Harold C. Standiford

Methicillin-resistant Staphylococcus aureus: A consensus review of the microbiology, pathogenesis, and epidemiology with implications for prevention and management

Methicillin-resistant Staphylococcus aureus (MRSA) has become a major nosocomial pathogen in community hospitals, long-term-care facilities, and tertiary care hospitals. The basic mechanism of resistance is alteration in penicillin-binding proteins of the organism. Methods for isolation by culture and typing of the organism are reviewed. MRSA colonization precedes infection. A major reservoir is the anterior nares. MRSA is usually introduced into an institution by a colonized or infected patient or health care worker. The principal mode of transmission is via the transiently colonized hands of hospital personnel. Indications for antibiotic therapy for eradication of colonization and treatment of infection are reviewed. Infection control guidelines and discharge policy are presented in detail for acute-care hospitals, intensive care and burn units, outpatient settings, and long-term-care facilities. Recommendations for handling an outbreak, surveillance, and culturing of patients are presented based on the known epidemiology.

Pharmacodynamics of a fluoroquinolone antimicrobial agent in a neutropenic rat model of Pseudomonas sepsis.

We examined the impact of dose fractionation and altered MICs on survivorship in a neutropenic rat model of Pseudomonas aeruginosa sepsis employing the new fluoroquinolone antibiotic lomefloxacin. Once-daily administration of a drug dose which produced a high peak concentration/MIC (peak/MIC) ratio (ca. 20/1) produced significantly better survivorship compared with regimens employing the same daily dose but on a more fractionated schedule. The use of a smaller dose, producing lower (< 10/1) peak/MIC ratios, did not show this effect, as once-daily and twice-daily regimens produced equivalent results (the area under the concentration-time curve/MIC ratio was linked to survivorship). Challenge with resistant mutants selected for altered MICs of fluoroquinolones (two and four times the MIC for the parent strain, respectively) resulted in markedly diminished survivorship. Challenge with the parent strain and use of a drug dose which produced a peak/MIC ratio identical to that for animals challenged with the mutant for which the MIC was four times that for the parent strain and treated with the larger drug dose produced survivorship curves which were not different. For this animal model, peak/MIC ratio was linked to survivorship, particularly when high ratios (10/1 to 20/1) were obtained. At lower doses, producing peak/MIC ratios < 10/1, the area under the concentration-time curve relative to the MIC appeared to be most closely linked to outcome. The time that levels in plasma exceeded the MIC did not influence survivorship. The hypothesis most likely to explain these findings is that higher peak/MIC ratios can suppress the parent strain and mutant organisms (gyrA and transport mutants) for which the MIC is higher but limited (no more than eight times that for the parent strain).

Multidrug-resistant Acinetobacter Infection Mortality Rate and Length of Hospitalization

Acinetobacter infections have increased and gained attention because of the organism’s prolonged environmental survival and propensity to develop antimicrobial drug resistance. The effect of multidrug-resistant (MDR) Acinetobacter infection on clinical outcomes has not been reported. A retrospective, matched cohort investigation was performed at 2 Baltimore hospitals to examine outcomes of patients with MDR Acinetobacter infection compared with patients with susceptible Acinetobacter infections and patients without Acinetobacter infections. Multivariable analysis controlling for severity of illness and underlying disease identified an independent association between patients with MDR Acinetobacter infection (n = 96) and increased hospital and intensive care unit length of stay compared with 91 patients with susceptible Acinetobacter infection (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.2–5.2 and OR 2.1, 95% CI 1.0–4.3] respectively) and 89 uninfected patients (OR 2.5, 95% CI 1.2–5.4 and OR 4.2, 95% CI 1.5–11.6] respectively). Increased hospitalization associated with MDR Acinetobacter infection emphasizes the need for infection control strategies to prevent cross-transmission in healthcare settings.

Spinal epidural abscess: a report of 40 cases and review.

Despite modern medical advances, the morbidity and mortality rates associated with spinal epidural abscess remain significant, and the diagnosis often is elusive. A retrospective study was undertaken to define better the incidence and clinical features of this infection, and to establish current diagnostic and therapeutic guidelines. Forty cases of spinal epidural abscess were encountered at our institution between July 1979 and March 1991. All medical records and radiological images were reviewed. We report a significant increase in the incidence of epidural abscess after June 1988 (p = 0.0195). Sixteen patients used drugs intravenously, and six had undergone spinal procedures. Twelve patients were misdiagnosed in various emergency rooms or clinics and discharged. Localized back pain, fever, and neurological deficit remained the typical clinical manifestations. Erythrocyte sedimentation rate was elevated uniformly when measured (21 cases). Magnetic resonance imaging was diagnostic specifically in 23 of 24 instances. The majority of patients underwent surgical drainage, but five selected patients were managed nonoperatively. The highly variable presentation of spinal epidural abscess may confuse the diagnosis and delay indicated surgical intervention. Localized back pain in a febrile patient at significant risk for epidural abscess warrants erythrocyte sedimentation rate measurement. The presence of erythrocyte sedimentation rate elevation or evidence of spinal cord compression on physical examination are indications for immediate magnetic resonance imaging examination with contrast enhancement. Surgical drainage with sustained intravenous antibiotic treatment remains the cornerstone of therapy. Nonoperative management may be considered in selected cases.

CANVAS 2: the second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections

OBJECTIVES New therapies for complicated skin and skin structure infections (cSSSIs) are needed because of significant morbidity and increasing antimicrobial resistance. Methicillin-resistant Staphylococcus aureus (MRSA) is a common cause of cSSSIs. Ceftaroline fosamil, a novel parenteral cephalosporin with excellent in vitro activity against Gram-positive pathogens, including MRSA, and many Gram-negative pathogens, was evaluated as therapy for cSSSIs in a multinational Phase III study. The primary study objective was to determine non-inferiority [lower limit of 95% confidence interval (CI), -10%] in the clinical cure rate of ceftaroline fosamil monotherapy to that achieved with vancomycin plus aztreonam combination therapy in the clinically evaluable (CE) and modified intent-to-treat (MITT) analysis populations. METHODS Adult patients with cSSSIs requiring intravenous therapy received 600 mg of ceftaroline fosamil every 12 h or 1 g of vancomycin plus 1 g of aztreonam every 12 h for 5-14 days (randomized 1 : 1). Clinical and microbiological response, adverse events (AEs) and laboratory tests were assessed. Registration number NCT00423657 (http://clinicaltrials.gov/ct2/show/NCT00423657). RESULTS The study enrolled 694 patients, 348 of whom received ceftaroline fosamil and 346 of whom received vancomycin plus aztreonam. The treatment groups had comparable baseline characteristics. Clinical cure rates for the ceftaroline fosamil and vancomycin plus aztreonam groups were similar in the CE (92.2%, 271/294 versus 92.1%, 269/292; 95% CI, -4.4, 4.5) and MITT (85.1%, 291/342 versus 85.5%, 289/338; 95% CI, -5.8, 5.0) populations, respectively. MRSA cSSSIs were cured in 91.4% (64/70) of patients in the ceftaroline fosamil group and 93.3% (56/60) of patients in the vancomycin plus aztreonam group. The microbiological success rate in the microbiologically evaluable population was 92.9% and 95.0% for ceftaroline fosamil and vancomycin plus aztreonam, respectively. Ceftaroline fosamil and vancomycin plus aztreonam had similar rates of AEs, serious AEs and discontinuations because of an AE. The most common AEs for ceftaroline fosamil and vancomycin plus aztreonam included diarrhoea (6.5% versus 4.4%), nausea (6.2% versus 5.6%), headache (5.3% versus 5.3%) and pruritus (3.8% versus 8.3%), respectively. CONCLUSIONS Ceftaroline fosamil demonstrated high clinical cure and microbiological success rates, was efficacious against cSSSIs caused by MRSA and other common cSSSI pathogens and was generally well tolerated. Monotherapy with ceftaroline fosamil has the potential to provide an alternative treatment for cSSSIs.

Risk Factors for Colonization with Extended-Spectrum β-Lactamase–producing Bacteria and Intensive Care Unit Admission

Coexisting conditions and previous antimicrobial drug exposure predict colonization.

Impact of a Computerized Clinical Decision Support System on Reducing Inappropriate Antimicrobial Use: A Randomized Controlled Trial

OBJECTIVE Many hospitals utilize antimicrobial management teams (AMTs) to improve patient care. However, most function with minimal computer support. We evaluated the effectiveness and cost-effectiveness of a computerized clinical decision support system for the management of antimicrobial utilization. DESIGN A randomized controlled trial in adult inpatients between May 10 and August 3, 2004. Antimicrobial utilization was managed by an existing AMT using the system in the intervention arm and without the system in the control arm. The system was developed to alert the AMT of potentially inadequate antimicrobial therapy. MEASUREMENTS Outcomes assessed were hospital antimicrobial expenditures, mortality, length of hospitalization, and time spent managing antimicrobial utilization. RESULTS The AMT intervened on 359 (16%) of 2,237 patients in the intervention arm and 180 (8%) of 2,270 in the control arm, while spending approximately one hour less each day on the intervention arm. Hospital antimicrobial expenditures were

Worldwide Assessment of Linezolid's Clinical Safety and Tolerability: Comparator-Controlled Phase III Studies

285,812 in the intervention arm and

Antimicrobial stewardship at a large tertiary care academic medical center: cost analysis before, during, and after a 7-year program.

370,006 in the control arm, for a savings of

Randomized double-blinded trial of rifampin with either novobiocin or trimethoprim-sulfamethoxazole against methicillin-resistant Staphylococcus aureus colonization: prevention of antimicrobial resistance and effect of host factors on outcome.

84,194 (23%), or