ACCEPTED. Association between staphylococcal PVL gene and a lower inhospital. survival in Pulmonary Patients. Spain. Científicas (CSIC), Madrid, Spain

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1 JCM Accepts, published online ahead of print on 8 November 006 J. Clin. Microbiol. doi:10.118/jcm Copyright 006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. A New Data Letter for Journal of Clinical Microbiology Association between staphylococcal PVL gene and a lower inhospital survival in Pulmonary Patients. Lopez-Aguilar C 1,7, Perez-Roth E 1, Moreno A, Duran MC 3, Casanova C 4, Aguirre- Jaime A 5, Mendez-Alvarez S 1,6,7,* 1 Molecular Biology Laboratory, Research Institute, Microbiology Service, 3 Internal Medicine Service, 4 Pneumology Department, 5 Research Support Service at NS Candelaria University Hospital, Tenerife, Spain 6 Microbiology and Cellular Biology Department, Universidad de La Laguna, Tenerife, Spain 7 Centro de Investigaciones Biológicas (CIB) del Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain Running title: PVL-S. aureus and patients decreased survival *Correspondence to: Dr. Sebastián Méndez-Álvarez Instituto de Investigación Ctra. del Rosario Santa Cruz de Tenerife SPAIN Phone // FAX: smenalv@gobiernodecanarias.org Downloaded from on September 4, 018 by guest

2 Staphylococcus aureus is responsible for more than % of cases of communityacquired pneumonia and 10% of cases of nosocomial-acquired pneumonia. The lethality rate of such infections ranges from 30% to 80%. These infections are complicated by the fact that these bacteria have acquired diverse genetic information that makes them resistant to most antibiotics. Methicillin-resistant S. aureus (MRSA) is the most common cause of serious hospital-acquired infections (1). Infections of the respiratory tract by S. aureus can be more severe if the infecting strain produces the Panton-Valentine leukocidin (PVL) (11). The serious impact of PVL positive S. aureus infections seems to be associated with pulmonary complications. We hypothesized that PVL-positive MRSA is associated with mortality in patients with S. aureus pneumonia. During a period of 1 months, all hospital-acquired MRSA isolates recovered from independent patients in the pulmonary ward at NS Candelaria University Hospital were included in the study. MRSA isolates were considered hospital acquired if they were recovered from a specimen collected 7h or more after admission to the hospital. A collection of 4 MRSA isolates was characterized using different molecular techniques (3, 8). Cases were analysed to assess the association between PVL and death in patients affected by different pulmonary diseases and co-morbidity charge summarised in the Modified Charlson Combined Index (). CT analysis was also performed when necessary. The concordant diagnosis of pneumonia was determined by chart review by two independent, blinded pulmonogists. Pneumonia or bronchitis was defined by signs and symptoms of lowerrespiratory-tract infection and chest radiograph. After detection of MRSA, antibiotic treatment was guided by the antibiotic susceptibilty results generated with the Vitek system (biomérieux, Lyon, France) and according to Clinical Laboratory Standards Institute (5). Generally, antibiotic treatment comprised a macrolide with a third generation cephalosporin or a quinolone. For other pathologies treatments were applied according to the Internationally approved Medical Standards.

3 The following data were recorded for each patient: age, gender, arterial oxygen pressure (apo) and oxygenation rate value (ORV) (apo/% O inhaled) at the admission, length of hospital stay from MRSA detection to discharge or exitus, pulmonary disease (bronchitis or pneumonia), main declared reason of mortality as principal or most important cause of death, Comorbidity Modified Charlson Combined Index, sample type for microbiological analysis, MRSA clone and PVL presence. Although the sample size is a constrain of this study, the number of patients in the sample guarantees a power of 80% to detect differences as small as 45% between groups in two-tailed tests at a statistical significance level p< Out of 4 patients included in the study, 14 died within 30 days after recovery of the MRSA isolate. Table 1 shows the measured parameters for dead and alive patients. The presence of PVL differed significantly between dead and alive patients, since all the PVL-positive patients died. Table shows the measured parameters in patients with PVL positive or PVL negative isolates of MRSA. The difference between the percentage of deaths for PVL-positive (100%) and for PVL-negative (47%) patients reached statistical significance. A noteworthy haematological finding was the average trough leukocyte and lymphocyte counts, which differed significantly between PVLpositive and PVL-negative patients. Interestingly, the leucocyte level was over the reference range for PVL-positive patients but lymphocytes were under the reference range. Although, some studies have shown that PVL-positive S. aureus isolates frequently cause hemorrhagic and necrotising pneumonia, this was not found in this population (4, 11). As shown in Table, the in-hospital survival time was substantially less for PVL positive patients and this difference reached statistical significance. The presence of the PVL gene increased the risk of death 1.56 fold (95%CI: ). The five isolates recovered from PVL-positive patients belonged to the ST15-IVA MRSA clone. PVL-negative ST15-IVA MRSA isolates were also detected in hospitalized patients without pulmonary MRSA infections during the same period of time, showing that this clone does not always harbour the PVL gene (data not shown). 3

4 Figure 1 represents Kaplan-Meier curves of in-hospital survival at 30 days for patients with PVL positive and negative MRSA isolates. These curves pointed out the abrupt decrease in survival in the PVL-positive patients compared to a slower death rate in the PVL-negative patients. The survival showed an abrupt decrease in presence of PVL, pointing out that carriage of a PVL-positive S. aureus strain may be critical to death for pulmonary patients. The findings of this study may have some implications for clinical decision making. PVL-positive MRSA strains seem to be dangerous for pulmonary patients so we recommend screening for the presence of PVL when an MRSA is detected in such patients. If the presence of a PVL-positive MRSA strain is confirmed, antibiotic treatment should be reinforced to ensure the elimination of this bacteria. An antibiotic for which resistance has not yet become a problem and with first-rate tissue distribution, as for example linezolide, should be administrated. Concomitantly, the spread of PVL-positive strains to other patients could have such deleterious consequences that we also recommend the isolation of patients with PVL positive MRSA to prevent spread of the organism. However, further studies are necessary to prove the validity and extension of these findings. 4

5 Acknowledgements We are grateful to J.P. de Torres for critical reading of the manuscript. The study was partially supported by grants FUNCIS 0/38 and MEC BIO00/00953, Spain, to S.M.A. S.M.A. was partially supported by Public Health Research Foundation (FIS) grant 99/3060, Spain. E.P.R. and C.L.A. were partially supported by grants from Consejería de Educación, Cultura y Deportes and FUNCIS, respectively, Gobierno de Canarias Autonomous Government, Spain. 5

6 References 1. Berger-Bachi, B. 00. Resistance mechanisms of gram-positive bacteria. Int. J. Med. Microbiol. 9: Charlson, M., T. P. Szatrowski, J. Peterson, and J. Gold Validation of a combined comorbidity index. J. Clin. Epidemiol. 47: Enright, M. C., N. P. Day, C. E. Davies, S. J. Peacock, and B Spratt Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus. J. Clin. Microbiol. 38: Gillet, Y., B. Issartel, P. Vanhems, J. C. Fournet, G. Lina, M. Bes, F. Vandenesch, Y. Piemont, N. Brousse, D. Floret, and J. Etienne. 00. Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359: National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests, 8 th ed. 003; Approved standard M-A8. National Committee for Clinical Laboratory Standards, Wayne, Pa. 6. Obed A., A. A. Schnitzbauer, T. Bein, N. Lehn, H. J. Linde, and H. J. Schlitt Fatal pneumonia caused by Panton-Valentine Leukocidine-positive Methicillin-Resistant Staphylococcus aureus (PVL-MRSA) transmitted from a healthy donor in living-donor liver transplantation. Transplantation 81: Pérez-Roth E., F. Claverie-Martín, J. Villar, and S. Méndez- Álvarez Multiplex PCR for simultaneous identification of 6

7 Staphylococcus aureus and detection of methicillin and mupirocin resistance. J. Clin. Microbiol. 39: Pérez-Roth E., F. Lorenzo-Díaz, N. Batista, A. Moreno, and S. Méndez-Álvarez Tracking methicillin-resistant Staphylococcus aureus clones during a 5-year period (1998 to 00) in a Spanish hospital. J. Clin. Microbiol. 4: Rainard P., J. C. Corrales, M. B. Barrio, T. Cochard, and B. Poutrel Leucotoxic activities of Staphylococcus aureus strains isolated from cows, ewes, and goats with mastitis: importance of LukM/LukF -PV leukotoxin. Clin. Diagn. Lab. Immunol. 10: Robinson D. A., A. M. Kearns, A. Holmes, D. Morrison, H. Grundmann, G. Edwards, F. G. O Brien, F. C. Tenover, L. K. McDougal, A. B. Monk, and M. C. Enright Re-emergence of early pandemic Staphylococcus aureus as a community-acquired meticillin-resistant clone. Lancet 365: Vandenesch F., T. Naimi, M. C. Enright, G. Lina, G. R. Nimmo, H. Heffernan, N. Liassine, M. Bes, T. Greenland, M. E. Reverdy, and J. Etienne. 003 Community-acquired methicillin-resistant Staphylococcus aureus carrying Panton-Valentine leukocidin genes: worldwide emergence. Emerg. Infect. Dis. 9:

8 Figure legends Fig. 1. Kaplan-Meier cumulative survival at 30 days curves for PVL as factor. 8

9 Table 1. Alive versus dead patients parameters Characteristic Dead (n=14) Alive (n=10) p-value Age (years old) 75 (67 85) 76 (67 81) Gender (M/F) 1/ 5/ Oxygenation rate value (ORV) at the admission 43 (198 73) 300 (48 346) Diagnostic at the admission (patients): Bronchitis Pneumonia Lung Fibrosis Lung Neoplasy Other Pneumology status at MRSA isolation (patients): Bronchitis Pneumonia Lung Neoplasy (patients) Charlson Combined Index (points) 7 (6 8) 7 (6 9) Clinical Sample (patients): Sputum Bronchoalveolar PVL Positive (patients) Median (5 th -75 th pc) compared by U Mann-Whitney Test. Number or percentage compared by Fisher Exact Test.

10 Table. Patients characteristics for positive vs negative PVL Characteristic Positive (n=5) PVL Negative (n=19) p-value Age (years old) 67 (56 86) 76 (73 81) Gender (M/F) 5/0 1/7 0.7 Oxygenation rate value (ORV) at the admission 54 (14 37) 6 (10 330) Pneumological situation (patients): Bronchitis Pneumonia Lung Neoplasy (patients) Leucocytes level >9.8 count/ml (patients) Linphocytes level <1.5 count/ml (patients) Charlson Combined Index (points) 7 (4 11) 7 (6 9) Clinical Sample (patients): Sputum Bronchoalveolar MRSA Clone (patients): ST36-II ST15-IVA Declared Cause of Death (patients): Respiratory Failure Lung fibrosis Pneumonia (60%) 1 (0%) 1 (0%) < (67%) 1 (11%) (%) Deaths (%) In-hospital survival at 30 days (days) 14(9 7) 30(9 30) Median (5th-75th pc) compared by U Mann-Whitney Test. Number or percentage compared by Fisher Exact Test or Pearson Chi-squared Test. 3 Time compared by log-rank Test

11 Cumulative survival 1,0 0,8 0,6 0,4 0, 0,0 Days p(log-rank)=0.05 PVL positive PVL negative Patients at risk: PVL PVL Median (5 th 75 th pc) survival time in days: 30 (9 30) PVL-negative vs 14 (9 9) PVL-positive

12 JOURNAL OF CLINICAL MICROBIOLOGY, Sept. 007, p Vol. 45, No /07/$ doi:10.118/jcm ERRATUM Association between the Presence of the Panton-Valentine Leukocidin-Encoding Gene and a Lower Rate of Survival among Hospitalized Pulmonary Patients with Staphylococcal Disease Volume 45, no. 1, p , 007. Page 76: Names of authors should read as follows. C. Lopez-Aguilar E. Perez-Roth Molecular Biology Laboratory Unidad de Investigación Ctra. del Rosario Santa Cruz de Tenerife, Spain A. Moreno Microbiology Service Santa Cruz de Tenerife, Spain M. C. Duran Internal Medicine Service Santa Cruz de Tenerife, Spain C. Casanova Pneumology Department Santa Cruz de Tenerife, Spain A. Aguirre-Jaime Research Support Service Santa Cruz de Tenerife, Spain S. Mendez-Alvarez Molecular Biology Laboratory Unidad de Investigación Ctra. del Rosario Santa Cruz de Tenerife, Spain 3150

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