Christopher J. Graber

Emergence of Multidrug-Resistant, Community-Associated, Methicillin-Resistant Staphylococcus aureus Clone USA300 in Men Who Have Sex with Men

Context Researchers have recently identified multidrug-resistant USA300, a clone of community-acquired, methicillin-resistant Staphylococcus aureus (MRSA) that is resistant to multiple antibiotics. Contribution The authors demonstrate that the incidence of multidrug-resistant USA300 MRSA is highest in the areas of San Francisco where more male same-sex couples reside. The infection frequently manifests as an abscess or cellulitis in the buttocks, genitals, or perineum, and malemale sex was a risk factor. Caution Data were passively reported or retrospectively collected and are therefore subject to bias. Implication Multidrug-resistant USA300 MRSA infection is especially common among men who have sex with men. It might be sexually transmitted in this population. The Editors Infections caused by community-associated, methicillin-resistant Staphylococcus aureus (MRSA) have become a major public health threat. A single clone of community-associated MRSA, USA300, was not seen before 2000 but is now widely disseminated in 38 U.S. states, Canada, and 9 European Union countries (117). It can cause unusually severe disease, including necrotizing fasciitis, sepsis, endocarditis, and pneumonia (1823). Infections occur predominantly among healthy, community-dwelling persons who lack traditional risk factors for MRSA (9, 18, 2426). Whereas hospital-associated MRSA strains are resistant to multiple antimicrobial classes, USA300 and other community-associated MRSA strains are typically resistant to -lactams and 1 or 2 other drug classes. Older generic antimicrobials, such as clindamycin, tetracycline, or trimethoprimsulfamethoxazole, are recommended for treating less serious community-associated MRSA infections, such as uncomplicated skin and soft tissue infections (3, 27). However, increased use of these antimicrobials could drive the emergence of new subclones of community-associated MRSA that are multidrug resistant. Recently, Diep and colleagues (28) described a multidrug-resistant USA300 isolate that had accumulated multiple resistance genes, rendering it resistant to -lactams, fluoroquinolones, tetracycline, macrolide, clindamycin, and mupirocin. Two of the resistance genes from this isolate, ermC and mupAwhich determine constitutive resistance to macrolides, clindamycin, and mupirocinare carried on a large conjugative plasmid called pUSA03 (28). Researchers have identified clusters of infections due to multidrug-resistant USA300 in San Francisco and Boston (29, 30), which could complicate disease management and contribute to development of persistent or recurrent community-associated MRSA infections (31, 32). We report the incidence of multidrug-resistant USA300 in San Francisco and Boston among men who have sex with men, and we describe factors associated with its spread in this high-risk population, on the basis of 4 studies: a population-based survey to estimate the incidence and spatial clustering of multidrug-resistant USA300 in San Francisco; 2 clinic-based, cross-sectional studies to identify risk factors for multidrug-resistant USA300 infection; and a post hoc analysis of multidrug-resistant USA300 isolates previously collected from emergency departments (1). Methods Population-Based Survey We characterized MRSA isolates previously collected in a population-based survey of MRSA infections at 9 of the 10 medical centers serving San Francisco in 2004 to 2005 (Liu C, Graber CJ, Karr M, Diep BA, Basuino L, Schwartz BS, et al. A population-based study of the incidence and molecular epidemiology of methicillin-resistant-Staphylococcus aureus disease in San Francisco, 2004-5. In preparation). The medical centers used passive surveillance for MRSA; physicians submitted cultures to laboratories for identification of pathogens when patients presented with a disease that, in the physicians opinion, required culture. The 9 medical centers operate 4368 licensed hospital beds; the medical center that did not participate in the survey operates 59 licensed hospital beds. The participating medical centers initiated routine specimen collection between February and September 2004 and collected clinical MRSA specimens from unique patients (n= 3929) for 12 consecutive months. If a specimen was submitted from a patient for whom a sample was cultured earlier in the study period, we used the first specimen. We excluded 103 isolates because they came from patient nares and did not represent active infection. Of the remaining 3826 MRSA specimens, 2495 were from patients residing in San Francisco. The 3826 MRSA specimens were stratified by the medical center of origin and then by the month of specimen collection, and we used a random-number generator to select up to 8 MRSA specimens from each stratum. The stratified random sample comprised 801 nonduplicated MRSA specimens, and of these, 532 were recovered from patients residing in San Francisco. We calculated the incidence of multidrug-resistant USA300 infection in each city ZIP code on the basis of the 532 cases, and we used 2000 U.S. Census data (33) to test the association between disease incidence estimates and the proportion of male same-sex couples living in those ZIP codes. HIV ClinicBased Study We conducted a retrospective chart review of consecutive patients (n= 183) who had MRSA cultured from an infection site from January 2004 through June 2006 at the San Francisco General Hospital (SFGH) Positive Health Program, an outpatient HIV clinic that provides specialized HIV and AIDS care in San Francisco, California. Of the 183 specimens, 83 were collected between 1 February 2004 and 31 January 2005 as part of the population-based survey; these 83 specimens represented a subset of 1014 unique MRSA isolates identified from all SFGH sites in the population survey. Using a standardized instrument, we abstracted information about patients demographic characteristics, male homosexual behavior, HIV viral load, CD4+ cell count, past culture-proven MRSA infection, past clinical presentation, and site of infection from medical records. We collected information about male homosexual behavior from the patients clinic intake form (typically administered by a social worker), in which the patient was asked for self-identification of sexual behavior. If the clinic intake form was incomplete or missing, we classified a male patient as a man who has sex with men if an anal Papanicolaou (Pap) smear was performed at any time during his history at the clinic in the absence of indications other than anal receptive intercourse (screening anal Pap smear). Eight patients had missing sexual behavior data and no history of anal Pap smears; we classified them as men who do not have sex with men. Seven of these men had nonmultidrug-resistant USA300 infection, and 1 had a non-USA300 infection. Our estimates of risk for multidrug-resistant USA300 with malemale sex did not change meaningfully when these 7 patients with nonmultidrug-resistant USA300 infection were reclassified as occurring in men who have sex with men or when they were excluded from analyses (data not shown). We also compared the proportion of patients with multidrug-resistant USA300 infection in the HIV clinic with a subset of 91 MRSA cases randomly selected from the 1014 MRSA isolates identified from SFGH in the population-based study. Community Health ClinicBased Study We conducted retrospective chart reviews of 130 consecutive patients with MRSA infection treated at Fenway Community Health, Boston, Massachusetts, from April 2004 through March 2006. Fenway Community Health is a community-based organization that provides primary care to more than 10000 patients annually (34). Reports have noted that a large proportion of MRSA isolates recovered from skin and soft tissue infection sites of patients seen at Fenway Community Health were resistant to multiple antimicrobial agents (30, 31). Using the same standardized instrument developed for the SFGH HIV clinic study, we abstracted clinical data from medical records of each patient at Fenway Community Health. Among these patients, 3 with missing data on sexual behavior and no history of screening anal Pap smears were classified as men who do not have sex with men; these 3 patients had nonmultidrug-resistant USA300 infections. We genotyped the multidrug-resistant USA300 isolate of 1 clinic patient who reported malemale sex and frequent travel to and from the Castro District in San Francisco to see whether frequent travel by men who have sex with men between the East and West coasts facilitates the clonal spread of multidrug-resistant USA300. Emergency DepartmentBased Study Because the spread of multidrug-resistant USA300 is a potential public health threat, we investigated the distribution of multidrug-resistant USA300 in the general population of patients with community-associated MRSA infections. To this end, we conducted a post hoc analysis of 212 USA300 isolates collected by Moran and colleagues (1) in August 2004 from emergency departments in 11 U.S. cities. The study was approved by the University of California, San Francisco, Committee on Human Research and the institutional review board of Fenway Community Health; the institutions waived the informed consent process because the study involved retrospective chart reviews. Antimicrobial Susceptibility Testing We tested isolates for susceptibility to oxacillin, ciprofloxacin, erythromycin, tetracycline, clindamycin, trimethoprimsulfamethoxazole, gentamicin, vancomycin, linezolid, and mupirocin and interpreted the results in accordance with the Clinical and Laboratory Standards Institute guidelines (35). We performed inducible clindamycin resistance (D-zone test) by using the agar disk diffusion method in accordance with Clinical and Laboratory Standards Institute guidelines (35). Molecular Analysis We genotyped isolates by using pulsed-field gel electrophoresis after SmaI-macrorestriction digest of chromosomal DNA (36), spa typing of the pol

The Arginine Catabolic Mobile Element and Staphylococcal Chromosomal Cassette mec Linkage: Convergence of Virulence and Resistance in the USA300 Clone of Methicillin-Resistant Staphylococcus aureus

The epidemic character of community-associated methicillin-resistant Staphylococcus aureus, especially the geographically widespread clone USA300, is poorly understood. USA300 isolates carry a type IV staphylococcal chromosomal cassette mec (SCCmec) element conferring beta-lactam antibiotic class resistance and a putative pathogenicity island, arginine catabolic mobile element (ACME). Physical linkage between SCCmec and ACME suggests that selection for antibiotic resistance and for pathogenicity may be interconnected. We constructed isogenic mutants containing deletions of SCCmec and ACME in a USA300 clinical isolate to determine the role played by these elements in a rabbit model of bacteremia. We found that deletion of type IV SCCmec did not affect competitive fitness, whereas deletion of ACME significantly attenuated the pathogenicity or fitness of USA300. These data are consistent with a model in which ACME enhances growth and survival of USA300, allowing for genetic hitchhiking of SCCmec. SCCmec in turn protects against exposure to beta-lactams.

A population-based study of the incidence and molecular epidemiology of methicillin-resistant Staphylococcus aureus disease in San Francisco, 2004-2005.

BACKGROUNDnMethicillin-resistant Staphylococcus aureus (MRSA) infections have become a major public health problem in both the community and hospitals. Few studies have characterized the incidence and clonal composition of disease-causing strains in an entire population. Our objective was to perform a population-based survey of the clinical and molecular epidemiology of MRSA disease in San Francisco, California.nnnMETHODSnWe prospectively collected 3985 MRSA isolates and associated clinical and demographic information over a 12-month period (2004-2005) at 9 San Francisco-area medical centers. A random sample of 801 isolates was selected for molecular analysis.nnnRESULTSnThe annual incidence of community-onset MRSA disease among San Francisco residents was 316 cases per 100,000 population, compared with 31 cases per 100,000 population for hospital-onset disease. Persons who were aged 35-44 years, were men, and were black had the highest incidence of community-onset disease. The USA300 MRSA clone accounted for 234 cases of community-onset disease and 15 cases of hospital-onset disease per 100,000 population, constituting an estimated 78.5% and 43.4% of all cases of MRSA disease, respectively. Patients with community-onset USA300 MRSA versus non-USA300 MRSA disease were more likely to be male, be of younger age, and have skin and soft-tissue infections. USA300 strains were generally more susceptible to multiple antibiotics, although decreased susceptibility to tetracycline was observed in both community-onset (P = .008) and hospital-onset (P = .03) USA300 compared to non-USA300 strains.nnnCONCLUSIONSnThe annual incidence of community-onset MRSA disease in San Francisco is substantial, surpassing that of hospital-onset disease. USA300 is the predominant clone in both the community and hospitals. The dissemination of USA300 from the community into the hospital setting has blurred its distinction as a community-associated pathogen.

Intermediate vancomycin susceptibility in a community-associated MRSA clone.

We describe a case of treatment failure caused by a strain of USA300 community-associated methicillin-resistant Staphylococcus aureus (MRSA) with intermediate susceptibility to vancomycin and reduced susceptibility to daptomycin. The strain was isolated from the bone of a 56-year-old man with lumbar osteomyelitis after a 6-week treatment course of vancomycin for catheter-associated septic thrombophlebitis.

Doxycycline, Not Minocycline, Induces Its Own Resistance in Multidrug-Resistant, Community-Associated Methicillin-Resistant Staphylococcus aureus Clone USA300

support of this, we found that expression of the pan-NK marker CD56 on malariaresponsive gd-T cells correlated with the magnitude of IFN-g responses in semiimmune Papua New Guinean children [1]. Similarly, in malaria-naive individuals, expression of the NK complex–encoded receptor CD94 on gd-T cells correlated with IFN-g output [8]. Thus, NK-receptor expression on NK-like gd-T cells (and possibly NK cells) may partially control IFN-g responsiveness to P. falciparum, as does NK-receptor expression in Plasmodium berghei murine malaria [14, 15]. Parasite factors, such as P. falciparum erythrocyte membrane-1, which negatively regulates early IFN-g production [16], may also be involved, as well as other factors, such as age and previous exposure to P. falciparum.

Elevated vancomycin trough is not associated with nephrotoxicity among inpatient veterans

BACKGROUNDnVancomycin troughs of 15-20 mg/L are recommended in the treatment of invasive staphylococcal disease, higher levels than previously recommended.nnnOBJECTIVE/SETTINGnWe sought to determine if there was an association between vancomycin trough and nephrotoxicity, defined as 0.5 mg/L or 50% increase in serum creatinine, at a large Veterans Affairs medical center.nnnPATIENTS AND METHODSnWe reviewed records of 348 inpatients at our institution who received ≥5 days of vancomycin during 2 time periods when vancomycin dosing protocols differed (May 2005-April 2006 and January 2007-December 2007). Potential risk factors for nephrotoxicity were collected prior to nephrotoxicity onset, and all patients with nephrotoxicity events occurring within 5 days of starting vancomycin were excluded.nnnRESULTSnOverall incidence of nephrotoxicity was 31/348 patients (8.9%). A similar percentage of patients experienced nephrotoxicity in 2005-2006 versus 2007 (16/201 vs 15/147, respectively; P = 0.57), despite a rise in mean (9.7 mg/L in 2005-2006 vs 13.2 mg/L in 2007; P < 0.0001) and highest (11.8 mg/L in 2005-2006 vs 15.7 mg/L in 2007; P < 0.0001) vancomycin trough levels achieved. In a multivariate logistic regression model, only receipt of intravenous contrast dye was significantly associated with nephrotoxicity (OR 4.01, P < 0.001), though there was a trend toward an association between maximum vancomycin trough ≥15 mg/L and nephrotoxicity (OR 2.05, P = 0.082). Overall reversibility of nephrotoxicity either prior to or within 72 hours of vancomycin discontinuation was 77.8%.nnnCONCLUSIONSnWe conclude that nephrotoxicity, with higher trough levels occurring at ≥5 days of vancomycin therapy, was uncommon at our institution and typically reversible.

Failure of decolonization in patients with infections due to mupirocin-resistant strains of community-associated methicillin-resistant Staphylococcus aureus.

To the Editor—We read the recent article by Rahimian et al. with great interest, and we applaud the authors for their efforts in addressing the role of treatment with mupirocin for recurrent methicillin-resistant Staphylococcus aureus (MRSA) skin and skin structure infections. We hypothesize that one potential reason for the high rate of recurrence of skin and skin structure infections observed by Rahimian et al. in patients with MRSA nasal colonization treated with mupirocin (6 [32%] of 19) may be plasmid-mediated resistance to mupirocin. In a prior publication, Shastry et al. demonstrated that there was a very high level of clindamycin resistance in their population of men who have sex with men (63 [63%] of 100). We have demonstrated that clindamycin resistance and mupirocin resistance are both encoded on a single plasmid, pUSA03, that is frequently identified in multidrug-resistant strains of community-associated MRSA genotype USA300. We have noted that the pUSA03-positive USA300 subclone is particularly prevalent as a cause of skin and skin structure infections in the population of men who have sex with men in San Francisco and Boston. Most notably, this subclone was the pathogen in skin and skin structure infections in men who have sex with men who had no history of prior clindamycin or mupirocin use, suggesting person-to-person transmission of the multidrug-resistant USA300 clone. With respect to the study by Rahimian et al., it would be of great interest to know (1) how many of the 19 patients treated with mupirocin had initial infecting and nasal colonizing strains resistant to both clindamycin and mupirocin (thus suggesting the presence of pUSA03) and (2) how many of these patients were men who have sex with men. Although the findings of Rahimian et al. indicate that an attempt at decolonization with mupirocin may not be beneficial in preventing recurrent disease due to community-associated MRSA in their patient population, the effect of decolonization with mupirocin in a population with lower rates of clindamycin and mupirocin resistance in colonizing and/or infecting MRSA strains remains undetermined.

Association of COPD With Risk for Pulmonary Infections Requiring Hospitalization in HIV-Infected Veterans.

Background:Pulmonary infections remain more common in HIV-infected (HIV+) compared with uninfected individuals. The increase in chronic lung diseases among aging HIV+ individuals may contribute to this persistent risk. We sought to determine whether chronic obstructive pulmonary disease (COPD) is an independent risk factor for different pulmonary infections requiring hospitalization among HIV+ patients. Methods:We analyzed data from 41,993 HIV+ Veterans in the nationwide Veterans Aging Cohort Study Virtual Cohort from 1996 to 2009. Using International Classification of Diseases, Ninth Revision codes, we identified baseline comorbid conditions, including COPD, and incident community-acquired pneumonia (CAP), pulmonary tuberculosis (TB), and Pneumocystis jirovecii pneumonia (PCP) requiring hospitalization within 2 years after baseline. We used multivariable Poisson regression to determine incidence rate ratios (IRRs) associated with COPD for each type of pulmonary infection, adjusting for comorbidities, CD4+ cell count, HIV viral load, smoking status, substance use, vaccinations, and calendar year at baseline. Results:Unadjusted incidence rates of CAP, TB, and PCP requiring hospitalization were significantly higher among persons with COPD compared to those without COPD (CAP: 53.9 vs. 19.4 per 1000 person-years; TB: 8.7 vs. 2.8; PCP: 15.5 vs. 9.2; P ⩽ 0.001). In multivariable Poisson regression models, COPD was independently associated with increased risk of CAP, TB, and PCP (IRR: 1.94, 95% confidence interval [CI]: 1.64 to 2.30; IRR: 2.60, 95% CI: 1.70 to 3.97; and IRR: 1.48, 95% CI: 1.10 to 2.01, respectively). Conclusions:COPD is an independent risk factor for CAP, TB, and PCP requiring hospitalization among HIV+ individuals. As the HIV+ population ages, the growing burden of COPD may confer substantial risk for pulmonary infections.

Inverse correlation of initial CD8 lymphocyte count and CD4 lymphocyte response to combination antiretroviral therapy in treatment-naive HIV-infected patients.

To the Editors: HIV mortality has dropped significantly since the advent of combination antiretroviral therapy (cART) in 1995. The overall increase in life expectancy among HIV patients can be attributed to a significant reduction in AIDS-related opportunistic infections. With a decline in AIDS-related deaths, there has been a subsequent increase in “non–AIDS”-related deaths. These “non-AIDS” events are generally considered any cause of death not attributed to opportunistic infections or malignancies but rather to non– AIDS-defining malignancies, cardiovascular, hepatic, or renal events. Results from the Strategies for Management of Antiretroviral Therapy trial suggest that many of these “non-AIDS” events may be a product of chronic HIV-induced inflammation. The Strategies for Management of Antiretroviral Therapy trial also found that traditional HIV biomarkers (HIV viral load and CD4 count) do not fully predict the differential effects of HIV therapy. Thus, indices that include non-HIV biomarkers may better predict mortality and response to therapy in HIVinfected patients. Here we assess HIV-related and HIV-unrelated biomarkers to determine which clinical factors best predict immunologic response to cART among HIV-infected patients who successfully obtain virologic control within 1 year of cART initiation. Of 1348 patients who were treated for HIV at the VA Greater Los Angeles Healthcare system from 1996 to 2010, we retrospectively identified 147 patients who (1) started cART at our facility during this time frame, (2) were antiretroviral naive before starting cART, and (3) achieved virologic response to cART, defined as consecutive HIV viral loads less than 400 for at least 6 months beginning within 1 year of cART initiation. Of these 147 patients, 131 had a complete data set of all laboratory biomarkers necessary for statistical analysis. For each patient, laboratory tests that were drawn closest to cART initiation were recorded. Test results obtained within 6 months before cART initiation were given priority, followed by tests results obtained any time before cART initiation and finally by tests results obtained within 30 days after cART initiation (HIV viral load must have been collected either before or within 7 days after cART initiation). The following HIV clinical indicators were tested: initial CD4 and CD8 count, log (HIV viral load), individual components of cART (including whether or not protease inhibitor was boosted), year of cART start (1996 = year 1). In addition, the following non-HIV clinical indices were tested: age, hemoglobin, modified FIB-4 {an index of liver dysfunction: modified FIB-4 = (age·ALT)/[platelets·sqrt (ALT)]}, estimated glomerular filtration rate (glomerular filtration rate = 186.3· creatinine−1.154 · age−0.203), and hepatitis C antibody positivity. CD4 counts were recorded from the time of cART start until the patient experienced virologic failure (HIV viral load .400 on 2 consecutive occasions), was lost to follow-up (no CD4 count determined in over one year), or until June 2010, whichever came earliest. Area under the curve of the CD4 count minus baseline (AUCMB) was calculated for each patient at 6 months and whenever possible at 1 year and 3 years as has been done previously. Multivariate linear regression with backwards elimination using a likelihood ratio of P , 0.20 was used to compare all indices. All statistical calculations were performed with Stata version 10 (College Station, TX). The multivariable regression analysis of the relationship between the measured biomarkers and CD4 AUCMB is reported in Table 1. For each variable that was significant enough to be included in the final multivariable model for CD4 AUCMB at any of the 3 time points, we report the estimated change in CD4 count from initial CD4 count that is predicted by each incremental change in that variable present at cART initiation (this value is reported for the sake of clarity and assumes a linear change in CD4 over time) and the P value that corresponds to that variable’s effect on CD4 AUCMB. For initial CD4 and CD8 count, estimated change in CD4 count is reported per 100 cells per cubic millimeter. A higher initial CD8 count was the strongest predictor for decreased CD4 response to cART at 6 months, 1 year, and 3 years after cART initiation. Every 100 cells per cubic millimeter increase in initial CD8 was associated with an estimated decrease in CD4 count of 9.2 cells per cubic millimeter at 6 months, 7.1 cells per cubic millimeter at 1 year, and 10.4 cells per cubic millimeter at 3 years. For example, if a patient had a starting CD8 count of 1237 cells per cubic millimeter (75th percentile among all patients in the dataset), our model would estimate a 70 cells per cubic millimeter lower CD4 response at 6 months compared with a patient with a starting CD8 count of 479 cells per cubic millimeter (25th percentile). This association was independent of starting CD4 count and consistent across all strata of starting CD4 count. The only other indices to reach significance were older age, which was associated with lower CD4 AUCMB at 6 months; presence of ritonavir in initial cART, which was associated with Supported by David Geffen School of Medicine at UCLA Short Term Training Program for medical students. Presented as an electronic poster (abstract CDB009) at the 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, July 17–20, 2011, Rome, Italy. The authors have no conflicts of interest to disclose.

Causal Conditions Supporting Antibiotic Stewardship Information Dashboards

Abstract Background Antibiotic stewardship is key to minimizing antibiotic resistance. To assist antibiotic stewards in dissecting population-level antibiotic use patterns, our study group developed a dashboard that displays consolidated patterns, supports data exploration, and compares facility-level antibiotic use to others. We report fuzzy set qualitative comparative analyses (QCA) of interviews designed to elicit user experiences to uncover different combinations of causal conditions supporting dashboard use. Methods Dashboards were iteratively designed based upon longitudinal feedback from stewards. Views include antibiotic use stratified by diagnoses and duration of therapy. Eight VAMCs, each with 0.5 to 2.0 FTE stewards, used the dashboard. One to 2 stewards from each site were interviewed using a structured script that focused on: 1) structure (i.e., program FTE) and functions of the local stewardship program; 2) critical incident or usage story; and 3) perceived knowledge and efficacy. Results Qualitative codes were developed from the interviews and were scaled in a fuzzy logic framework (i.e., between 0 and 1) to reflect the degree to which the qualitative theme was present in the stewardship program at participating clinical sites. The scaling was assigned using prior knowledge external to the data. The most parsimonious QCA solution identified just the absence of program structure (program FTE) a sufficient causal configuration to the frequency of dashboard use (coverage = 0.612, consistency = 0.813). Intermediate solutions added stewardship activities, dashboard self-efficacy, and trust in the data (coverage = 0.502, consistency = 0.952) as sufficient conditions. The coverage for both solutions exceeded 0.75, which was the lower bound of acceptability. Conclusion The dashboard may be successfully integrated into institutions based on the complicated interplay between program structure (e.g., # FTE) and dashboard self-efficacy, experience with data-activities, and trust of population data. Incorporating user-centered design of dashboards supports the development of fully functional teams and has the potential for important population health impact. Disclosures All authors: No reported disclosures.