the evolution of DAPr also provide MRSA with enhanced survivability against HDPs. Such adaptations appear to correlate with MRSA variations in cell membrane order and cell wall structure. DAPr strains with or without mutations in the mprF locus demonstrated significant cross-resistance profiles to these unrelated CAPs.
PMCID: PMC3165344  PMID: 21709105
11.  Nitrofurantoin Compares Favorably to Recommended Agents as Empirical Treatment of Uncomplicated Urinary Tract Infections in a Decision and Cost Analysis 
Mayo Clinic Proceedings  2011;86(6):480-488.
OBJECTIVE: To analyze the costs of nitrofurantoin use compared to those of other antibiotics recommended for treatment of uncomplicated urinary tract infection (UTI).
PATIENTS AND METHODS: We used a decision analysis model to perform cost-minimization and sensitivity analyses to determine the level of trimethoprim-sulfamethoxazole (TMP-SMX) and fluoroquinolone resistance that would favor the use of nitrofurantoin as a first-line empirical treatment of uncomplicated UTIs. The model used a program perspective to evaluate costs.
RESULTS: Nitrofurantoin was cost-minimizing when the prevalence of fluoroquinolone resistance exceeded 12% among uropathogens or the prevalence of TMP-SMX resistance exceeded 17%. On 2-way sensitivity analysis, variables that had a significant impact on our cost-minimization threshold included cost of antibiotics and probability of clinical cure with antibiotics.
CONCLUSION: From a payer perspective, nitrofurantoin appears to be a reasonable alternative to TMP-SMX and fluoroquinolones for empirical treatment of uncomplicated UTIs, especially given the current prevalence of antibiotic resistance among community uropathogens. On the basis of efficacy, cost, and low impact on promoting antimicrobial resistance, clinicians should consider nitrofurantoin as a reasonable alternative to TMP-SMX and fluoroquinolones for first-line therapy for uncomplicated UTIs.
From a payer perspective, nitrofurantoin appears to be a reasonable alternative to trimethoprim-sulfamethoxazole and fluoroquinolones for empirical treatment of uncomplicated urinary tract infections, especially given the current prevalence of antibiotic resistance among community uropathogens.
PMCID: PMC3104907  PMID: 21576512
12.  Impact of Methicillin-Resistant Staphylococcus aureus Prevalence among S. aureus Isolates on Surgical Site Infection Risk after Coronary Artery Bypass Surgery 
Cephalosporins are recommended for antibiotic prophylaxis to prevent cardiothoracic surgical site infections (SSIs) except in patients with β-lactam allergy or in settings with a “high” prevalence of methicillin-resistant Staphylococcus aureus (MRSA) among S. aureus isolates (hereafter, “MRSA prevalence”); however, “high” remains undefined. We sought to identify the MRSA prevalence at which glycopeptide prophylaxis would minimize SSIs relative to β-lactam prophylaxis.
We developed a decision analysis model to estimate SSI likelihood when either glycopeptides or β-lactams were used for prophylaxis in cardiothoracic surgery. Event probabilities were derived from a systematic literature review. A similar cost-minimization model was also developed.
At 0% MRSA prevalence, SSI probability was 3.64% with glycopeptide prophylaxis and 3.49% with β-lactam prophylaxis. At MRSA prevalences of 10%, 20%, 30%, or 40%, SSI probabilities with glycopeptide prophylaxis did not change, but they were 3.98%, 4.48%, 4.97%, and 5.47% with β-lactam prophylaxis. The threshold of MRSA prevalence at which glycopeptide prophylaxis minimized SSI probability and cost was 3%. In sensitivity analyses, variations in most model estimates only modestly affected the threshold.
Glycopeptide prophylaxis minimizes the risk of SSIs and cost when MRSA prevalence exceeds 3%. At very low MRSA prevalence (between 3% and 10%), the SSI minimization provided by glycopeptide prophylaxis is small and may be within the error of the model. Given the current MRSA prevalence in most community and healthcare settings, clinicians should consider routine prophylaxis with vancomycin. Our findings may have important policy implications, as benefits in cardiothoracic surgery antibiotic prophylaxis must be weighed against the limitations of increased glycopeptide use.
PMCID: PMC3193178  PMID: 21460485
13.  Carotenoid-Related Alteration of Cell Membrane Fluidity Impacts Staphylococcus aureus Susceptibility to Host Defense Peptides▿  
Carotenoid pigments of Staphylococcus aureus provide integrity to its cell membrane (CM) and limit oxidative host defense mechanisms. However, the role of carotenoids in staphylococcal resistance to nonoxidative host defenses has not been characterized. The current study examined the relationship among CM carotenoid content, membrane order, and in vitro susceptibility to daptomycin or to prototypic neutrophil-derived, platelet-derived, or bacterium-derived cationic antimicrobial peptides (human neutrophil defensin-1 [hNP-1], platelet microbicidal proteins [PMPs], or polymyxin B, respectively). A previously characterized methicillin-susceptible Staphylococcus aureus (MSSA) isogenic clinical strain set was used, including a parental isolate with an intact carotenoid biosynthetic operon (crtOPQMN) containing the crtM gene encoding early steps in staphyloxanthin biosynthesis, a crtM deletion mutant, and a crtMN multicopy plasmid-complemented variant. Compared to the parental and crtM knockout strains, the crtMN-complemented strain exhibited (i) increased carotenoid production, (ii) increased CM rigidity (P < 0.001), and (iii) uniformly reduced susceptibility to killing by the above-mentioned range of cationic peptides (statistically significant for hNP-1 [20 μg/ml]; P = 0.0037). There were no significant differences in phospholipid composition and asymmetry, fatty acid profiles, surface charge, or cell wall thickness among the strain set. Collectively, these data support the concept that carotenoid biosynthesis can contribute to the ability of S. aureus to subvert nonoxidative host defenses mediated by cationic peptides, potentially by increasing target membrane rigidity.
PMCID: PMC3028772  PMID: 21115796
14.  Combinatorial Phenotypic Signatures Distinguish Persistent from Resolving Methicillin-Resistant Staphylococcus aureus Bacteremia Isolates ▿  
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (PB) (positive blood cultures after ≥7 days of therapy) represents a clinically challenging subset of invasive MRSA infections. In this investigation, we examined the potential correlation of specific virulence signatures with PB versus resolving MRSA bacteremia (RB) (negative blood cultures within 2 to 4 days of therapy) strains. Thirty-six MRSA isolates from patients enrolled in a recent multinational clinical trial were studied for (i) susceptibility to host defense cationic peptides (HDPs) (i.e., thrombin-induced platelet microbicidal proteins [tPMPs] and human neutrophil peptide 1 [hNP-1]); (ii) adherence to host endovascular ligands (fibronectin) and cells (endothelial cells); and (iii) biofilm formation. We found that PB isolates exhibited significantly reduced susceptibilities to tPMPs and hNP-1 (P < 0.001 and P = 0.023, respectively). There was no significant association between the PB outcome and fibronectin binding, endothelial cell binding, or biofilm formation (P = 0.25, 0.97, and 0.064 versus RB strains, respectively). However, multiple logistic regression analysis revealed that the PB outcome was significantly associated with the combination of reduced susceptibilities to HDPs and extent of biofilm formation (P < 0.0001). Similar results were obtained in a second analysis using days of bacteremia as a continuous outcome, showing that reduced HDP susceptibilities and increased biofilm formation cocontributed to predict the duration of bacteremia. Our data indicate that PB isolates have specific pathogenic signatures independent of conventional antimicrobial susceptibility. These combinatorial mosaics can be defined and used to prospectively distinguish PB from RB strains in advance and potentially to predict ultimate clinical outcomes.
PMCID: PMC3028773  PMID: 21098242
15.  Antiretroviral Prescribing Patterns in Treatment-Naïve Patients in the United States 
AIDS Patient Care and STDs  2010;24(2):79-85.
Numerous antiretroviral therapy (ART) regimens are recommended for first-line and subsequent HIV care, but regimen selection for clinical use may not represent the full range of options. We hypothesized that despite an increase in available antiretrovirals, clinical trial data on regimen efficacy and fixed-dose combination options have lead to uniformity in initial ART. We evaluated regimen selection for ART-naïve patients at the University of Alabama at Birmingham (UAB) 1917 Clinic between January 2000 and December 2007. The annual number of unique initial regimens was quantified. Initial regimen variability was expressed as regimens per 100 patients. Subsequent ART regimens were characterized for complexity via regimen sequence trees detailing the first three generations of regimens for patients starting the two most common initial combinations. Four hundred eighty-two ART-naïve patients were treated with 39 unique initial regimens (8.0 regimens per 100 patients). Variability in initial regimen selection was highest in the first 6 years (14.9–24.4 regimens per 100 patients). A sharp decline was observed in 2006 (16.1 regimens per 100 patients) and 2007 (6.5 regimens per 100 patients). The most dramatic shift in drug selection involved an increase in emtricitabine plus tenofovir plus efavirenz, from 0% in 2003 to 85% in 2007. During the study period, 205 of 482 (43%) patients required a change in initial therapy. Of these, 156 of 205 (76%) had a unique sequence of regimens. A shift toward homogeneity of initial ART was observed (85% of patients received the same first-line regimen in 2007). In contrast, regimen sequencing beyond the first regimen remained complex. These shifts in ART prescribing patterns may have implications for collaborative HIV care.
PMCID: PMC3826470  PMID: 20059309

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