Infectious Diseases in Clinical Practice:
Risk Factors for Multidrug-Resistant Pneumococcal Pneumonia
Aspa, Javier PhD*; Rajas, Olga PhD*; Rodríguez de Castro, Felipe PhD†; Torres, Antoni PhD‡; Blanquer, José PhD§; Zalacain, Rafael MD∥; Vendrell, Montserrat PhD¶; Gallego, Miguel PhD#; Puzo, Carmen MD**; Andreu, Felipe PhD††; Menéndez, Rosario PhD‡‡; Martínez, Eva MD§§; Roig, Jordi PhD∥∥; Martín, Juan PhD¶¶; Benítez, José María MD##; Melchor, Rosario PhD***; González, Rocío PhD†††; Tillotson, Glenn PhD‡‡‡; on behalf of The Pneumococcal Pneumonia in Spain Study Group
*Hospital de la Princesa, Madrid; †Hospital de Gran Canaria Dr. Negrín, Las Palmas; ‡Institut Clínic de Pneumología i Cirugía Torácica, Hospital Clínic, Barcelona; §Hospital Clínico de Valencia, Valencia; ∥Hospital de Cruces, Bilbao; ¶Hospital Dr. Josep Trueta, Girona; #CH Parc Taulí; **Hospital Santa Creu i Sant Pau; ††Hospital Germans Trias i Pujol, Barcelona; ‡‡Hospital La Fe; §§Hospital de Sagunto, Valencia; ∥∥Hospital Ntra. Sra. de Meritxell, Andorra; ¶¶Hospital Carlos Haya, Málaga; ##Hospital Virgen Macarena, Sevilla; ***Fundación Jiménez Díaz, Madrid; †††Fundación de Investigación, Unidad de Epidemiología Clínica, Hospital de la Princesa, Madrid, Spain; ‡‡‡Replidyne Inc, Milford, CT; and §§§Grupo TIR, Sociedad Española de Neumología y Cirugía Torácica (SEPAR), Barcelona, Spain.
This study was designed by an ad hoc Scientific Committee created by the "Sociedad Española de Neumologia y Cirugía Torácica (SEPAR)" through its "Area de Tuberculosis e Infecciones Respiratorias (TIR)." An independent firm (Pharma Consult Madrid) was engaged to carry out the administrative management, the cost of which was paid by AVENTIS. Expenses arising from the study on antibiotic sensitivity of pneumococcal strains and their serotypes, performed in the "Centro Nacional de Microbiología" (Majadahonda, Madrid), were supported by a grant from the Fundación RESPIRA, Fundación Española del Pulmón. Data analysis was carried out by the signatory authors of this manuscript with support of the Red-Respira (RTIC C03/11). The final manuscript was approved by all the named authors, and care was taken to ensure the integrity of the work. All the authors fulfill the authorship criteria and declare no competing interests.
Address correspondence and reprint requests to Javier Aspa, Olga Rajas, Servicio de Neumología, Hospital Universitario de la Princesa, C/Diego de León, 62 28006, Madrid, Spain. E-mail: email@example.com.
Background: Several patient-related factors for acquisition of penicillin/erythromycin-resistant pneumococcal community-acquired pneumonia (CAP) have been reported. However, risk factors associated with CAP caused by multidrug-resistant Streptococcus pneumoniae (MDRSP) have not been extensively studied.
Methods: From January 1999 to April 2000, a prospective-multicenter study was conducted in 35 Spanish hospitals to determine the risk factors associated with CAP caused by MDRSP. Pneumococci resistant to multiple antimicrobial agents were defined by the presence of intermediate or high-level resistance to penicillin plus intermediate resistance/resistance to ≥2 non-β-lactam agents (erythromycin, tetracycline, vanco mycin, chloramphenicol, or respiratory quinolones).
Results: One hundred forty-two of 638 isolates were found to be MDRSP. The 30-day survival probability was 79.5 and 86.6 for MDRSP-CAP and non-MDRSP-CAP, respectively (P = 0.059). Using multivariate survival analysis, only shock (hazard ratio: 16.4) showed an association with 30-day mortality in MDRSP-CAP. Multivariate analysis showed that asthma (odds ratio [OR], 2.17), HIV infection (OR, 1.97), previous hospital admission (OR, 1.75), nursing home residence (OR, 2.94), and Pneumonia Severity Index (PSI) classes ≥ III (PSI-III, P = 0.008; PSI-IV, P = 0.022; PSI-V, P = 0.005) were significantly associated with MDRSP-CAP.
Conclusions: Pneumonia Severity Index score, asthma, HIV infection, previous hospital admission, and nursing home residence are risk factors for MDRSP in CAP patient.
The first Streptococcus pneumoniae infection resistant to penicillin emerged in Boston in 1965.1 A few years after this initial description, Jacobs et al2 reported the emergence of pneumococci resistant to multiple antimicrobial agents in Durban, South Africa. After this sentinel report, multidrug-resistant S. pneumoniae (MDRSP) have become a widespread problem. When only invasive pneumococcal disease was considered, the proportion MDRSP increased from 9% to 14% between 1995 and 1998 in the United States.3 A global surveillance study (Alexander Project, 1992-2001),4 which collected strains (sputum and blood) isolated from upper and lower respiratory tract infections, proved that the combined resistance to penicillin and erythromycin had increased 4.9 times, up to 15.3%, and that 3 of 4 penicillin-resistant S. pneumoniae isolates were also multiresistant. A report from the SENTRY Antimicrobial Surveillance Program (1997-2003),5 with pneumococcal strains obtained mainly from community-acquired respiratory tract infections (70.7%) and bloodstream infections (19.5%), showed that the multiple resistance rate ranged from 17.6% (penicillin and erythromycin resistance only) to 5.7% (resistance to 5 drugs). An evaluation of 6362 S. pneumoniae isolates collected during the 2000-2001 community-acquired respiratory tract infection season showed that 88.1% and 80.2% of the 1077 isolates with high-level penicillin resistance were also resistant to trimethoprim-sulfamethoxazole and azithromycin, respectively.6 The Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin study also showed a steady rise in pneumococcal resistance (respiratory isolates) among common antibiotics as well as an increase in MDRSP.7 Doern et al,8 in 1817 S. pneumoniae isolates obtained from patients with community-acquired respiratory tract infections in 44 US medical centers (2002-2003), reported that 22.2% of isolates were multidrug resistant. Samples for this study were obtained from middle ear fluid, sinus aspirates, cerebrospinal fluid, blood cultures, sputum, and bronchoalveolar lavage. Finally, in Spain, Fenoll et al,9 in a report from the National Pneumococcal Laboratory Reference (1990-96), have also described that multiple drug-resistant strains are steadily increasing, with rates ranging from 1.1% in 1979 to 1984 to 7.7% in 1985 to 1989 and 12.5% in 1990 to 1996 (9.5% in 1990 to 16.6% in 1996). The collection of isolates was mainly from invasive sources (51%) and, in the case of noninvasive samples, mainly from sputum (15.6%).
There is widespread variability in the resistance trends identified, depending on factors such as the respiratory specimen evaluated, the class of the antimicrobial agent tested, the geographic region where the isolate was collected, and various patient characteristics. Several patient-related factors for acquisition of penicillin-resistant pneumococci have been reported.10-15 However, factors associated with the acquisition of pneumonia caused by erythromycin-resistant or MDRSP have been less frequently addressed.15-17 We have conducted a prospective multicenter study to analyze the risk factors for community-acquired pneumonia (CAP) caused by MDRSP.
Study Population and Diagnostic Criteria
From January 1999 to April 2000, 682 consecutive adults older than 18 years with community-acquired pneumococcal pneumonia (CAP-SP) were included from 35 Spanish hospitals geographically distributed across the nation.15,18 Community-acquired pneumonia was assumed in the presence of acute onset of signs and symptoms suggesting lower respiratory tract infection and radiographic evidence of a new pulmonary infiltrate that neither was preexisting nor had another known cause. Microbial investigation techniques, administration of antimicrobial agents, and other therapies were left to the discretion of the attending physician. Investigators of every collaborative institution prospectively collected all data, according to a standardized protocol. A diagnosis of probable CAP-SP was made in cases of predominance of gram-positive cocci in pairs and chains and heavy growth of S. pneumoniae in sputum (validated by gram stain and cytology examination) and/or tracheobronchial aspirates. A definite diagnosis of pneumococcal pneumonia was considered with one of the following criteria: (1) at least 1 blood, pleural fluid, or transthoracic-needle-aspiration culture positive for S. pneumoniae; (2) bacterial growth ≥103 colony-forming units per milliliter (CFU/mL) of S. pneumoniae from a protected-specimen brush and/or ≥104 CFU/mL in bronchoalveolar lavage; (3) positive urinary antigen (Binax-NOW, Portland, ME) for S. pneumoniae with a diagnosis of probable pneumococcal pneumonia.
Antimicrobial Susceptibility Testing
Pneumococcal isolates were available for examination from every patient included in the study. All pneumococcal isolates were submitted to the National Center of Microbiology for serotyping9,15 and antimicrobial susceptibility verification according to the National Committee and Clinical Laboratory Standards-2002.19 The following antibiotics were tested: penicillin, amoxicillin, cefuroxime, cefotaxime, imipenem, vancomycin, teicoplanin, erythromycin, tetracycline, chloramphenicol, levofloxacin, and trovafloxacin. Levofloxacin and trovafloxacin were considered to be equivalent with regard to resistance; clarithromycin, azithromycin, and erythromycin were also considered equivalent in terms of susceptibility/resistance. Multiresistance was defined as intermediate or resistant to penicillin plus intermediate or resistant to at least 2 non-β-lactam agents. According to this definition, 142 pneumococcal isolates were considered to be multiresistant.
Data Collection and Definitions
Baseline data and clinical, laboratory, and radiographic findings were collected by clinical researchers using a standardized data collection. Suspected aspiration was established on clinical evidence. The presence of asthma, HIV infection, and diabetes were assessed for all patients.
Results are expressed as mean ± SD. Continuous variables were compared using Students t test; categorical variables were compared using Fisher exact test and the χ2 test (with Yates correction, when necessary). To define which variables were significantly and independently associated with resistance, regression logistic analyses that tested several models were performed. Significance was defined as P < 0.05. The choice of models was performed on the basis of the criteria defined by Hosmer and Lemeshow.20 Age and nursing home residence are variables included in the Pneumonia Severity Index (PSI) score, another variable included in our analysis, so for the final analysis, we used several models, including those that assess the potential interaction between these variables. For the analysis of factors related to 30-day survival probability, we used the same schedule previously published by our group.18 The independent variables are shown in Table 3. Survival curves were constructed according to the methods of Kaplan and Meier, and comparisons of the survival curves were performed with a 2-sided log-rank test. Multivariate analyses were performed with the use of a Cox proportional-hazards regression model to identify variables that were independently predictive of outcome.21 Those variables showing an association with survival in the univariate analysis with significance level of P < 0.2 were included in the Cox model. Data were analyzed using computer software (SPSS 10.0). Institutional review board approval was obtained according to local requirements.
One hundred forty-two (22.2%) of the 638 patients initially recruited fulfill the operative definition of MDRS. The mean age of patients infected with an MDRSP strain was 65 years (95% confidence interval [CI]: 62.1-68), and 60.9 years (95% CI: 59.3-62.6; P = 0.018) for patients infected with susceptible or single-drug-resistant pneumococcal isolates. Eighty-nine (62.7%; 95% CI: 54.2-70.6) MDRSP patients were male; 16 (11.3%; 95% CI: 6.6-17.7) lived in a nursing home residence; 15 (10.6%; 95% CI: 6-16.8) had previously received β-lactam treatment; 28 (19.7%; 95% CI: 13.5-27.2) had had a previous hospital admission; 19 (13.4%; 95% CI: 8.3-20.1) had been diagnosed with HIV infection; and 14 (9.9%; 95% CI: 5.5-16) had asthma. The yields of the various microbiological investigations are shown in Table 1. Susceptibiliites of isolated S. pneumoniae are shown in Table 2.
The 30-day survival probability of the MDRSP-CAP cohort was 79.5 (95% CI: 76-83), and 86.6 (95% CI: 85-88.2) among non-MDRSP-CAP patients (P = 0.059). The univariate survival analysis of factors related to 30-day mortality in MDRSP-CAP patients is shown in Table 3. Using multivariate survival analysis, only shock (hazard ratio: 16.4; 95% CI: 7-38.45; P < 0.0001) showed association with 30-day mortality.
Among multiresistant pneumococcal isolates, serotype 19 was the predominant (28.3%), followed by serotype 6B (22.5%), 23F (19.1%), and 14 (15.5%). The frequencies of different serotypes in the studied population are shown in Table 4.
Logistic regression determined that MDRSP was more likely to be isolated in CAP-SP patients with asthma (odds ratio [OR], 2.17; 95% CI, 1.08-4.36; P = 0.030) and with HIV infection (OR, 1.97; 95% CI, 1.06-3.65; P = 0.031), in those previously admitted to hospital (OR, 1.75; 95% CI, 1.05-2.91; P = 0.033), and in nursing home residents (OR, 2.94; 95% CI, 1.43-26; P = 0.003) (Table 5). Using the PSI class I as reference category, the variable PSI as a whole was almost significant (P = 0.054). When every category of this variable was compared with the reference group (PSI class I), the regression analysis showed that PSI classes III (P = 0.008), IV (P = 0.022), and V (P = 0.005) were significantly associated with MDRSP-CAP (Table 5).
The most important findings of this study are that CAP-SP adult patients with asthma, high PSI scores, HIV infection, and recent hospital admissions, or those living in nursing homes are more likely to be infected with multidrug-resistant strains. Using the same population, we have previously reported an analysis of factors related to decreased susceptibility to penicillin. In that study,15 we found that chronic pulmonary disease, HIV infection, clinically suspected aspiration, and previous hospital admission were independent risk factors for penicillin resistance. Previous hospital admission and decreased susceptibility to penicillin were also significantly more frequent in patients with erythromycin-resistant pneumococcal pneumonia. When MDRSP strains are now considered, PSI score, asthma, and nursing home residence are shown to be new risk factors.
Several risk factors for penicillin-resistant/erythromycin-resistant pneumococci have been reported by different authors, including us,10-17,23,24 but the risk factors for pneumonia caused by MDRSP have been studied less frequently. Clavo-Sanchez et al,10 in a multicenter study including 95 patients with pneumococcal disease, detected age younger than 5 years or of 65 years or older and previous use of β-lactam antibiotics as parameters associated with increased risk. In our study, only CAP-SP adult patients are included, and therefore, we cannot assess if those pneumococcal pneumonia patients with less than 5 years have an increased risk of having an MDRSP strain. On the other hand, we did not find in our series that older patients had an increased risk. It is important to note that age is a key component of the PSI score and might be considered as a potential surrogate marker for other comorbidities or patient characteristics, such as nursing home residence, an associated risk factor in our study. Logistic regression analysis showed the PSI score close to the significance level. When every category of the variable was compared with the reference category (PSI class I), the PSI classes III, IV, and V had OR values of 3.6, 2.9, and 3.7, respectively.
Talbot et al25 have recently reported that asthma is an independent risk factor for invasive pneumococcal disease. These authors concluded that the risk among persons with asthma is at least double that among controls. According to the authors, chronic inflammation and impaired clearance of asthmatic airways may serve as a focus for localized infection that can develop into invasive bacterial infection. However, several surveillance studies have reported lower rates of antimicrobial resistance among pneumococcal isolates from blood or cerebral spinal fluid.11,26-28 In our series, it is noticeable that the yield of sputum culture is higher in the MDRSP subgroup than in the whole series: 60/142 (42.3%) versus 181/638 (28.4%), respectively (Table 1). In contrast, the yield of blood culture shows opposite results [(67/142 (42.2%) vs 427/638 (67%)]. The high rates of resistance to multiple agents observed in asthma patients may better reflect selection pressure from more liberal use of antimicrobials.29-31 This is not unexpected considering that these patients are more likely to be hospitalized and receive antibiotics, factors repeatedly associated with penicillin-resistant pneumococci.12 In our series, we have only tested previous β-lactam treatment and not the consumption of other antibiotics possibly involved such us macrolides or respiratory quinolones. Nevertheless, we could not assess the relationship between previous β-lactam treatment and MDRSP infection. The limited number of patients with previous β-lactams (9.7%) in our series might preclude their identification as potential risk factors for MDRSP. Moreover, a longer interval for assessing "prior exposure to β-lactams" should have been considered to test this association in our study.
A significant relationship between the prolonged use of β-lactams and the carriage of pneumococcal resistant strains has been established in children, particularly when low doses of antibiotics are used.32 A change in the nasopharyngeal carriage of resistant pneumococci could also be related to the clinical scenarios we try to depict: high PSI score, nursing home residence, previous hospital admission, or HIV-infected patient, and perhaps the previous performance status could be closely related to the infection with MDRSP. Chronic obstructive pulmonary disease has been identified as a major risk factor for acquisition of MDRSP during a nosocomial outbreak in The Netherlands,33 probably because the spread of pneumococci is biased toward the most vulnerable patients. Ho et al34 also reported that patients with chronic obstructive pulmonary disease could be an important reservoir of levofloxacin-resistant pneumococci.
In this study, the 30-day survival probability was 79.5 for MDRSP-CAP and 86.6 for non-MDRSP patients (P = 0.059). It is reasonable to assume that an inadequate antimicrobial therapy leads to an excess of mortality. However, this is only true in some patients. In another study using this same series of patients, we analyzed the impact of initial antibiotic choice on mortality18 and found that when the entire population was evaluated, neither the initially prescribed antimicrobial regimen nor its concordance was independently associated with mortality. We also evaluated some clinically relevant situations, mainly patients in intensive care units and those with renal failure, chronic lung disease and bacteremic pneumonia or with PSI class >III. In this latter case, the initial antimicrobial choice was associated with mortality. This means that in patients with PSI class >III, the choice of an antimicrobial regimen other than β-lactam monotherapy, macrolide monotherapy, β-lactam + macrolide, or levofloxacin alone or in combination was associated with higher mortality. In the current study, using multivariate survival analysis, only shock (hazard ratio: 16.4; P < 0.0001) showed an association with 30-day mortality. This could represent that even in the case of MDRSP-CAP patients, the cascade of events related to inflammation is more important than the level of antibiotic resistance. Current levels of penicillin resistance rarely exceed minimum inhibitory concentrations of 2 μg/mL,15 and, in general, serum and pulmonary levels achieved with β-lactams are several times higher. Therefore, even high-level penicillin-resistant strains may be successfully treated if high enough doses of penicillin, in frequent enough dosing intervals, are given. In the current study, discordant antimicrobial therapy is not related to 30-day mortality in the univariate analysis (Table 3).
In this article, we have analyzed various factors related to pneumonia caused by MDRSP in a multicenter-selected adult population. It should be noted that although there is a clear association between high PSI score, asthma, HIV infection, previous hospital admission, and living in nursing homes and multi-drug-resistant pneumococcal infection, it is possible that some biases have been made, especially those related to the previous use of different antibiotics and the real performance status of patients. In this sense, the Charlson Index35 could be a suitable tool to use in the future.
Pneumococcal Pneumonia in Spain Study Group. Participating physicians and number of patients included per hospital (in brackets): (1) H. Universitario Puerto Real (Cadiz) (9 patients). Antonio Vargas (PML); Iria de la Calle (MCR). (2) H. Virgen Macarena (Sevilla) (11 patients). José Ma. Benítez (PML); Ma. José Espinosa (MCR). (3) H. Gral. Serranía De Ronda (Malaga) (25 patients). Francisco Cabello (PML); Ana López (PML); Ma. Jesús Pérez (MCR). (4) H. Carlos Haya (Malaga) (13 patients). Juan Martín (PML); Marta Arzola (PML); Pedro Manchado (MCR). (5) H. Juan Ramón Jimenez (Huelva) (30 patients). Carmen Huertas (PML); José Ma. Saavedra (MCR); José García (PML). (6) H. Clínico Universitario (Valencia) (39 patients). José Blanquer (ICU-PML); Diego Pérez (PML); Rafael Borras (MCR). (7) H. Universitario Doctor Peset (Valencia) (6 patients). Rafael Blanquer (PML); Ángela Cervera (PML); José Cervera (MCR). (8) H. Francesc De Borja (Valencia) (7 patients). Ma. Jesús Cremades (PML); Carlos Navarro (PML); Rafael Igual (MCR). (9) H. Marina Baixa (Alicante) (20 patients). Adela Martínez (PML); José Calpe (PML); Mar López (MCR). (10) H. La Fe (Valencia) (18 patients). Rosario Menéndez (PML); José Vallés (PML); Miguel Gobernado (MCR). (11) H. De Sagunto (Valencia) (16 patients). Eva Martínez (PML); Estrella Fernández (PML); Rosa Escoms (MCR). (12) H. Los Arcos (Murcia) (7 patients). Ma. Jesús Avilés (PML); Margarita Cámara (MCR). (13) H. Universitario De La Princesa (Madrid) (65 patients). Javier Aspa (PML); Olga Rajas (PML); Buenaventura Buendía (MCR). (14) C.H. Ntra Sra De Alarcos (Ciudad Real) (4 patients). Amir Mohamed (PML); Fernando Mora (MCR); Dolores Romero (MCR). (15) H. Doce De Octubre (Madrid) (5 patients). Carlos Álvarez (PML); Dolores Folgueira (MCR); Manuel Lizasoaín (PML). (16) H. Militar Del Aire (Madrid) (9 patients). Javier Jareño (PML); Ma. Jesús Chillón (PML); Francisco Villegas (PML). (17) Fundación Jimenez Díaz (Madrid) (10 patients). Rosario Melchor (PML); Javier García (PML); Ricardo Fernández (MCR). (18) H. Universitario De Guadalajara (Guadalajara) (2 patients). José Gallardo (PML); Jorge Castelao (PML); Teresa Pérez (MCR). (19) H. De Cruces (Vizcaya) (49 patients). Rafael Zalacain (PML); Ainhoa Gómez (PML); José Hernández (MCR). (20) H. San Millan-San Pedro (Logroño) (7 patients). Manuel Barrón (PML); Ma. José Gastañares (MCR); Ma. Jesús Hermosa (PML). (21) H. Cristal Piñor (Orense) (25 patients). Julia Tábara (PML); Joaquín Lamela (PML); Luis Barbeito (MCR). (22) H. San Jorge (Huesca) (27 patients). Luis Borderías (PML); Miguel Ferrero (MCR). (23) H.U. De Canarias (La Laguna, Tenerife) (2 patients). Ramón Fernández (PML); José Gullón (PML); Álvaro Torres (MCR). (24) H. Central De Asturias (Asturias) (9 patients). Luis Molinos (PML); Isabel Folgueras (MCR). (25) H. Universitario Doctor Negrin (Gran Canaria) (12 patients). Felipe Rodríguez de Castro (PML); Isabel Álamo (MCR). (26) H. De Galdakao (Vizcaya) (37 patients). Pedro P. España (PML); Inmaculada Gorordo (PML); Pilar Berdonoes (MCR). (27) H. Clinico (Barcelona) (26 patients). Rosa de Celis (PML); Francesc Marco (MCR); Antoni Torres (PML). (28) H. Comarcal De Igualada (Barcelona) (6 patients). Ma. José Cardona (PML); Carmen Sarrasela (MCR); Jordi Zapater (PML). (29) C.H. Parc Tauli (Barcelona) (37 patients). Jordi Rello (ICU-PML); Miguel Gallego (PML)/Manuel Lujan (PML); Dionisia Fontanals (MCR). (30) H. Sant Joan (Tarragona) (23 patients). Salvador Hernández (PML); Rosa Tomás (PML); Frederic Ballester (MCR). (31) H. Municipal Badalona (Barcelona) (3 patients). Jaume Oriol (PML); Ignacio Carrasco (PML); Ana Calderón (MCR). (32) H. Santa Creu I Sant Pau (Barcelona) (19 patients). Carmen Puzo (PML); Julia Tárrega (PML); Ferran Sánchez (MCR). (33) H. Nostra Sra De Meritxell (Andorra) (14 patients). Jordi Roig (PML); Juan Martínez (PML); Xavier Casal (MCR). (34) H. Germans Trias I Pujol (Barcelona) (19 patients). Juan Ruiz (PML); Felipe Andreu (PML); José Manterola (MCR). (35) H.U. Dr. Josep Trueta (Girona) (27 patients). Montserrat Vendrell (PML); Antonio Castro (IRM); Jordi Batlle (MCR). H indicates hospital; PML, pulmonologist; MCR, microbiologist; IRM, internal medicine; ICU-PML, respiratory intensive care unit.
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