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1 AAC Accepts, published online ahead of print on 13 April 2009 Antimicrob. Agents Chemother. doi: /aac Copyright 2009, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved. Title: Early and late onset pneumonia: Is this still a useful classification? Authors: Petra Gastmeier* 1,2, Dorit Sohr 2, Christine Geffers 2, Henning Rüden 2, Ralf-Peter Vonberg 1, Tobias Welte 3 Affiliations: 1 Institute for Medical Microbiology and Hospital Epidemiology, Medical School Hannover 2 Institute of Hygiene and Environmental Medicine, Charité University Medicine Berlin 3 Department of Pneumology, Medical School Hannover Running title: Early and late onset pneumonia (30 characters including spaces) No. Words: (including references) No. Tables: 4 No. Figures: 0 Key words: early onset; late onset; pneumonia; intensive care unit; surveillance *Contact address: Prof. Dr. med. Petra Gastmeier Institute of Hygiene and Environmental Medicine Charité University Medicine Berlin Hindenburgdamm 27 D Berlin Tel: Fax: Mail: petra.gastmeier@charite.de 1

2 1 ABSTRACT (250 words) The choice of empiric treatment of nosocomial pneumonia on the intensive care unit used to rely on the duration after starting mechanical ventilation. However, nowadays it is under debate whether or not there in fact is a difference in the distribution of causative pathogens. Data from 308 ICUs from the German national nosocomial infection surveillance system were used for the evaluation and included information on relevant pathogens isolated from 11,285 cases of nosocomial pneumonia from Each individual pneumonia case was allocated either to early or late onset pneumonia with three differentiation criteria: 4 th day, 5 th day and 7 th day in the ICU. The frequency of pathogens was evaluated according to these categories. 5,066 additional cases of pneumonia were reported from after CDC criteria had been modified. From the most frequent micro-organisms were S. aureus (2,718 cases, including 720 with MRSA), followed by P. aeruginosa (1,837), K. pneumoniae (1,305), E. coli (1,137), Enterobacter spp. (937), streptococci (671), H. influenzae (509), Acinetobacter spp. (493) and S. maltophilia (308). The order of the four most frequent pathogens (covering 53.7 % of all pathogens) was the same in both groups independent of the cut-off of the categories applied: S. aureus was first, followed by P. aeruginosa, K. pneumoniae and E. coli. Thus, the predictability of occurrence of pathogens was similar when evaluation the prior ( ) and the latter ( ) time frame. For empiric antibiotic therapy this classification is not helpful any more as the pathogens are the same for both groups. 2

3 24 INTRODUCTION For a long time it was common to distinguish between early onset (first 4 days) and 27 late onset (after 4 th day) of ventilator-associated pneumonia (VAP) (19). Early onset nosocomial pneumonia was believed to be due primarily to enteric gram-negative bacteria, H. influenzae and methicillin-sensitive S. aureus (MSSA) and S. pneumoniae. For late onset nosocomial pneumonia the most commonly encountered causative pathogens reported were higher level antibiotic resistant gram-negative bacteria such as P. aeruginosa, Acinetobacter spp., or methicillin-resistant S. aureus (MRSA). This classification leads to different strategies for empiric antimicrobial treatment: monotherapy with narrow spectrum antibiotics for the treatment of early onset pneumonia, but broad spectrum therapy for Pseudomonas spp. or MRSA with late onset infection (2). Meanwhile guidelines and articles which discuss this classification are using different criteria for distinguishing between early and late onset nosocomial pneumonia. Some authors regard the 4 th day in the ICU as the last day of an early onset (4,6,17,21,23), others set the 5 th (24) or even the 7 th day (12,15,25) as the limit. Furthermore, it still remains uncertain from the relevant literature as to whether the given threshold refers to the number of days in hospital, or the number of days following intubation (24). The concept itself still, though, remains accepted in general (3,24). During our surveillance activities in several intensive care units (ICUs) however, we got the impression that this widely used classification may no longer be appropriate for determining the antimicrobial therapy required. We have therefore used data from the German National Nosocomial Infection Surveillance System KISS (KISS = Krankenhaus-Infektions- Surveillance-System) to investigate this question drawing on a huge database provided by German ICUs (10). 3

4 49 MATERIALS and METHODS The ICU component of KISS was established in Since then the number of participating ICUs has increased continuously (10). The method used by KISS is almost identical to the surveillance method of the National Nosocomial Infections Surveillance (NNIS) System in the US (8). The definitions from the Centers for Disease Control and Prevention (CDC) (9) are used for the diagnosis of nosocomial infections in KISS as well. The KISS methodology for calculating device-associated infection rates, comparing infection rates and recording of complications also derive from the NNIS system. Whenever a nosocomial infection occurred, the identified pathogens in the specimen are reported to the surveillance system. Up to 4 pathogens can be recorded for each infection site. For S. aureus it was also recorded whether this isolate is an MSSA or an MRSA. For the current analysis we calculated the percentage of nosocomial pneumonia cases with MSSA, MRSA, P. aeruginosa and other pathogens out of all the pneumonia cases identified on any given ICU day during the first 14 ICU days. In addition, we compared the pathogens identified according to three cut offs (4 th day, 5 th day and 7 th day) to distinguish between early and late onset nosocomial pneumonia. These time frames refers to the day of admission of the patient to the ICU until the first day on which clinical signs or symptoms of pneumonia were noticed (or alternatively the day on which (positive) samples were drawn for microbiologic testing whatever happened first). To compare both groups for the 7 day limit relative risks with 95 % confidence intervals were calculated. Since the CDC definitions of nosocomial pneumonia were recently modified (16), we also looked separately at the time frames and to evaluate whether this has influenced the distribution of pathogens in our surveillance system. 4

5 Because the majority of pneumonia cases were diagnosed on the basis of clinical criteria and endotracheal aspirate cultures, we performed a distinct analysis for those pneumonia cases diagnosed by quantitative bronchoalveolar lavage (BAL) cultures, because such samples are considered to yield more accurate data than endotracheal aspirates (6). Uniform threshold values for cultured specimens in the diagnosis of pneumonia were 10 4 colony-forming units per ml. RESULTS Time frame Up to the end of 2004 we had an overview of 11,285 pneumonia cases from 308 ICUs monitored during 12,879 observation months (KISS). Most of the ICUs are interdisciplinary ICUs (48.1%), followed by surgical (21.4%), medical (19.2%), neurosurgical (3.6%), paediatric (3.2%), neurological (2.6%) and cardio-surgical ICUs (1.9%). 87.4% of pneumonia cases were considered to be ventilator-associated. The overall ventilator-associated pneumonia rate was 7.5 per 1,000 ventilator days (11). In 1,305 pneumonia cases (11.6%) no detectable pathogens were recorded. For the remaining 9,980 cases a total of 14,911 pathogens were recorded, which means an average of 1.5 pathogens per pneumonia case. In 1,609 cases the pathogens were identified using BAL quantitative culture, which is in 14.3 % of all cases. The 9 most frequent pathogens on the basis of all the material sent in for microbiological investigation or based only on BAL quantitative cultures can be found in TABLE 1. The most frequent pathogens were S. aureus (2,718 cases, of which 720 with MRSA), followed by P. aeruginosa (1,837), K. pneumoniae (1,305), E. coli (1,137), Enterobacter spp. (937), S. pneumoniae (671), Haemophilus spp. (509), Acinetobacter spp. 5

6 (493) and S. maltophilia (308). The order of frequency is almost identical for both groups (based on all kinds of specimens or considering BAL cultures only). The distribution of pneumonia cases according to the categories of early and late onset pneumonia can be found in TABLE 2. This distribution is also almost identical when considering all VAP cases or only those cases that got confirmed by BAL cultures. TABLE 3 shows the number of isolates per 100 pneumonia cases for the same pathogens. The order of frequency of the four most frequent micro-organisms is also shown in TABLE 3. There are no major differences on the order of pathogens regardless of the definition of early and late. The 7 day cut-off seems to be the most appropriate for evaluating differences between both onset groups because it yields groups with a similar size and also corresponds to the median time of occurrence of pneumonia in our data base of 7 days. We therefore used this cut-off to calculate relative risks for the number of isolates in both groups per 100 pneumonia cases (TABLE 4). After considering only those results with significant confidence intervals, we confirmed Methicillin susceptible S. aureus, S. pneumoniae, and Haemophilus spp. as early onset pathogens and P. aeruginosa, MRSA, Enterobacter spp., Acinetobacter spp., and S. maltophilia as late onset pathogens. Time frame When the CDC definitions of nosocomial pneumonia were changed, the German KISS system adapted the diagnosis criteria accordingly. That is why, as mentioned in the method s section earlier, we evaluated pathogens from nosocomial pneumonia separately for this time period. Additional 5,068 cases of nosocomial pneumonia were reported during these 2 years. For 5,066 of those, data on the time between ICU admission and onset of infection was also 6

7 available. A total of 5,969 pathogens were reported for the 5,068 pneumonia cases (1.47 pathogens per case in average). The order of the 5 most frequent pathogens showed to be identical regardless of the chosen patient s length of ICU stay before infection. There were no differences in the order of pathogen when compared to the earlier time frame ( ) DISCUSSION The administration of accurate and timely initial empiric antibiotic therapy has been shown to have a major impact on mortality from nosocomial pneumonia (1,5,7,26). Because early onset nosocomial pneumonia is most often reported as being due to antibiotic-sensitive pathogens, while late onset nosocomial pneumonia is frequently caused by more resistant ones, guidelines recommend monotherapy with narrow spectrum antibiotics for early onset and broad spectrum therapy for late onset infection (2,6,13). To our knowledge we present here the largest study of its kind ever published (contribution of >300 ICUs; surveillance of > cases of VAP; > pathogens recovered). According to our data, the frequency order of microorganisms is almost the same in both groups not distinctive enough for a decision about appropriate initial therapy, regardless of the modification of the CDC definitions. The cut-off day used for distinguishing between early and late onset pneumonia also has only a minor impact. Thus, the absolute duration of mechanical ventilation seems to be insufficient in order to choose the kind of antimicrobial treatment. That is why the classification of nosocomial pneumonia as early and late onset pneumonia should in our view no longer be recommended. In particular the high percentage of P. aeruginosa pneumonia in the early onset pneumonia group together with the increasing percentage of MRSA pneumonia could result in under-treating patients when following this concept of classification too rigidly. The frequent identification of P. 7

8 aeruginosa and MRSA in the early onset pneumonia group may be due to hospitalization prior to ICU admission and preceding exposure to antibiotics. Micek et al. showed that a prior hospital stay within 12 months increases the risk for infection by gram negative pathogens (20). Kothe et al. identified age and certain co-morbidities as additional risk factors for colonization by gram negative bacteria (18). The latest guidelines of the American Thoracic Society have already been modified and note that patients with early onset pneumonia who have received antibiotics or been hospitalized within the past 90 days have a greater risk of being colonized and infected with multi resistant pathogens and should be treated in the same way as patients with late onset pneumonia (3). Other colleagues doubt the usefulness of this classification. When comparing patients with early and late onset pneumonia, Mosconi et al. discovered a similar risk of death in both groups (22). This was also concluded by Heyland et al. (15) for the 7 day limit and by Ibrahim et al. (17) for the 4 day limit. Giantsou et al. investigated this question, focussing on pneumonia cases diagnosed by BAL, and came to the same conclusion (12). Hedrick et al. did find some differences in the distribution of organisms in early onset (predominantly gram positives) and late onset (predominantly gram negatives) ventilator-associated pneumonia in trauma surgical patients, but was unable to detect any significant differences in non-trauma surgical patients; no differences in mortality from early an late onset pneumonia were found neither in trauma nor in non-trauma patients (14). Verhamme et al. report that pathogens potentially resistant to multiple drugs were isolated in more than half (52%) of cases in the early onset ICU-acquired pneumonia. However, all these authors used data from individual institutions and their data may not be representative for all intensive care patients. Our analysis, too, has some potential limitations: We used the sensitive, but somewhat less specific, CDC criteria for diagnosing nosocomial infections (9), which can lead to classifying patients as pneumonia patients when there is actually no pneumonia. These criteria 8

9 are mainly based on clinical signs and symptoms as well as on microbiological findings. Since 2005 radiological abnormalities and/or changes are always required in order to diagnose any case of pneumonia. However, there is not always a proven link between the results from the microbiological laboratory and the infection. For example S. maltophilia represents a quite frequently detected bacterium in specimens from the respiratory tract but it is of rather low pathogenicity and thus may in fact not be the actual cause of infection. While interpreting the data the diagnostic quality of the individual ICUs should also be taken into account. Depending upon the type of ICU the frequency of disease and diagnostic effort may differ. Only a subgroup of ICUs routinely perform bronchoalveolar lavage when nosocomial pneumonia is suspected, while others use clinical criteria for diagnosing pneumonia in combination with identification of pathogens from tracheal secretions. Only in 14.3% of the pneumonia cases in our database were the pathogens identified from bronchoalveolar secretions or blood. Some uncertainty therefore remains as to whether some patients are included in our study that, in fact, did not have infection but were colonized by the pathogens only. However, most probably this is true for both groups, though, early as well as late onset pneumonia. In addition the order of frequency did not change substantially when considering the cases diagnosed by BAL quantitative cultures only. Furthermore, as mentioned earlier, up to 4 pathogens can be recorded and referred to the surveillance system for each pneumonia case. By this it is almost impossible to identify one single causative organism for the specific nosocomial infection. Instead all microorganisms were considered equally for this analysis. Moreover usually many different microbiology laboratories are involved in national surveillance systems. Almost all the laboratories in our surveillance system apply standard procedures, though the diagnostic quality may still differ. However, differences in laboratory practice most probably influenced both category groups in the same way. 9

10 Despite the above-mentioned limitations we conclude that our data does confirm classification of the most important pathogens that cause pneumonia. However, in our findings the distribution of pathogens remains unchanged regardless of the time point of onset of symptoms. Thus, in our view the concept of early and late onset pneumonia pathogens is not helpful for the management of empiric antibiotic therapy any more. The empiric antimicrobial therapy should be identical in both groups. Since inadequate initial antimicrobial treatment increases the risk for a fatal outcome of VAP, we recommend starting therapy with broad spectrum antibiotics at high dosages. However, as soon as a microbiological result is available that narrows the spectrum of potential causative agents (which happens usually after approximately 3 days), the current antimicrobial regimen should become modified accordingly. Other diagnostic tools such as rapid Gram staining, urinary Legionella antigen, or a test of multiplex PCR for respiratory viral agents could also contribute to a more rapid diagnosis of the causative agent and thus restrict the antibiotic use. In addition, more randomized controlled trials are necessary that address the issue of risk factors for the development of VAP and the impact of multi drug resistant pathogens on morbidity and mortality due to this disease. REFERENCES 1. Alvarez-Lerma, F Modification of empiric antibiotic treatment in patients with pneumonia acquired in the intensive care unit. ICU-Acquired Pneumonia Study Group. Intensive Care Med. 22:

11 American Thoracic Society Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus statement, November Am. J. Respir. Crit. Care Med. 153: American Thoracic Society Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am. J. Respir. Crit. Care Med. 171: Baker, A. M., J. W. Meredith, and E. F. Haponik Pneumonia in intubated trauma patients. Microbiology and outcomes. Am. J. Respir. Crit. Care Med. 153: Celis, R., A. Torres, J. M. Gatell, M. Almela, R. Rodriguez-Roisin, and A. Agusti- Vidal Nosocomial pneumonia. A multivariate analysis of risk and prognosis. Chest 93: Chastre, J. and J. Y. Fagon Ventilator-associated pneumonia. Am. J. Respir. Crit. Care Med. 165: Dupont, H., H. Mentec, J. P. Sollet, and G. Bleichner Impact of appropriateness of initial antibiotic therapy on the outcome of ventilator-associated pneumonia. Intensive Care Med. 27: Emori, T. G., D. H. Culver, T. C. Horan, W. R. Jarvis, J. W. White, D. R. Olson, S. Banerjee, J. R. Edwards, W. J. Martone, and R. P. Gaynes National nosocomial infections surveillance system (NNIS): description of surveillance methods. Am. J. Infect. Control 19: Garner, J. S., W. R. Jarvis, T. G. Emori, T. C. Horan, and J. M. Hughes CDC definitions for nosocomial infections, Am. J. Infect. Control 16:

12 Gastmeier, P., C. Geffers, D. Sohr, M. Dettenkofer, F. Daschner, and H. Ruden Five years working with the German nosocomial infection surveillance system (Krankenhaus Infektions Surveillance System). Am. J. Infect. Control 31: German National Reference Centre for the Surveillance of Nosocomial Infections Giantsou, E., N. Liratzopoulos, E. Efraimidou, M. Panopoulou, E. Alepopoulou, S. Kartali-Ktenidou, G. I. Minopoulos, S. Zakynthinos, and K. I. Manolas Both early-onset and late-onset ventilator-associated pneumonia are caused mainly by potentially multiresistant bacteria. Intensive Care Med. 31: Giard, M., A. Lepape, B. Allaouchiche, C. Guerin, J. J. Lehot, M. O. Robert, G. Fournier, D. Jacques, D. Chassard, P. Y. Gueugniaud, F. Artru, P. Petit, D. Robert, I. Mohammedi, R. Girard, J. C. Cetre, M. C. Nicolle, J. Grando, J. Fabry, and P. Vanhems Early- and late-onset ventilator-associated pneumonia acquired in the intensive care unit: comparison of risk factors. J. Crit. Care 23: Hedrick, T. L., R. L. Smith, S. T. McElearney, H. L. Evans, P. W. Smith, T. L. Pruett, J. S. Young, and R. G. Sawyer Differences in early- and late-onset ventilator-associated pneumonia between surgical and trauma patients in a combined surgical or trauma intensive care unit. J. Trauma 64: Heyland, D. K., D. J. Cook, L. Griffith, S. P. Keenan, and C. Brun-Buisson The attributable morbidity and mortality of ventilator-associated pneumonia in the critically ill patient. The Canadian Critical Trials Group. Am. J. Respir. Crit. Care Med. 159: Horan, T. C. and R. P. Gaynes Surveillance of nosocomial infections., p In C. G. Mayhall (ed.), Hospital Epidemiology and Infection Control. Lippincott Williams & Wilkins, Philadelphia. 12

13 Ibrahim, E. H., S. Ward, G. Sherman, and M. H. Kollef A comparative analysis of patients with early-onset vs late-onset nosocomial pneumonia in the ICU setting. Chest 117: Kothe, H., T. Bauer, R. Marre, N. Suttorp, T. Welte, and K. Dalhoff Outcome of community-acquired pneumonia: influence of age, residence status and antimicrobial treatment. Eur. Respir. J. 32: Langer, M., M. Cigada, M. Mandelli, P. Mosconi, and G. Tognoni Early onset pneumonia: a multicenter study in intensive care units. Intensive Care Med. 13: Micek, S. T., K. E. Kollef, R. M. Reichley, N. Roubinian, and M. H. Kollef Health care-associated pneumonia and community-acquired pneumonia: a single-center experience. Antimicrob. Agents Chemother. 51: Moine, P., J. F. Timsit, A. De Lassence, G. Troche, J. P. Fosse, C. Alberti, and Y. Cohen Mortality associated with late-onset pneumonia in the intensive care unit: results of a multi-center cohort study. Intensive Care Med. 28: Mosconi, P., M. Langer, M. Cigada, and M. Mandelli Epidemiology and risk factors of pneumonia in critically ill patients. Intensive Care Unit Group for Infection Control. Eur. J. Epidemiol. 7: Prod'hom, G., P. Leuenberger, J. Koerfer, A. Blum, R. Chiolero, M. D. Schaller, C. Perret, O. Spinnler, J. Blondel, H. Siegrist, L. Saghafi, D. Blanc, and P. Francioli Nosocomial pneumonia in mechanically ventilated patients receiving antacid, ranitidine, or sucralfate as prophylaxis for stress ulcer. A randomized controlled trial. Ann. Intern. Med. 120: Torres, A. and J. Carlet Ventilator-associated pneumonia. European Task Force on ventilator-associated pneumonia. Eur. Respir. J. 17:

14 Trouillet, J. L., J. Chastre, A. Vuagnat, M. L. Joly-Guillou, D. Combaux, M. C. Dombret, and C. Gibert Ventilator-associated pneumonia caused by potentially drug-resistant bacteria. Am. J. Respir. Crit. Care Med. 157: Valles, J., A. Pobo, O. Garcia-Esquirol, D. Mariscal, J. Real, and R. Fernandez Excess ICU mortality attributable to ventilator-associated pneumonia: the role of early vs late onset. Intensive Care Med. 33:

15 TABLE 1: The nine most frequent pathogens identified from patients with nosocomial pneumonia on the basis of all materials sent for microbiological investigation or based only on BAL quantitative cultures (KISS ) pathogen identification on the basis of all materials sent for microbiological investigation identification based on BAL quantitative cultures only n = 11,285 % n = 1,609 % S. aureus 2, P. aeruginosa 1, K. pneumoniae 1, E. coli 1, Enterobacter spp S. pneumoniae Haemophilus spp Acinetobacter spp S. maltophilia

16 TABLE 2: Number of pneumonia cases according to the different limits for classification (KISS ) early onset pneumonia late onset pneumonia 1-4 days 1-5 days 1-7 days > 4 th day > 5 th day > 7 th day pneumonia cases 2,235 3,271 5,124 9,050 8,041 6,161 percentage of all pneumonia cases among them ventilator associated percentage of all VAP cases pneumonia cases identified with BAL cultures percentage of all pneumonia cases identified with BAL 19.8 % 29.0 % 45.4 % 80.2 % 71.0 % 54.6 % 1,799 2,705 4,325 8,080 7,174 5, % 27.4 % 43.8 % 81.8 % 72.6 % 56.2 % ,294 1, % 28.8 % 46.4 % 80.4 % 71.2 % 53.6 % 16

17 TABLE 3: Isolates per 100 pneumonia cases for the most frequent micro-organisms together with the order of frequency of the four most frequent pathogens (KISS ) early onset pneumonia late onset pneumonia pathogen 1-4 days 1-5 days 1-7 days > 4 th day > 5 th day > 7 th day (order) (order) (order) (order) (order) (order) S. aureus (1 st ) (1 st ) (1 st ) (1 st ) (1 st ) (1 st ) MSSA MRSA P. aeruginosa (2 nd ) (2 nd ) (2 nd ) (2 nd ) (2 nd ) (2 nd ) K. pneumoniae (3 rd ) (4 th ) (3 rd ) (3 rd ) (3 rd ) (3 rd ) E. coli (4 th ) (3 rd ) (4 th ) (4 th ) (4 th ) (4 th ) S. pneumoniae Enterobacter spp Haemophilus spp Acinetobacter spp S. maltophilia

18 TABLE 4: Relative risks for the comparison of early and late onset isolates per 100 pneumonia cases using the 7 days cut-off for distinguishing both groups (KISS ) # isolates per 100 type of pathogen 307 pneumonia cases according to the relative risk pathogen occurrence of early onset late onset (CI 95) pneumonia* (1-7 days) (>7 days) S. aureus ( ) early MSSA ( ) early MRSA ( ) late P. aeruginosa ( ) late K. pneumoniae ( ) --- E. coli ( ) --- S. pneumoniae ( ) early Enterobacter spp ( ) late Haemophilus spp ( ) early Acinetobacter spp ( ) late S. maltophilia ( ) late * recorded for significant results only 18