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.
1. Kislak JW, Razavi LM, Daly AK, et al. Susceptibility of pneumococci to nine antibiotics. Am J Med Sci
2. Jacobs MR, Koornhof HJ, Robins-Browne RM, et al. Emergence of multiply resistant pneumococci. N Engl J Med
3. Whitney CG, Farley MM, Hadler J, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae
in the United States. N Engl J Med
4. Mera RM, Miller LA, Daniels JJ, et al. Increasing prevalence of multidrug-resistant Streptococcus pneumoniae
in the United States over a 10-year period: Alexander project. Diagn Microbiol Infect Dis
5. Pottumarthy S, Fritsche TR, Jones RN. Comparative activity of oral and parenteral cephalosporins tested against multidrug-resistant Streptococcus pneumoniae
: report from the SENTRY Antimicrobial Surveillance Program (1997-2003). Diagn Microbiol Infect Dis
6. Kelly LJ. Multidrug-resistant pneumococci isolated in the US: 1997-2001 TRUST surveillance (abstract). In: Microbiology ASf, ed. Program and Abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy (Chicago)
. Washington, DC: American Society for Microbiology; 2001:142.
7. Karchmer AW. Increased antibiotic resistance in respiratory tract pathogens: PROTEKT US-an update. Clin Infect Dis
. 2004;39(suppl 3):S142-S150.
8. Doern GV, Richter SS, Miller A, et al. Antimicrobial resistance among Streptococcus pneumoniae
in the United States: have we begun to turn the corner on resistance to certain antimicrobial classes? Clin Infect Dis
9. Fenoll A, Jado I, Vicioso D, et al. Evolution of Streptococcus pneumoniae
serotypes and antibiotic resistance in Spain: update (1990 to 1996). J Clin Microbiol
10. Clavo-Sanchez AJ, Giron-Gonzalez JA, Lopez-Prieto D, et al. Multivariate analysis of risk factors for infection due to penicillin-resistant and multidrug-resistant Streptococcus pneumoniae
: a multicenter study. Clin Infect Dis
11. Ewig S, Kleinfeld T, Bauer T, et al. Comparative validation of prognostic rules for community-acquired pneumonia in an elderly population. Eur Respir J
12. Nava JM, Bella F, Garau J, et al. Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae
: a population-based study. Clin Infect Dis
13. Campbell GD Jr, Silberman R. Drug-resistant Streptococcus pneumoniae
. Clin Infect Dis
14. Bedos JP, Chevret S, Chastang C, et al. Epidemiological features of and risk factors for infection by Streptococcus pneumoniae
strains with diminished susceptibility to penicillin: findings of a French survey. Clin Infect Dis
15. Aspa J, Rajas O, Rodriguez de Castro F, et al. Drug-resistant pneumococcal pneumonia: clinical relevance and related factors. Clin Infect Dis
16. Hyde TB, Gay K, Stephens DS, et al. Macrolide resistance among invasive Streptococcus pneumoniae
17. Moreno S, Garcia-Leoni ME, Cercenado E, et al. Infections caused by erythromycin-resistant Streptococcus pneumoniae
: incidence, risk factors, and response to therapy in a prospective study. Clin Infect Dis
18. Aspa J, Rajas O, Rodriguez de Castro F, et al. Impact of initial antibiotic choice on mortality from pneumococcal pneumonia. Eur Respir J
19. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing: Twelfth Informational Supplement. Document M100-S12. National Committee for Clinical Laboratory Standards. Wayne, PA: Clinical and Laboratory Standards Institute; 2002.
20. Hosmer DW, Lemeshow S. Applied Logistic Regression
. New York: John Wiley and Sons; 1989.
21. Parmar M, Machin D. Survival Analysis. A practical Approach
. New York: John Wiley and Sons; 1995.
22. Fine MJ, Auble TE, Yealy DM, et al. A prediction rule to identify low-risk patients with community-acquired pneumonia. N Engl J Med
23. Karlowsky JA, Thornsberry C, Jones ME, et al. Factors associated with relative rates of antimicrobial resistance among Streptococcus pneumoniae
in the United States: results from the TRUST Surveillance Program (1998-2002). Clin Infect Dis
24. Bauer T, Ewig S, Marcos MA, et al. Streptococcus pneumoniae
in community-acquired pneumonia. How important is drug resistance. Med Clin North Am
25. Talbot TR, Hartert TV, Mitchel E, et al. Asthma as a risk factor for invasive pneumococcal disease. N Engl J Med
26. Pallares R, Linares J, Vadillo M, et al. Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med
27. Feikin DR, Dowell SF, Nwanyanwu OC, et al. Increased carriage of trimethoprim/sulfamethoxazole-resistant Streptococcus pneumoniae
in Malawian children after treatment for malaria with sulfadoxine/pyrimethamine. J Infect Dis
28. Metlay JP, Hofmann J, Cetron MS, et al. Impact of penicillin susceptibility on medical outcomes for adult patients with bacteremic pneumococcal pneumonia. Clin Infect Dis
29. Garcia-Rey C, Aguilar L, Baquero F, et al. Importance of local variations in antibiotic consumption and geographical differences of erythromycin and penicillin resistance in Streptococcus pneumoniae
. J Clin Microbiol
30. Granizo JJ, Aguilar L, Casal J, et al. Streptococcus pneumoniae
resistance to erythromycin and penicillin in relation to macrolide and beta-lactam consumption in Spain (1979-1997). J Antimicrob Chemother
31. Baquero F, Baquero-Artigao G, Canton R, et al. Antibiotic consumption and resistance selection in Streptococcus pneumoniae
. J Antimicrob Chemother
. 2002;50(suppl C):27-38.
32. Guillemot D, Carbon C, Balkau B, et al. Low dosage and long treatment duration of beta-lactam: risk factors for carriage of penicillin-resistant Streptococcus pneumoniae
33. de Galan BE, van Tilburg PM, Sluijter M, et al. Hospital-related outbreak of infection with multidrug-resistant Streptococcus pneumoniae
in the Netherlands. J Hosp Infect
34. Ho PL, Tse WS, Tsang KW, et al. Risk factors for acquisition of levofloxacin-resistant Streptococcus pneumoniae
: a case-control study. Clin Infect Dis
© 2008 Lippincott Williams & Wilkins, Inc.
35. Librero J, Peiro S, Ordinana R. Chronic comorbidity and outcomes of hospital care: length of stay, mortality, and readmission at 30 and 365 days. J Clin Epidemiol