Eur J Clin Microbiol Infect Dis (2007) 26:247253 DOI 10.

1007/s10096-007-0283-7

ARTICLE

Streptococcus pneumoniae skin and soft tissue infections: characterization of causative strains and clinical illness
J. M. Garcia-Lechuz & O. Cuevas & C. Castellares & C. Perez-Fernandez & E. Cercenado & E. Bouza & Spanish Pneumococcal Study Network

Received: 4 August 2006 / Accepted: 19 January 2007 / Published online: 20 March 2007 # Springer-Verlag 2007

Abstract Streptococcus pneumoniae is an uncommon cause of skin and soft tissue infections, yet the incidence and clinical significance of its isolation in samples of skin or soft tissues in unselected hospital samples is poorly understood. In the present study, a review was conducted of the records of all patients with skin and soft tissue infections due to S. pneumoniae at a university hospital between January 1994 and December 2005. The isolates were identified by standard methods and were serotyped, and susceptibility testing was performed by the broth microdilution method following the guidelines of the Clinical and Laboratory Standards Institute. During the study period, 3,201 isolates of S. pneumoniae were recovered from several sources. Of these, 69 (2.2%) were from skin and soft tissue samples (69 patients). Complete information could not be obtained for 13 patients. Of the 56 patients remaining, 36 (64.3%) were infected and fulfilled the inclusion criteria. The following types of infections were observed: surgical wound infection (n=11), burn infection (n=7), pyomyositis (n=6), cellulitis (n=4), perineal or scrotal abscess (n=3), and other (n=5). Thirty-one (86%) patients had a favorable outcome, and 5 (13.8%) patients died. Mortality was directly attributable to S. pneumoniae infection in three of the five fatal cases. Of the 39 S. pneumoniae isolates obtained (36 from skin and

soft tissues, three from blood cultures), 58.9% were penicillin nonsusceptible, 7.7% were cefotaxime nonsusceptible, and 20.5% were erythromycin resistant. The most frequent serotypes were 3, 19, 11, and 23. Of the overall number of isolates of S. pneumoniae recovered in a general institution, 2.2% involved skin and soft tissues (of which 64% were clinically significant). Mortality due to pneumococcal skin and soft tissue infections was low.

Introduction Streptococcus pneumoniae may be either a colonizer of the skin and soft tissues or a pathogen. As a pathogen, it causes clinical diseases that vary widely in prognosis and severity [1, 2]. Its pathogenic role in pneumonia, otitis media, bacteremia, and meningitis is undisputed. Nevertheless, the isolation of S. pneumoniae from skin and soft tissues is an unusual finding with difficult clinical interpretation [3] that can range from simple colonization in immunocompetent hosts to severe infection in patients with different underlying conditions [36]. Moreover, there are very few data on the antimicrobial susceptibility of S. pneumoniae isolated from skin and soft tissues [7, 8]. In this study, we evaluated the clinical significance of S. pneumoniae isolated from skin and soft tissues in a large teaching hospital as well as the characteristics of those patients who were infected. We also determined the antimicrobial susceptibility patterns and the serotypes of the strains involved.

R. Pallars, coordinator (e-mail: rpallares@bell.ub.es) J. M. Garcia-Lechuz (*) : O. Cuevas : C. Castellares : C. Perez-Fernandez : E. Cercenado : E. Bouza Department of Clinical Microbiology and Infectious DiseasesHIV, Hospital General Universitario Gregorio Maran, Dr. Esquerdo 46, 28007 Madrid, Spain e-mail: lechuz@efd.net

Materials and methods The study was performed in a 1,750-bed general, teaching, and referral hospital serving a population of approximately

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650,000 inhabitants in Madrid. The records of all patients in whom S. pneumoniae was isolated from skin and soft tissues from January 1994 to December 2005 were reviewed retrospectively. Data were recorded using a uniform protocol that included age, sex, hospital ward, underlying disease(s), clinical condition, factors associated with the infection, place of acquisition, and outcome. Cases with insufficient clinical data were rejected. Patients were classified as having been either infected or colonized by S. pneumoniae. Infection was defined as the appearance of clinical signs plus positive culture (S. pneumoniae) of either wound exudates collected by fine-needle aspiration or surgical specimens (tissue biopsies and abscess). Colonization was defined as the isolation of S. pneumoniae in wound exudates collected by swabbing or the isolation of a polymicrobial flora with more than two microorganisms, in the absence of clinical signs of infection. In the cases in which S. pneumoniae and another microorganism were isolated in a clinically significant sample, we did not attribute the sole pathogenicity of the infection to S. pneumoniae. The results at the end of the treatment were classified as follows: (a) favorable (clearing of signs and symptoms of infection at the site of infection) or (b) failure (absence of clinical response, with persistence of skin and soft tissue infection that required modification of antibiotic treatment and intensified surgical therapy). Isolates were identified by sensitivity to optochin, capsule production, and lysis by bile salts (deoxycholate) [9]. Serotyping was performed with standard antisera at the National Reference Laboratory for Microbiology, Virology and Immunology (Majadahonda, Madrid, Spain). Antimicrobial susceptibility testing was performed by the broth microdilution method with 5% lysed horse blood following Clinical and Laboratory Standards Institute (CLSI) guidelines. The criteria of the CLSI were used for the definition of resistance or susceptibility to the antimicrobial agents studied [10]. The breakpoints used in the susceptibility study were those used for nonmeningeal isolates: penicillin-nonsusceptible, MIC0.12 mg/l; cefotaxime-nonsusceptible, MIC2 mg/l; and erythromycinresistant, MIC1 mg/l. All statistical analyses were performed with SPSS (version 8.0, SPSS, Chicago IL, USA) and Microsoft Access. Qualitative variables are described as percentages, and quantitative variables are reported as the mean and standard deviation.

Results Over the 12-year study period, 3,201 isolates of S. pneumoniae were obtained in our institution. Of these, 1,054 were isolated from blood and 2,147 from other

sources. Sixty-nine isolates (2.15%) from 69 patients were from skin and soft tissue samples. We were able to retrieve significant clinical information from 56 cases, which represent the basis of this report. Twenty (35.7%) patients had S. pneumoniae isolates that were not considered clinically significant (colonization) and were excluded from further analysis. Finally, 36 (64.3%) patients were evaluated as being infected by S. pneumoniae. These 36 cases corresponded to 25 adults (14 males and 11 females) and 11 children (seven males and four females). The adults ranged in age from 21 to 91 years (60.5 19.9 years, meanSD) and children from 1 to 15 years (11.46.2 months). Tables 1 and 2 summarize the clinical characteristics of the patients and the results of susceptibility testing and serotyping. The main underlying conditions of patients were burns, HIV infection, diabetes mellitus, cancer, alcoholism, and various entities related to immunosuppression. Seven patients presented with pneumococcal infection without known pre-existing underlying disease. The main clinical infections included surgical site infection (11 cases), burn infection (seven cases), pyomyositis (six cases), cellulitis (four cases) (Fig. 1), perineal or scrotal abscess (three cases), corneal abscess (two cases), pustulosis (one case), fasciitis (one case), and mucous ulcer (one case). There were no differential clinical signs for other types of soft tissue infections. Blood cultures were taken in 19 (52.7%) cases, and S. pneumoniae was isolated in 3 (15.8%). Infections were polymicrobial (two bacteria) in 18 (50%) cases, with the following isolated in addition to S. pneumoniae: Staphylococcus aureus (seven cases), Escherichia coli (four cases), anaerobes (three cases), Haemophilus influenzae (two cases), and Pseudomonas aeruginosa (two cases). Infections were community acquired in 55.5% of the cases. Thirty-two of the 39 isolates were serotyped (two had unknown serotypes, and five were nontypable). Serotypes 3, 19, 11, and 23 were the most frequent (Table 2). Antimicrobial susceptibility testing showed that 58.9% (23/39) of the isolates were nonsusceptible to penicillin (MIC0.12 mg/l), 7.7% (3/39) were nonsusceptible to cefotaxime (MIC2 mg/l), and 20.5% (8/39) were erythromycin resistant (MIC1 mg/l). Antimicrobial therapy was administered in 89% of the cases. Surgical debridement or drainage was performed in 63.8% of cases (both were performed in 22 cases, 61%). Outcome was favorable in 31 (86%) patients, despite inadequate antimicrobial treatment in nine patients. Treatment failure was observed in four patients, and one patient was lost to follow-up after discharge. Overall mortality was 13.8% (5/36), but only in three cases was death directly attributable to infection (fulminant sepsis in two cases).

Eur J Clin Microbiol Infect Dis (2007) 26:247253 Table 1 Characteristics of patients with S. pneumoniae soft tissue infections between 1994 and 2005 Patient no. Age of adult patients (years) 32 44 87 76 30 68 91 83 48 54 74 73 42 83 49 15 11 3 15 2 14 14 13 59 11 23 85 21 4 37 41 40 81 43 59 Age of pediatric patients (months) Sex Hospital department Underlying disease or condition Clinical source of infection Blood cultures drawn Positive blood culture

249

Isolation of mono- vs. polymicrobial flora Poly Mono Poly Poly Poly Poly Mono Mono Mono Poly Mono Poly Poly Poly Mono Poly Poly Mono Mono Poly Poly Poly Poly Mono Mono Mono Poly Poly Poly Mono Mono Mono Mono Mono Mono

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

F M F F M M M F M M F F M F M F M M F M F M M M F M M F M M M F F M M

General General surgery General surgery ICU HIV Emergency room Ophthalmology ICU Plastic surgery General surgery General surgery Oncology Oncology Neurology Thoracic surgery Pediatric Pediatric General surgery Pediatric Pediatric surgery Pediatric Pediatric Pediatric Respiratory diseases Pediatric surgery Neonatology ENT Plastic surgery Neurosurgery Nephrology HIV HIV Orthopedic HIV Ophthalmology

HIV None Diabetes None HIV Alcoholism None Diabetes Alcoholism None Diabetes Cancer Cancer Psoriasis None Obesity Burns Burns Burns Burns Burns Burns Burns COPD HIV None COPD None Myelomeningocele SLE HIV HIV Dementia, COPD Trauma Diabetes

Pyomyositis Pyomyositis SWI SWI SWI Pyomyositis Other (corneal abscess) Cellulitis LL Pyomyositis SWI SWI SWI SWI Pustules SWI Abscess Burn infection Burn infection Burn infection Burn infection Burn infection Burn infection Burn infection Pyomyositis Abscess Other (mucous sore) SWI SWI Cellulitis LL Cellulitis Fasciitis UL Pyomyositis SWI Cellulitis Other (corneal abscess, endophthalmitis) Scrotal abscess

Yes No Yes Yes No Yes Yes Yes No Yes No Yes Yes Yes No No No No No No Yes No Yes Yes No Yes Yes No No Yes Yes No No Yes Yes

No No No No No Yes No No No No No No No Yes No Yes No No No

36

30

Emergency room

CVID

No

Mono

COPD chronic obstructive pulmonary disease, HIV human immunodeficiency virus, SLE systemic lupus erythematosus, CVID common variable immunodeficiency, SWI surgical wound infection, LL lower limb, UL upper limb

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Table 2 Results of susceptibility testing and serotyping of S. pneumoniae isolates causing soft tissue infections between 1994 and 2005, along with results of therapy Patient no. Penicillin MIC (mg/l) 0.12a 0.03 0.25a 1a 4a 0.03 0.03 0.03 0.5a 0.03 0.03 2a 0.03 1a 1a 1a 1a 0.03 2a 2a 2a 1a 2a 0.03 2a 4a 0.25a 0.03 0.03 1a 0.03 0.03 0.03 0.5a 2a 0.03 Cefotaxime MIC (mg/l) 0.12 0.06 0.06 0.5 2b 0.06 0.06 0.06 0.25 0.06 0.06 1 0.06 0.5 0.06 0.5 1 0.06 1 1 1 0.5 1 0.06 1 2b 0.06 0.06 0.06 0.06 0.06 0.06 0.06 0.06 1 0.06 Erythromycin MIC (mg/l) 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.25 8c 0.25 0.25 4c 4c 0.25 0.25 0.25 0.25 0.25 2c 8c 0.25 0.25 0.25 0.25 8c 0.25 0.25 0.25 0.25 8c 0.25 0.25 0.25 0.25 0.25 0.25 Serotype Therapy Progress Outcome

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
a

19 11 11 9 14 13 ND 7 35 ND 3 6B 11 23F 3 NA 19 3 6A 19 ND 6 23 ND 19 23 3 15F NA 23 20 ND 8 11 1 6A

Ab + surgery Surgery Ab + surgery Ab + surgery Ab Ab Ab + surgery Ab Ab + surgery Ab + surgery Ab Ab + surgery Ab + surgery Ab Ab + surgery Ab + surgery Ab + surgery Topical Ab + surgery Topical Ab + surgery Ab + surgery Topical Ab + surgery Ab + surgery Ab Ab + surgery Ab Ab Ab Ab + surgery Ab + FNA Ab + FNA Ab Ab + surgery Ab + surgery

Favorable Favorable Favorable Favorable Unknown Favorable Favorable Failure Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Favorable Failure Favorable Favorable Favorable Failure Cure Cure Cure Failure Cure

Survived Survived Survived Survived NA Survived Survived Died Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Survived Died Survived Survived Died Died Survived Died Survived Survived Survived

NA not available, ND not determined (nontypable), Ab antibiotics, FNA fine needle aspiration Penicillin nonsusceptible MIC 0.12 mg/l b Cefotaxime nonsusceptible MIC 2 mg/l c Erythromycin resistant MIC 1 mg/l

Discussion Despite being a common pathogen, S. pneumoniae remains a rare cause of soft tissue infections. However, our experience suggests that these infections are not uncommon, especially in patients with severe underlying conditions. In our hospital, 2.15% of S. pneumoniae isolates are recovered from skin and soft tissues. Sixty-five percent of these are clinically significant, causing in most cases surgical wound infections, subcutaneous abscesses, or burn infections. The finding that 50% of our cases were due to

mixed infection of S. pneumoniae plus another microorganism (H. influenzae, E. coli, anaerobes, S. aureus, P. aeruginosa) is a matter of concern. In these cases, the pathogenicity of the infection cannot be attributed solely to S. pneumoniae, and in some cases of dual infection the second causative agent might be related to the type of infection (i.e. burn infection and Pseudomonas). The clinical characteristics of soft tissue infections due to Streptococcus spp., including S. pneumoniae, appear to overlap, and outcome after therapy is not helpful in determining the causative agent. The clinical samples in

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251

Fig. 1 A 37-year-old woman with systemic lupus erythematosus, and S. pneumoniae cellulitis, empyema, and sepsis. Cured with cefotaxime and thoracocentesis

our study met strict definitions of infection, and the isolation of S. pneumoniae should not be underestimated [6], especially in patients with connective tissue diseases. The detection of some virulence factors of S. pneumoniae related to soft tissue infections, such as pneumococcal surface protein C (PspC) [11], would have been of value, but such investigations are beyond the purpose of this study. The first description of cutaneous infection caused by S. pneumoniae (previously Diplococcus erysipela) was made by Connio in 1917, but the first confirmed case of cellulitis

was published in 1975 [12]. Up to March of 2001, fewer than 80 cases of cellulitis due to S. pneumoniae had been published [13]. Since then, several cases of pneumococcal soft tissue infection have been described, mostly as single case reports [4, 1417]. In Table 3, we summarize five important published studies of skin and soft tissue infections caused by S. pneumoniae. Overall, 66100% of cases occurred in patients with severe underlying conditions, including HIV infection [18, 19], diabetes [20], alcoholism [21], connective tissue diseases [22, 23], and other forms of immunosuppression [4, 2426]. In agreement with other published data [2729], surgical wound infections (frequently in the abdominal wall) and soft tissue abscesses were the most frequent clinical conditions in our study. Other authors reviewed or described short case series of cellulitis, fasciitis, pyomyositis, or gluteal abscesses [4, 1417]. The frequency of concomitant bacteremia with skin and soft tissue infection by S. pneumoniae is variable and ranges from 0 to 88% [3, 4, 30, 31]. In the series of 12 pneumococcal soft-tissue infections described by DiNubile et al. [23], six cases of pneumococcal bacteremia were detected. The series included three patients with systemic lupus erythematosus and two HIV-positive patients. In our study, bacteremia was detected in three of the 19 (15.8%) patients from whom blood cultures were obtained, but the clinical presentation of many cases did not prompt blood culturing. All three of these bacteremic patients had underlying immunodeficiencies (diabetes, lupus, and low birth weight, respectively).

Table 3 Comparative summary of published case series of skin and soft tissue infections caused by S. pneumoniae Author [ref. no.] No. of cases Age range Most frequent underlying diseases No. of polymicrobial infections No. with positive blood culture 7/12 4/5 0/6 No. due to penicillinnonsusceptible isolates 0/12 0/5 2/6 No. with surgery No. with favourable clinical outcome 10/12 5/5 6/6

DiNubile 1991 [23] Patel 1994 [6] CuencaEstrella 1995 [27] Givner 2000 [32] Kalima 2001 [3] PR

12 5 6

Adults 6 months 60 years 3176 years

SLE, HIV SLE, CRF HIV, tumour, COPD, surgery Tumour, HIV, hygroma CRF, diabetes, trauma HIV, diabetes, COPD, CVID, SLE, alcoholism, cancer

1/12? 1/5 4/6

8/12 2/5 6/6

52 3 36

<36 months 3273 years 191 years

0/3 18/36

52/52 2/3 3/19

3/51 0/3 23/39

0/3 23/36

52/52 3/3 31/36

SLE systemic lupus erythematosus, CRF chronic renal failure, COPD chronic obstructive pulmonary disease, PR present report, CVID common variable immunodeficiency

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In a study comparing bacteremic cellulitis [30] caused by S. pneumoniae with that caused by S. aureus or Streptococcus pyogenes, the bacteremic cellulitis caused by S. pneumoniae was more frequently related to underlying diseases and had lower mortality than that caused by S. pyogenes. Cases caused by pneumococci were more frequently part of a disseminated disease with multifocal involvement. The similarity between the clinical presentation of pneumococcal necrotizing fasciitis and the disease caused by group A beta-hemolytic Streptococcus has important therapeutic implications. Kwak et al. [5] investigated the pathogenesis of three cases of pneumococcal necrotizing fasciitis and compared these cases with S. pyogenes necrotizing fasciitis. Western immunoblot revealed no evidence of SpeA, SpeB or SpeC protein expression, and the evaluation for protease production and cytotoxicity was unrevealing. Thus, the molecular pathogenesis is unclear. Givner et al. [32] reported 52 retrospectively collected cases of bacteremic pneumococcal cellulitis in children from eight pediatric hospitals in the USA. Most patients were under 36 months of age and previously healthy. Overall, patient outcome was good. In our study, the longest series in adults reported to date, the most frequent serotypes of the 32 strains tested were 3 and 19, followed by 11 and 23. These data are not in agreement with the results of published series of facial pneumococcal cellulitis, in which the most common serotypes were 14 (53%) and 6B (27%) [8, 32, 33], but all the strains in these series came from children (96% of the serotypes were included in the heptavalent antipneumococcal vaccine), whereas our strains were obtained mainly from adults. The serotypes responsible for pneumococcal disease vary with patient age, geographic zone, and period of study. In Spain, the most common serotypes are serotypes 6, 14, and 19 in children and serotypes 3, 9, and 19 in adults [34]. We found a high rate of S. pneumoniae not susceptible to penicillin (63% of isolates causing skin and soft tissue infection). This was higher than rates published elsewhere, which varied from 0 to 33% [3, 4, 24, 35]. The finding of strains that were nonsusceptible to cefotaxime (7%) and resistant to erythromycin (23%) means that the selection of antibiotic treatment for these infections should be considered carefully [35, 36]. In this study, we used the new MIC interpretative breakpoints for S. pneumoniae in nonmeningeal infections [10]. In the most severe cases, the best outcome is achieved with a combination of surgery and appropriate antibiotics. In our study, combined treatment was used in 61% of cases, a percentage similar to that reported by other authors [3, 4, 6, 23]. Despite the pattern of antibiotic resistance presented by our S. pneumoniae isolates, the clinical evolution of the

patients was favorable in almost 90% of the cases, even when susceptibility tests revealed that antibiotic treatment was inadequate. Five deaths were registered in our series, although only three were directly attributable to the infection. The favorable prognosis and outcome of our cases is in agreement with the findings of other published studies [4, 7, 30, 35, 37]. S. pneumoniae should be included in the list of microorganisms causing skin and soft tissue infections, both in the community and in the hospital setting. It is more frequent in patients with severe underlying conditions, although mortality was lower than expected in our series.
Acknowledgements This study is part of the Red Espaola de Estudio de la Infeccin Neumoccica (G03/103). The following participants and centers are acknowledged: Ernesto Garca (Centro de Investigaciones Biolgicas, Madrid); Julio Casal, Asuncin Fenoll, Adela G. de la Campa (Centro Nacional de Microbiologa, Instituto de Salud Carlos III, Madrid); Emilio Bouza (Hospital Gregorio Maran, Madrid); Fernando Baquero (Hospital Ramn y Cajal, Madrid); Francisco Soriano, Jos Prieto (Fundacin Jimnez Daz and Faculty of Medicine, Universidad Complutense, Madrid); Romn Pallars, Josefina Liares (Hospital Universitari de Bellvitge, Barcelona); Javier Garau, Javier Martnez Lacasa (Hospital Mutua de Terrassa, Barcelona); Cristina Latorre (Hospital Sant Joan de Deu, Barcelona); Emilio Prez-Trallero (Hospital Donostia, San Sebastin); Juan Garca de Lomas (Hospital Clnico, Valencia); and Ana Fleites (Hospital Central de Asturias). We would like to thank Thomas OBoyle for his help in the translation of the manuscript. This work was supported in part by the Red Espaola de Investigacin en Patologa Infecciosa (REIPI-ISCIII-C03/14).

References
1. Musker DM (2000) Streptococcus pneumoniae, vol. 2. Churchill Livingstone, Philadelphia, pp 21282146 2. Friedland IR, McCracken GH (1999) Streptococcus pneumoniae. Williams and Wilkins, Baltimore, pp 433443 3. Kalima P, Riordan T (2001) Streptococcus pneumoniae: a rare skin pathogen? J Infect 42:210212 4. Taylor SN, Sanders CV (1999) Unusual manifestations of invasive pneumococcal infection. Am J Med 107:12S27S 5. Kwak E, McClure JA, McGeer A, Lee C (2002) Exploring the pathogenesis of necrotizing fasciitis due to Streptococcus pneumoniae. Scand J Infect Dis 34:639644 6. Patel M, Ahrens JC, Moyer DV, DiNubile MJ (1994) Pneumococcal soft-tissue infections: a problem deserving more recognition. Clin Infect Dis 19:149151 7. Kaplan SL, Maason EOJ, Barson WJ, Wald ER, Arditi M, Tan TQ, Schutze GE, Bradley JS, Givner LB, Kim KS, Yogev R (1998) Three-year multicenter surveillance of systemic pneumococcal infections in children. Pediatrics 102:538545 8. Fenoll A, Jado I, Vicioso D, Prez A, Casal J (1998) Evolution of Streptococcus pneumoniae serotypes and antibiotic resistance in Spain: update (19901996). J Clin Microbiol 36:34473454 9. Ruoff KL, Whiley RA, Beighton D (1999) Streptococcus, 7th edn. ASM, Washington DC, pp 283296

Eur J Clin Microbiol Infect Dis (2007) 26:247253 10. Clinical and Laboratory Standards Institute (2005) Performance standards for antimicrobial susceptibility testing. 15th informational supplement, M100S15, CLSI, Wayne, PA 11. Ogunniyi AD, Woodrow MC, Poolman JT, Paton JC (2001) Protection against Streptococcus pneumoniae elicited by immunization with pneumolysin and CbpA. Infect Immun 69:59976003 12. Lewis RJ, Richmond AS, McGrory JP (1975) Diplococcus pneumoniae. Cellulitis in drug addicts. JAMA 232:5455 13. Parada JP, Maslow JN (2000) Clinical syndromes associated with adult pneumococcal cellulitis. Scand J Infect Dis 32:133136 14. Lawlor MT, Crowe HM, Quintiliani R (1992) Cellulitis due to Streptococcus pneumoniae: case report and review. Clin Infect Dis 14:247250 15. Frick S, Cerny A (2001) Necrotizing fasciitis due to Streptococcus pneumoniae after intramuscular injection of nonsteroidal antiinflammatory drugs: report of 2 cases and review. Clin Infect Dis 33:740744 16. Ejlertsen T, Dossing K (1997) Pneumococcal pyomyositis secondary to pneumonia. Scand J Infect Dis 29:520521 17. Choudhri SH, Brownstone R, Hashem F, Magro CM, Crowson AN (1995) A case of necrotizing fasciitis due to Streptococcus pneumoniae. Br J Dermatol 133:128131 18. Mofredj A, Guerin JM, Leibinger F, Masmoudi R (2000) Pneumococcal cellulitis in an HIV-infected adult. Infection 28:175177 19. Rodriguez Barradas MC, Musher DM, Hamill RJ, Dowell M, Bagwell JT, Sanders CV (1992) Unusual manifestations of pneumococcal infection in human immunodeficiency virusinfected individuals: the past revisited. Clin Infect Dis 14:192199 20. Verhelst JA, Delvigne C (1988) Pneumococcal osteomyelitis and cellulitis in an adult patient with diabetes mellitus. Diabet Med 5:393395 21. Parada JP, Maslow JN (1999) Adult pneumococcal cellulitis: case report and review. Clin Infect Dis 28:918 22. Hill MD, Karsh J (1997) Invasive soft tissue infections with Streptococcus pneumoniae in patients with systemic lupus erythematosus: case report and review of the literature. Arthritis Rheum 40:17161719 23. DiNubile MJ, Albornoz MA, Stumacher RJ, Van Uitert BL, Paluzzi SA, Bush LM, Nelson SC, Myers AR (1991) Pneumococcal soft-tissue infections: possible association with connective tissue diseases. J Infect Dis 163:897900 24. Souweine B, Mom T, Bret L, Klisnick A, Baguet JC, Gilain L (1997) Cellulitis due to Streptococcus pneumoniae with diminished susceptibility to penicillin in an immunocompromised patient. Scand J Infect Dis 29:518519

253 25. Peyronnet P, Aldigier J, Bernard P, Weinbreck P, Leroux-Robert C (1985) Pneumococcal cellulitis in an immunosuppressed patient. Presse Med 14:1386 26. Hammad A, Zittel M, Kalmuk E, Mylotte J (1992) Pneumococcal cellulitis and dysgammaglobulinemia. NY State J Med 92:113 114 27. Cuenca-Estrella M, Ramos JM, Esteban J, Soriano F (1995) Pneumococcal soft-tissue infections. Clin Infect Dis 21:697698 28. Bolanos M, Alfonso O, Evora Santana O, Gil G, Martin Sanchez AM (2001) Gluteal abscess caused by Streptococcus pneumoniae. Enferm Infecc Microbiol Clin 19:455456 29. Granowitz EV, Donaldson WR, Skolnik PR (1992) Gas-forming soft tissue abscess caused by Streptococcus pneumoniae. Am J Med 93:105107 30. Capdevila O, Grau I, Vadillo M, Cisnal M, Pallares R (2003) Bacteremic pneumococcal cellulitis compared with bacteremic cellulitis caused by Staphylococcus aureus and Streptococcus pyogenes. Eur J Clin Microbiol Infect Dis 22:337341 31. Peters NS, Eykyn SJ, Rudd AG (1989) Pneumococcal cellulitis: a rare manifestation of pneumococcaemia in adults. J Infect 19:57 59 32. Givner LB, Mason EO Jr, Barson WJ, Tan TQ, Wald ER, Schutze GE, Kim KS, Bradley JS, Yogev R, Kaplan SL (2000) Pneumococcal facial cellulitis in children. Pediatrics 106:E61E64 33. Shutze GE, Mason JEO, Wald ER, Barson WJ, Bradley JS, Tan TQ, Kim KS, Givner LB, Yogev R, Kaplan SL (2001) Pneumococcal infections in children after transplantation. Clin Infect Dis 33:1621 34. Fenoll A, Casal J (2001) Estudio de los serotipos de Streptococcus pneumoniae en Espaa. Prous Science, Barcelona, pp 5567 35. Pallares R, Liares J, Vadillo M, Cabellos C, Manresa F, Viladrich PF, Martin R, Gudiol F (1995) Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain. N Engl J Med 333:474480 36. Kaplan SL, Mason EO Jr, Barson WJ, Tan TQ, Schutze GE, Bradley JS, Givner LB, Kim KS, Yogev R, Wald ER (2001) Outcome of invasive infections outside the central nervous system caused by Streptococcus pneumoniae isolates nonsusceptible to ceftriazone in children treated with beta-lactam antibiotics. Pediatr Infect Dis J 20:392396 37. Laurichesse H, Romaszko JP, Nguyen LT, Souweine B, Poirier V, Guolon D, Andre M, Ruivard M, De Champs C, Caillaud D, Labbe A, Beytout J (2001) Clinical characteristics and outcome of patients with invasive pneumococcal disease, Puy-de-Dome, France, 19941998. Eur J Clin Microbiol Infect Dis 20:299 308