Juan J. Picazo

Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit.

CONTEXT Linezolid resistance is extremely uncommon in Staphylococcus aureus. OBJECTIVE To report an outbreak with linezolid and methicillin-resistant S. aureus (LRSA) in an intensive care department and the effective control measures taken. DESIGN, SETTING, AND PATIENTS Outbreak study of consecutive critically ill patients colonized and/or infected with LRSA at an intensive care department of a 1000-bed tertiary care university teaching hospital in Madrid, Spain. Patients were placed under strict contact isolation. Daily updates of outbreak data and recommendations for the use of linezolid were issued. Extensive environmental sampling and screening of the hands of health care workers were performed. MAIN OUTCOME MEASURES Linezolid use and clinical and epidemiological characteristics and outcomes using minimal inhibitory concentrations, pulsed-field gel electrophoresis, and polymerase chain reaction of LRSA isolates. RESULTS Between April 13 and June 26, 2008, 12 patients with LRSA were identified. In 6 patients, LRSA caused ventilator-associated pneumonia and in 3 patients it caused bacteremia. Isolates were susceptible to trimethoprim-sulfamethoxazole, glycopeptides, tigecycline, and daptomycin. Genotyping identified 1 predominant clone and 3 other types. Cfr-mediated linezolid resistance was demonstrated in all isolates. Potential hospital staff carriers and environmental samples were negative except for one. Six patients died, 5 of them in the intensive care unit, with 1 death attributed to LRSA infection. Linezolid use decreased from 202 defined daily doses in April 2008 to 25 defined daily doses in July 2008. Between July 2008 and April 2010, no new cases have been identified in the weekly surveillance cultures or diagnostic samples. CONCLUSIONS The first clinical outbreak, to our knowledge, with LRSA mediated by the cfr gene developed at our center, was associated with nosocomial transmission and extensive usage of linezolid. Reduction of linezolid use and infection-control measures were associated with the termination of the outbreak.

Resistance to Linezolid Is Mediated by the cfr Gene in the First Report of an Outbreak of Linezolid-Resistant Staphylococcus aureus

BACKGROUND From April through June 2008, we identified 12 patients in the intensive care unit and 3 patients on other wards infected with methicillin-resistant Staphylococcus aureus that was also resistant to linezolid. We investigated the mechanism of resistance--point mutations in domain V of 23S ribosomal RNA (rRNA) or presence of the cfr gene--involved in the outbreak. METHODS Strains for the study were obtained in the intensive care unit and other wards. Minimal inhibitory concentrations were determined using automated methods, the E-test, or dilution in Mueller-Hinton agar in accordance with Clinical and Laboratory Standards Institute guidelines. Strains were genotyped using pulsed-field gel electrophoresis and were sequenced to determine the presence of point mutations in 23S rRNA. The presence of the cfr gene was determined by specific polymerase chain reaction. RESULTS The minimal inhibitory concentrations of linezolid ranged from 16 mg/L to 32 mg/L, and all the strains were susceptible to tigecycline, vancomycin, and daptomycin. Typing of strains sequentially isolated by pulsed-field gel electrophoresis showed that each patient carried only 1 clonal type of linezolid-resistant, methicillin-resistant S. aureus as detected by sequential isolations. The presence of the cfr gene was confirmed in all the isolates. Furthermore, sequencing of domain V of 23S rRNA showed that the most common mechanism of linezolid resistance reported to date, mutation G2576T, was not detected in any of the strains analyzed. CONCLUSIONS We report the presence of the cfr gene underlying the resistance mechanism involved in a clinical outbreak of linezolid-resistant S. aureus.

In Vitro Activities of Tigecycline (GAR-936) against Recently Isolated Clinical Bacteria in Spain

ABSTRACT The antimicrobial activities of tigecycline (GAR-936) were compared with those of other agents against 1,087 strains recently isolated in 12 Spanish medical centers. Tigecycline showed activity against a wide spectrum of aerobic and anaerobic bacteria, including strains such as methicillin-resistant Staphylococcus aureus, coagulase-negative staphylococci, penicillin-resistant Streptococcus pneumoniae, Enterococcus faecium, Acinetobacter baumannii, and Stenotrophomonas maltophilia.

The central nervous system and infection by Candida species.

In this paper we have reviewed the main clinico-pathologic disease groups of neurocandidiasis: the microabscesses, the macroabscesses, and the meningitis. Special attention has been paid to the predisposing conditions for the appearance of neurocandidiasis, the neuroimaging techniques, and the study of the cerebrospinal fluid, needed for diagnosis. We have also discussed the differential diagnosis with other illnesses. Treatment should be given with amphotericin-B and 5-fluorocytosine. The use of other antifungal drugs for neurocandidiasis is also discussed.

Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant Staphylococcus aureus Strains Possessing the cfr Methyltransferase Gene or Ribosomal Mutations

ABSTRACT Staphylococcal resistance to linezolid (LZD) is mediated through ribosomal mutations (23S rRNA or ribosomal proteins L3 and L4) or through methylation of 23S rRNA by the horizontally transferred Cfr methyltransferase. To investigate the structural basis for oxazolidinone activity against LZD-resistant (LZDr) strains, we compared structurally diverse, clinically relevant oxazolidinones, including LZD, radezolid (RX-1741), TR-700 (torezolid), and a set of TR-700 analogs (including novel CD-rings and various A-ring C-5 substituents), against a panel of laboratory-derived and clinical LZDrStaphylococcus aureus strains possessing a variety of resistance mechanisms. Potency against all strains was correlated with optimization of C- and D-rings, which interact with more highly conserved regions of the peptidyl transferase center binding site. Activity against cfr strains was retained with either hydroxymethyl or 1,2,3-triazole C-5 groups but was reduced by 2- to 8-fold in compounds with acetamide substituents. LZD, which possesses a C-5 acetamide group and lacks a D-ring substituent, demonstrated the lowest potency against all strains tested, particularly against cfr strains. These data reveal key features contributing to oxazolidinone activity and highlight structural tradeoffs between potency against susceptible strains and potency against strains with various resistance mechanisms.

Antibiotic resistance and penicillin tolerance in clinical isolates of group B streptococci.

The aim of this study was to determine the susceptibility patterns of 100 group B streptococcal strains isolated in our hospital and to ascertain tolerance to penicillin by determining quantitative killing curves. We found two strains with intermediate susceptibility to penicillin and eight strains to ampicillin. Seventeen isolates were tolerant to penicillin, with bacterial counts decreasing 2 to 3 log during the first 8 h but still above 10(2) CFU/ml after 24 h. The kinetic study shows that penicillin tolerance is not rare among group B streptococci isolated in our hospital.

Erythromycin and Clindamycin Resistance and Telithromycin Susceptibility in Streptococcus agalactiae

ABSTRACT The rates of resistance to erythromycin and clindamycin among Streptococcus agalactiae strains isolated in our hospital increased from 4.2 and 0.8% in 1993 to 17.4 and 12.1%, respectively, in 2001. Erythromycin resistance was mainly due to the presence of an Erm(B) methylase, while the M phenotype was detected in 3.8% of the strains. Telithromycin was very active against erythromycin-resistant strains, irrespective of their mechanisms of macrolide resistance.

Vigilancia de resistencias a los antimicrobianos : estudio VIRA 2004

INTRODUCTION The objective of this study was to determine the current antimicrobial susceptibility patterns of the most frequent multi-resistant bacteria and to analyze any possible changes with respect to the two VIRA studies carried out in 2001 and 2004. METHODS In February 2006, the 40 participating hospitals sent the following microorganisms: non-penicillin-susceptible Streptococcus pneumoniae (92), methicillin-resistant Staphylococcus aureus (MRSA) (290), clinically significant coagulase-negative staphylococci (136), ampicillin-resistant Enterococcus faecium (89), ampicillin-resistant Haemophilus influenzae (67), ciprofloxacin-resistant Escherichia coli (365), Pseudomonas aeruginosa (181), and Acinetobacter baumannii (92). The hospitals provided epidemiological data on these microorganisms. Susceptibility was determined with a broth microdilution method. RESULTS Among the non-penicillin-susceptible S. pneumoniae isolates, the proportion of those ones resistant to this antibiotic showed a significant (p < 0.001) decrease (59.8% in 2001, 30.2% in 2004 and 14.3% in 2006). Among MRSA, we detected one isolate nonsusceptible to linezolid, four resistant to quinupristin-dalfopristin and one strain with a vancomycin MIC of 4 microg/mL. The prevalence of extended-spectrum beta-lactamase-producing E. coli was 12.1%. Resistance of A. baumannii to imipenem varied from 27% in the 2001-2004 period to 47.8% in 2006 (p < 0.005). CONCLUSION These results again emphasize that resistance surveillance systems are an important tool for preventing the emergence and spread of multi-resistant pathogens.

In vitro activity of tedizolid (TR-700) against linezolid-resistant staphylococci

OBJECTIVES To compare the activity of tedizolid (formally known as torezolid and TR-700) with that of 15 agents against a collection of linezolid-resistant staphylococci (164 coagulase-negative staphylococci and 5 Staphylococcus aureus). METHODS Antimicrobial susceptibility tests were performed using the broth microdilution method following the recommendations of the CLSI. RESULTS All isolates were susceptible to vancomycin and tigecycline. Based on the MIC(90) values, the potency of tedizolid against coagulase-negative staphylococci was >16-fold greater than that of linezolid. Tedizolid retained activity against most of the linezolid-resistant staphylococci tested, including multidrug-resistant isolates with elevated linezolid MICs (32 to >128 mg/L). Of the isolates, 79.2% and 31.4% were inhibited by tedizolid at ≤ 4 mg/L and ≤ 2 mg/L, respectively. CONCLUSIONS The results of this study confirm the activity of tedizolid against linezolid-resistant staphylococci. This new oxazolidinone could have an important role as a potential therapeutic agent against multidrug-resistant staphylococci.

Relationship between serotypes, age, and clinical presentation of invasive pneumococcal disease in Madrid, Spain, after introduction of the 7-valent pneumococcal conjugate vaccine into the vaccination calendar.

ABSTRACT To assess invasive pneumococcal disease (IPD) clinical presentations and relationships with age and serotype in hospitalized children (<15 years) after PCV7 implementation in Madrid, Spain, a prospective 2-year (May 2007 to April 2009) laboratory-confirmed (culture and/or PCR) IPD surveillance study was performed (22 hospitals). All isolates (for serotyping) and culture-negative pleural/cerebrospinal fluids were sent to the reference laboratory for pneumolysin (ply) and autolysin (lyt) gene PCR analysis. A total of 330 IPDs were identified: 263 (79.7%) confirmed by culture and 67 (20.3%) confirmed by PCR. IPD distribution by age (months) was as follows: 23.6% (<12), 15.8% (12 to 23), 15.5% (24 to 35), 22.4% (36 to 59), and 22.7% (>59). Distribution by clinical presentation was as follows: 34.5% bacteremic pneumonia, 30.3% pediatric parapneumonic empyema (PPE), 13.6% meningitis, 13.3% primary bacteremia, and 8.2% others. Meningitis and primary bacteremia were the most frequent IPDs in children <12 months old, and bacteremic pneumonia and PPE were most frequent in those >36 months old. Frequencies of IPD-associated serotypes were as follows: 1, 26.1%; 19A, 18.8%; 5, 15.5%; 7F, 8.5%; 3, 3.9%; nontypeable/other 30 serotypes, 27.3%. Serotype 1 was linked to respiratory-associated IPD (38.6% in bacteremic pneumonia and 38.0% in PPE) and children of >36 months (51.4% for 36 to 59 months and 40.0% for >59 months), while serotype 19A was linked to nonrespiratory IPDs (31.1% in meningitis, 27.3% in primary bacteremia, and 51.9% in others) and children of <24 months (35.9% for children of <12 months and 36.5% for those 12 to 23 months old), with high nonsusceptibility rates for penicillin, cefotaxime, and erythromycin. After PCV7 implementation, non-PCV7 serotypes caused 95.5% of IPDs. The new 13-valent conjugate vaccine would provide 79.1% coverage of serotypes responsible for IPDs in this series.