Silvano Esposito

New insights into meticillin-resistant Staphylococcus aureus (MRSA) pathogenesis, treatment and resistance

Meticillin-resistant Staphylococcus aureus (MRSA) remains one of the principal multiply resistant bacterial pathogens causing serious healthcare-associated and community-onset infections. This paper reviews recent studies that have elucidated the virulence strategies employed by MRSA, key clinical trials of agents used to treat serious MRSA infections, and accumulating data regarding the implications of antibacterial resistance in MRSA for clinical success during therapy. Recent pre-clinical data support a species-specific role for Panton-Valentine leukocidin in the development of acute severe S. aureus infections and have elucidated other virulence mechanisms, including novel modes of internalisation, varying post-invasion strategies (featuring both upregulation and downregulation of virulence factors) and phenotypic switching. Recent double-blind, randomised, phase III/IV clinical trials have demonstrated the efficacy of linezolid and telavancin in hospital-acquired pneumonia (HAP) and complicated skin and skin-structure infections (cSSSIs) caused by MRSA. Tigecycline was non-inferior to imipenem/cilastatin in non-ventilator-associated HAP but was inferior in ventilator-associated pneumonia and has shown a higher rate of death than comparators on meta-analysis. Ceftaroline was clinically and microbiologically non-inferior to vancomycin/aztreonam in the treatment of MRSA cSSSI. Key resistance issues include a rise in vancomycin minimum inhibitory concentrations in MRSA, reports of clonal isolates with linezolid resistance mediated by acquisition of the chloramphenicol/florfenicol resistance gene, and case reports of daptomycin resistance resulting in clinical failure. Novel antimicrobial targets must be identified with some regularity or we will face the risk of untreatable S. aureus infections.

Prosthetic joint infections: microbiology, diagnosis, management and prevention

Infections associated with prosthetic joints occur less frequently than aseptic failures but represent the most devastating complication, with high morbidity and substantial cost. The most important risk factors are co-morbidity and prior joint replacement (revision surgery). No single routinely used clinical or laboratory test has been shown to achieve ideal sensitivity, specificity and accuracy for the diagnosis of prosthetic joint infection (PJI). Therefore, only the sum of clinical signs and symptoms, blood tests, histopathology, radiography, bone scans and a microbiological work-up can provide an accurate diagnosis. Antimicrobial therapy must always be combined with the correct surgical treatment, which is chosen according to the duration of the infection and co-morbidities of the patient. This review will briefly discuss the microbiology, diagnosis, management and prevention of PJI.

Drug treatment for multidrug-resistant Acinetobacter baumannii infections

Acinetobacter baumannii has emerged in the last decades as a major cause of healthcare-associated infections and nosocomial outbreaks. Multidrug-resistant (MDR) A. baumannii is a rapidly emerging pathogen in healthcare settings, where it causes infections that include bacteremia, pneumonia, meningitis, and urinary tract and wound infections. Antimicrobial resistance poses great limits for therapeutic options in infected patients, especially if the isolates are resistant to the carbapenems. Other therapeutic options include sulbactam, aminoglycosides, polymixyns and tigecycline. The discovery of new therapies coupled with the development of controlled clinical trial antibiotic testing combinations and the prevention of transmission of MDR Acinetobacter infection are essential to face this important hospital problem.

Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits?☆

Severe (life-threatening) meticillin-resistant Staphylococcus aureus (MRSA) infection continues to be treated with vancomycin despite accumulating evidence of poor outcome, increasing resistance and unachievable pharmacokinetic/pharmacodynamic (PK/PD) targets. The minimum inhibitory concentration (MIC) susceptibility breakpoint for vancomycin was recently reduced to 2 mg/L. Whilst the great majority of clinical isolates are thus still classified as susceptible, the available clinical evidence argues for a method-dependent breakpoint of 0.5 mg/L (broth dilution) or 1.0 mg/L (Etest), which would classify many strains as resistant, or at best intermediate. However, automated susceptibility testing systems are not currently capable of performing accurately at this low level, and such low breakpoints are unsatisfactory because the poor reproducibility of tests (plus or minus one doubling dilution) results in a critical non-reproducibility around the modal MIC of 1 mg/L described in most published data. Therefore, vancomycin should be used with caution in severe (life-threatening) staphylococcal disease and the MIC should always be reported by method. Daptomycin is generally preferred for bacteraemia/endocarditis and linezolid for pneumonia. Better outcome data for vancomycin, based on achievable PK/PD targets and using robust MIC tests, are urgently required.

Italian Guidelines for the Diagnosis and Infectious Disease Management of Osteomyelitis and Prosthetic Joint Infections in Adults

Bone and joint infections are recognized as difficult-to-treat infections that result in significant morbidity and mortality among patients and increased healthcare costs. This article presents the recommendations for the diagnosis and management of osteomyelitis and prosthetic joint infections in adults developed by Bone and Joint Infections Committee for the Italian Society of Infectious and Tropical Diseases. It contains data published through to November 2007. An evidence-based scoring system that is used by the Infectious Diseases Society of America was applied to treatment recommendations.

Current Status of Newer Carbapenems

OBJECTIVES Beta-lactam antibiotics represent the most commonly prescribed antibacterial agents. Since many bacteria have developed resistance to older agents, new beta-lactams have been introduced constantly. In the late 1970s, a new class of exceptionally broad-spectrum beta-lactams, the carbapenems, was identified. The carbapenems, such as the most popular imipenem and meropenem, have the widest spectra of antibacterial activity of all the beta-lactams and provide excellent coverage of many gram-negative and gram-positive aerobic and anaerobic bacteria. Despite the wide antibacterial spectrum, the carbapenems globally lack activity against Enterococcus faecium, methicillin-resistant Staphylococcus aureus (MRSA) and Stenotrophomonas maltophilia. METHODS We reviewed the principal characteristics of the novel carbapenems and their clinical implications. RESULTS AND CONCLUSIONS We included in our review: ertapenem, biapenem, panipenem, doripenem, tebipenem pivoxil and tomopenem.

Considerations of antibiotic therapy duration in community- and hospital-acquired bacterial infections

Despite the large number of suggestions available in the literature, the optimal duration of antibiotic treatment remains an individual decision mainly based on clinical criteria. Shorter but equally effective regimens would reduce the side effect rates, including both antibiotic resistance and drug expenses. Although several prospective, randomized trials and meta-analyses with the aim of comparing a standard duration with a shorter one for most bacterial infections have been published, to date most current recommendations carry little weight, as they are based on expert opinions or practical experience. This review will briefly touch upon the clinical evidence of short-course versus long-course antibiotic therapy for the most common community- and hospital-acquired bacterial infections.

Epidemiology and microbiology of skin and soft tissue infections.

Purpose of review Skin and soft tissue infections (SSTIs) are a broad spectrum of diseases, including uncomplicated and complicated infections. Herein, we review the current epidemiology and microbiology of SSTIs. Recent findings In the last decades, a significant growing trend of SSTIs both in the community and healthcare settings with a dramatic increase of the economic burden for these diagnoses was observed. Several observational studies found that SSTIs are a substantial cause of ambulatory and emergency department visits, and of hospitalizations. Although, microbiology of SSTIs changes according to the clinical feature and the severity of illness, Staphylococcus aureus being the leading cause of both uncomplicated infections and complicated infections. Moreover, the increasing prevalence of infections because of multidrug-resistant bacteria, mainly methicillin-resistant S. aureus (both community-acquired and healthcare-associated methicillin-resistant S. aureus), are associated with significantly increased morbidity, mortality, length of hospital stay, and costs, compared with infections because of susceptible strains. Moreover, although it is unclear whether high vancomycin minimum inhibitory concentration is associated with a worse outcome, it poses a further challenge for the clinicians. Summary The understanding of the current epidemiology and microbiology of SSTIs is indicated for an appropriate antimicrobial therapy and an overall optimal management of SSTIs.

Macrolide-resistance genes in clinical isolates of Streptococcus pyogenes.

Macrolide-resistance genes were investigated in 103 macrolide-resistant strains of Streptococcus pyogenes, isolated from children with pharyngotonsillitis. The presence of mef(A), erm(B), and erm(TR) genes was detected by PCR. mef(A) was found in 48 out of 103 (46.6%) strains, whereas erm(B) was detected in 43 isolates (41.7%). All mef(A) strains showed a typical M phenotype (resistance to 14- and 15-membered macrolides, and sensitivity to lincosamides and streptogramin B), whereas erm(B) strains had the MLSB phenotype (resistance to macrolides, lincosamides, and streptogramin B antibiotics). erm(TR) was found in 10 strains, always together with other resistance genes. In seven cases erm(TR) was associated with erm(B), and three cases with mef(A). In two isolates with the M phenotype (1.9%), it was not possible to detect the presence of any of the three macrolide resistance genes tested. Inducible resistance to macrolides was shown for 24 out of the 53 MLSB strains. Analysis of macrorestriction fragment patterns by pulsed-field gel electrophoresis showed that erythromycin-resistant S. pyogenes are polyclonal, however each phenotype, MLSB and M, formed essentially homogeneous groups.

Outpatient parenteral antibiotic therapy in the elderly: an Italian observational multicenter study

Abstract Bacterial infections are the most frequent cause of hospitalization in elderly patients. In the early eighties, the advantages of Outpatient parenteral Antibiotic therapy (OPAT) were identified in the United States, and suitable therapeutic programs were established. In order to understand the different ways of managing OPAT, a National OPAT Registry was set up in 2003 in Italy. This study analyzes data concerning bacterial infections in 176 elderly patients including demographics, therapeutic management, clinical response, and side-effects. Bone and joint infections (48.9%) and skin and soft tissue infections (27.8%) were the most common infections treated with OPAT. Teicoplanin (28.9%) and ceftriaxone (22.1%) were the top two antibiotics chosen. OPAT was mainly performed at a hospital infusion center (52.8%). The clinical success rate was high and side-effects were low (12.6% of cases). Management of bacterial infections in the elderly with an outpatient program is effective and safe.