Meticillin-resistant Staphylococcus aureus (MRSA) update: New insights into bacterial adaptation and therapeutic targets.

Successful meticillin-resistant Staphylococcus aureus (MRSA) clones have evolved to adapt to healthcare, community and livestock environments. This review will bring together recent studies into clone adaptation and the importance of genes acquired during horizontal gene transfer to survival in specific environments. It will also discuss the role of global regulators controlling virulence gene expression and resistance to antibiotics, such as the agr and vraRS systems. Understanding these processes in successful clones could reveal novel targets for therapeutic agents, which are urgently required to reduce the infection burden and improve treatment options.

The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA).

The economic impact of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) remains unclear. We developed an economic simulation model to quantify the costs associated with CA-MRSA infection from the societal and third-party payer perspectives. A single CA-MRSA case costs third-party payers $2277-$3200 and society $7070-$20 489, depending on patient age. In the United States (US), CA-MRSA imposes an annual burden of $478 million to 2.2 billion on third-party payers and $1.4-13.8 billion on society, depending on the CA-MRSA definitions and incidences. The US jail system and Army may be experiencing annual total costs of $7-11 million ($6-10 million direct medical costs) and $15-36 million ($14-32 million direct costs), respectively. Hospitalization rates and mortality are important cost drivers. CA-MRSA confers a substantial economic burden on third-party payers and society, with CA-MRSA-attributable productivity losses being major contributors to the total societal economic burden. Although decreasing transmission and infection incidence would decrease costs, even if transmission were to continue at present levels, early identification and appropriate treatment of CA-MRSA infections before they progress could save considerable costs.

Community-acquired methicillin-resistant Staphylococcus aureus colonization in healthy children attending an outpatient pediatric clinic.

BACKGROUND: We previously showed that children attending an inner city pediatric emergency department were sometimes asymptomatically colonized with clindamycin-susceptible community-acquired methicillin-resistant Staphylococcus aureus (MRSA) and borderline methicillin-resistant S. aureus (BRSA) as well. We wished to ascertain whether healthy children attending an outpatient clinic were colonized with these organisms. Therefore to estimate the prevalence of community-acquired MRSA and BRSA nasal colonization in a well child population, we cultured children attending an inner city pediatric outpatient clinic. STUDY DESIGN: This was a prospective cross-sectional study conducted from January to August, 1999, at a primary care outpatient facility at the University of Chicago. The target population was 500 healthy children < or = 16 years of age who attended this facility to receive well child care. RESULTS: One hundred twenty-two (24.4%) children were colonized with S. aureus. Three of the 122 (2.5%) S. aureus isolates were MRSA; they came from children who lacked predisposing risk factors and were susceptible to clindamycin, gentamicin, trimethoprim-sulfamethoxazole, rifampin and ciprofloxacin. Two (1.6%) additional S. aureus isolates were BRSA; both children had predisposing risk factors for MRSA colonization. The mecA gene was present in the 3 MRSA isolates and absent in both BRSA isolates. CONCLUSIONS: These data document that a reservoir of asymptomatic MRSA colonization exists among healthy children who lack traditional risk factors for MRSA infections.

Development of vancomycin and lysostaphin resistance in a methicillin-resistant Staphylococcus aureus isolate.

Glycopeptide resistance in Staphylococcus aureus is poorly understood. The diversity of change documented in cell walls of clinical glycopeptide-intermediate S. aureus (GISA) isolates is evidence that a single genetic or biochemical change cannot account for resistance in all isolates described to date. Therefore, identification of new GISA clinical isolates provides an opportunity to gain insight into the range of adaptive strategies employed by staphylococci to survive in the presence of glycopeptides. In April 1999, a GISA isolate was obtained from the blood of a 63-year-old dialysis patient in Illinois. This isolate was one of six clonally identical MRSA isolates (A-F) serially obtained from the blood of this patient who was receiving vancomycin therapy. All isolates were resistant to oxacillin (MIC > 256 mg/L). The initial isolate had an MIC of vancomycin of 1 mg/L. However, the presence of a subpopulation that could grow in the presence of 5 mg/L of vancomycin indicated that this isolate was predisposed to the acquisition of the GISA phenotype (MIC of vancomycin 10-12 mg/L), which occurred 13 days later, associated with an increased MIC of the endopeptidase lysostaphin and slightly increased cell wall thickness. The first and last isolates in the series, A and F, resisted killing when incubated in vancomycin 2 mg/L, resisted autolysis when incubated in Triton X-100 and had a decreased expression of a c. 116 kDa autolytic band, properties that were different from glycopeptide-susceptible control isolates. Lysostaphin resistance was not accompanied by alterations in the peptidoglycan pentaglycine cross-bridge or a decrease in oxacillin MIC. These data, when taken together with the demonstration of increased cross-linking in isolate F compared with isolate A, demonstrate that vancomycin resistance in these isolates probably occurred by a mechanism different from that of other GISA isolates described to date.

Magnitude of interference after diphtheria-tetanus toxoids-acellular pertussis/Haemophilus influenzae type b capsular polysaccharide-tetanus vaccination is related to the number of doses administered.

We compared the antibody response to Haemophilus influenzae type b capsular polysaccharide (PRP) after 1, 2, or 3 doses of a diphtheria-tetanus toxoids-acellular pertussis (DTaP) vaccine combined with a PRP-tetanus conjugate (PRP-T) vaccine, followed by separate injections of DTaP and PRP-T vaccines for the last 1 or 2 doses. Healthy infants were recruited from pediatric practices and were immunized according to recommended schedules. A significant decrease in the mean anti-PRP (from 5.25 to 2.68 microg/mL) and anti-tetanus toxoid antibody responses (from 0.13 to 0.09 Eq/mL) was observed as the number of doses of the DTaP/PRP-T combination vaccine increased (P<.02 and P=.01, respectively). In contrast, the mean anti-diphtheria toxoid antibody response increased with increasing numbers of DTaP/PRP-T doses (P=.0001). The effects of interference were not eliminated by the completion of the primary series with 1 or 2 doses of the DTaP and PRP-T vaccines given separately.

Impact of recommendations to suspend the birth dose of hepatitis B virus vaccine.

CONTEXT: In July 1999, due to concerns about thimerosal content, the American Academy of Pediatrics (AAP) and the Public Health Service (PHS) recommended suspending hepatitis B virus (HBV) vaccination at birth except for mothers who had positive or unknown hepatitis B surface antigen (HBsAg) status. In September 1999, the Centers for Disease Control and Prevention recommended that hospitals resume HBV vaccination at birth with a new thimerosal-free vaccine. Whether the 2 changes in recommendations within 3 months led to less-than-optimal compliance in hospital nurseries is unknown. OBJECTIVE: To determine hospital HBV vaccination policy before the recommendation for delay of HBV vaccination and 1 year later. DESIGN, SETTING, AND PARTICIPANTS: Survey of all 46 hospitals with obstetric services and neonatal nurseries in Cook County, Illinois. MAIN OUTCOME MEASURES: Hepatitis B virus immunization practices before July 1999 and in August 2000; hospital factors associated with routine HBV immunization and compliance with AAP and PHS recommendations. RESULTS: Before July 1999, 74% of surveyed hospital nurseries offered HBV vaccine to all neonates; only 39% did so in August 2000. Being located in the Chicago city limits (88% vs 57%; P =.02) and having an academic affiliation (93% vs 66%; P =.05) were positively associated with routine neonatal immunization before July 1999. Both academic affiliation and city location were associated with routine immunization in August 2000 (71% vs 25% [P =.003] and 60% vs 14% [P =.002], respectively) and with compliance with recommendations for suspension (57% vs 25% [P =.03] and 56% vs 10% [P =.001]). CONCLUSIONS: We documented a 35% decrease in hospital nurseries that routinely offered HBV immunization 1 year after the AAP and PHS recommendations were made. Special efforts may be required to make at-birth administration of HBV vaccination universal.

Evolving antimicrobial chemotherapy for Staphylococcus aureus infections: Our backs to the wall.

Staphylococcus aureus is responsible for many nosocomial and community-acquired infections. Its evolving resistance to traditional antimicrobial chemotherapy and emerging prevalence outside of the healthcare environment are serious concerns. This review of the changing epidemiology of methicillin-resistant S. aureus, the emergence of vancomycin (glycopeptide)-resistant isolates, and the mechanisms of resistance to beta-lactams and glycopeptides provides an update for clinicians regarding effective strategies for treatment.

A spectrum of changes occurs in peptidoglycan composition of glycopeptide-intermediate clinical Staphylococcus aureus isolates.

The mechanism of glycopeptide resistance in Staphylococcus aureus is not known with certainty. Because the target of vancomycin is the D-Ala-D-Ala terminus of the stem peptide of the peptidoglycan precursor, by subjecting muropeptides to reversed-phase high-performance liquid chromatography, we investigated peptidoglycan obtained from glycopeptide-intermediate S. aureus (GISA) isolates for changes in composition and evaluated whether any peptidoglycan structural change was a consistent feature of clinical GISA isolates. GISA isolates Mu50 and Mu3 from Japan had the large glutamate-containing monomeric peak demonstrated previously, although strain H1, a vancomycin-susceptible MRSA isolate from Japan that was clonally related to Mu3 and Mu50, and a femC mutant that we studied, did also. For the U.S. GISA isolates, strain NJ had a large monomeric peak with a retention time identical to that described for the glutamate-containing monomer in strains H1, Mu3, and Mu50. However, a much smaller corresponding peak was seen in GISA MI, and this peak was absent from both GISA PC and a recent GISA isolate obtained from an adult patient in Illinois (strain IL). These data suggest that a uniform alteration in peptidoglycan composition cannot be discerned among the GISA isolates and indicate that a single genetic or biochemical change is unlikely to account for the glycopeptide resistance phenotype in the clinical GISA isolates observed to date. Furthermore, a large monomeric glutamate-containing peak is not sufficient to confer the resistance phenotype.

Knowledge of Centers for Disease Control and Prevention guidelines for the use of vancomycin at a large tertiary care children's hospital.

OBJECTIVE: In 1994, the Centers for Disease Control and Prevention (CDC) published guidelines to encourage prudent use of vancomycin. We sought to determine whether physicians could demonstrate knowledge consistent with the guidelines. DESIGN: Survey consisting of 18 clinical vignettes based on the CDC guidelines. PARTICIPANTS: All residents, fellows, and attending physicians involved in pediatric inpatient services. SETTING: Tertiary care children's hospital providing service to an inner-city population and community referral base. MAIN OUTCOME MEASURES: Comparison of survey scores and individual responses among respondents. RESULTS: Survey scores did not vary with level of training or whether the respondent was a pediatrician or non-pediatrician. Average scores of attending physicians, fellows, and residents were 74.1% (SD = 13.1), 77.2% (SD = 11.5), and 73.4% (SD = 10.5), respectively, and did not differ significantly. Questions incorrectly answered by more than 30% of respondents concerned the use of vancomycin as: (1) first-line treatment of Clostridium difficile colitis, (2) a topical solution for wound infection, (3) initial, empiric treatment of patients with fever and neutropenia, (4) peri-operative prophylaxis, (5) a preferred agent over beta-lactam antimicrobial agents. CONCLUSION: Deficits in knowledge regarding appropriate vancomycin use can be localized to certain clinical settings. This observation lends optimism to the notion that targeted educational intervention may improve the appropriate use of vancomycin.

Structural and topological differences between a glycopeptide-intermediate clinical strain and glycopeptide-susceptible strains of Staphylococcus aureus revealed by atomic force microscopy.

Novel cell surface topography was revealed on cocci from a glycopeptide-intermediate Staphylococcus aureus (GISA) clinical strain by using atomic force microscopy. The GISA isolate and its revertant had two parallel circumferential surface rings. One equatorial surface ring was observed in control strains. In vancomycin-susceptible strains, additional rings were formed in the presence of vancomycin. Ring depth measurements also revealed striking differences between the GISA strain and susceptible strains grown with or without vancomycin.

Absence of a significant interaction between a Haemophilus influenzae conjugate vaccine combined with a diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine in the same syringe and inactivated polio vaccine.

BACKGROUND: We compared the antibody response to Haemophilus influenzae type b capsular polysaccharide (PRP) after three doses of a diphtheria toxoid, tetanus toxoid and acellular pertussis vaccine (DTaP) combined with a PRP-tetanus conjugate (PRP-T) in infants randomized to receive oral polio vaccine (OPV) or inactivated polio vaccine (IPV). The polio vaccine was given separately at the same visit. METHODS: Three hundred fifty-six infants from pediatric practices in suburban Chicago and New Orleans were randomized into two groups. Group A received OPV at 2 and 4 months of age; Group B received IPV at 2 and 4 months of age. Both groups received DTaP/PRP-T at 2, 4 and 6 months of age and hepatitis B vaccine at 2 and 4 months of age. A serum sample was obtained before immunization (age 2 months) and 1 month after 3 doses of DTaP/PRP-T (age 7 months). Sera were assayed for antibody responses to all relevant vaccine antigens. RESULTS: No significant vaccine antigen interference was found when polio immunization was provided by IPV or OPV for anti-PRP, diphtheria, tetanus or pertussis antibodies. OPV recipients had a significantly higher mean antibody response to serotype 1 (P = 0.03) and 2 (P = 0.0001) poliovirus. CONCLUSION: Whether polio immunization was accomplished with IPV or OPV did not significantly influence the antibody responses in sera obtained at 7 months of age for anti-PRP, anti-diphtheria and anti-tetanus toxoid antibodies and antibodies to pertussis antigens, when DTaP/PRP-T was given in the primary series.

Reversion of the glycopeptide resistance phenotype in Staphylococcus aureus clinical isolates.

The recent identification of glycopeptide intermediate-resistant Staphylococcus aureus (GISA) clinical isolates has provided an opportunity to assess the stability of the glycopeptide resistance phenotype by nonselective serial passage and to evaluate reversion-associated cell surface changes. Three GISA isolates from the United States (MIC of vancomycin = 8 microg/ml) and two from Japan (MICs of vancomycin = 8 and 2 microg/ml) were passaged daily on nutrient agar with or without vancomycin supplementation. After 15 days of passage on nonselective medium, vancomycin- and teicoplanin-susceptible revertants were obtained from each GISA isolate as determined by broth dilution MIC. Revertant isolates were compared with parent isolates for changes in vancomycin heteroresistance, capsule production, hemolysis phenotype, coagulase activity, and lysostaphin susceptibility. Several revertants lost the subpopulations with intermediate vancomycin resistance, whereas two revertants maintained them. Furthermore, although all of the parent GISA isolates produced capsule type 5 (CP5), all but one revertant tested no longer produced CP5. In contrast, passage on medium containing vancomycin yielded isolates that were still intermediately resistant to vancomycin, had no decrease in the MIC of teicoplanin, and produced detectable CP5. No consistent changes in the revertants in hemolysis phenotype, lysostaphin susceptibility, or coagulase activities were discerned. These data indicate that the vancomycin resistance phenotype is unstable in clinical GISA isolates. Reversion of the vancomycin resistance phenotype might explain the difficulty in isolating vancomycin-resistant clinical isolates from the blood of patients who fail vancomycin therapy and, possibly, may account for some of the difficulties in identifying GISA isolates in the clinical laboratory.

Current trends in community-acquired methicillin-resistant Staphylococcus aureus at a tertiary care pediatric facility.

BACKGROUND: The prevalence of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) infections increased at the University of Chicago Children's Hospital (UCCH) from 10 per 100,000 admissions from 1988 to 1990 to 259 per 100,000 admissions from 1993 to 1995. Because this increase may have represented a one time occurrence or a limited disease outbreak, we updated our previous observations at UCCH in 1998 and 1999 to see whether this trend had continued. DESIGN: Prospective observational study. RESULTS: Twenty-three hospitalized children had an MRSA isolate during the 1-year study period. Ten were community-acquired, equally distributed between children with predisposing risk factors and those without. The overall prevalence of community-acquired MRSA was 208 per 100,000 admissions. Seven of the 10 community-acquired MRSA isolates were susceptible to clindamycin. Skin and soft tissue infections predominated among the children with a community-acquired MRSA isolate. Pulsed field gel electrophoresis of the 10 community-acquired MRSA isolates revealed 8 distinct patterns; these data suggest that multiple clones were circulating at UCCH. CONCLUSION: MRSA are no longer confined to children with established risk factors. The prevalence of community-acquired MRSA among children without identified risk factors is high in our institution.

Immunization outreach in an inner-city housing development: reminder-recall on foot.

OBJECTIVE: To determine rates of immunization coverage among children 3 to 72 months of age in a large public housing development, to develop a community-based outreach program to increase coverage, and to evaluate the effect of the program. DESIGN: A door-to-door canvass of the development by specially trained emergency medical technicians to enroll families, to determine immunization status from written records, and to follow-up to encourage immunizations and well-child care. The program was evaluated, comparing rates of immunization by age with an expectation based on the immunization histories before enrollment. SETTING: A Chicago public housing development, October 1993 through December 1996. OUTCOME VARIABLES: Antigen-specific and series-specific coverage based on written records. RESULTS: Of the caregivers, 92% were able to identify a primary care provider. At the time of enrollment, 37% of 1075 children were up-to-date, but that proportion varied by age with 27% of children 19 to 35 months of age being up-to-date. The program increased rates of immunization compared with the expectation from the preenrollment rates. At their final assessment, 50% of the children were up-to-date. For individual vaccines, there was a positive program effect. For example, before enrollment, 22% of children 15 months of age had received measles, mumps, and rubella vaccine. However, 39% of children who were enrolled in the program before they were 12 months of age had received their first immunizations by 15 months of age. CONCLUSIONS: Children in the housing development had very low rates of immunization before enrollment. An in-person intervention was effective in reaching families and determining immunization status. In the 3-year enrollment and observation period, rates of immunization increased.

Hepatitis B vaccination among children in inner-city public housing, 1991-1997.

CONTEXT: In 1991, the Advisory Committee on Immunization Practices recommended universal vaccination of infants against hepatitis B virus (HBV), with series initiation within days of birth. OBJECTIVE: To determine HBV vaccine coverage in a low-income urban population and to examine whether HBV immunization within the first month of life affects subsequent vaccine receipt. DESIGN: Cohort study based on immunization records collected in the Pediatric Immunization Program. Setting Large public housing development in Chicago, Ill. PARTICIPANTS: All 1143 children who were born between 1991 and 1997 and enrolled between 1993 and mid-1998, with follow-up to age 35 months. MAIN OUTCOME MEASURES: On-time vaccine receipt of HBV vaccine doses, diphtheria-tetanus-pertussis vaccine (DTP) dose 1, and the 4:3:1 series (4 doses of DTP vaccine, 3 doses of poliomyelitis vaccine, and 1 dose of measles-containing vaccine), analyzed by year. RESULTS: On-time HBV vaccination increased quickly following new guidelines and reached a plateau of about 50% coverage for those born in or after 1995. Since 1994, more children (64%) received the first HBV vaccine dose on time than any other vaccine. Children who received a dose of HBV vaccine during their first month of life were more likely to receive the first DTP vaccine dose on time (60.1%) than those who did not get an HBV vaccine dose during the first month (36.4%; chi2 = 53.7; P<.001). Children who received the first HBV vaccine dose during their first month were more likely than those receiving it at age 1 to 2 months to complete 3 HBV doses by 19 months (70.6% vs 51.1%; chi2 = 11.6; P = .001) and to complete the 4:3:1 series by age 19 months (49.8% vs 37.9%; chi2 = 4.0; P = .05). CONCLUSIONS: In this inner-city population, HBV vaccine has been received at rates similar to those of other vaccines within 3 years of issuance of new recommendations. Of note, immunization with HBV vaccine at birth was associated with timely receipt of other vaccines and, therefore, may have the potential to increase vaccination among groups less likely to be up-to-date on early childhood vaccines.

Methicillin-resistant and borderline methicillin-resistant asymptomatic Staphylococcus aureus colonization in children without identifiable risk factors.

BACKGROUND: The recent evolution in the epidemiology of methicillin-resistant asymptomatic Staphylococcus aureus (MRSA) infections in children, whereby children without traditional risk factors for MRSA have been hospitalized in increasing numbers, prompted us to establish whether a parallel increase in "asymptomatic" MRSA colonization had occurred. METHODS: We cultured the nares and perineum of 500 children attending our Pediatric Emergency Department. RESULTS: One hundred thirty-two (26.4%) of these children were colonized with S. aureus. Eleven (8.3%) of the S. aureus isolates were MRSA; 4 (36.4%) of the 11 subjects colonized with MRSA had no risk factors. Seven (5.3%) of the 132 S. aureus isolates were borderline methicillin-resistant S. aureus (BRSA); 5 (71.4%) of the 7 subjects colonized with BRSA had no MRSA risk factors. CONCLUSIONS: These findings indicate that MRSA and BRSA isolates are circulating in the community and that MRSA isolates are no longer confined to children with frequent contact with a health care environment.