Fluoroquinolone treatment as a protective factor for 10-day mortality in Streptococcus pneumoniae bacteremia in cancer patients.

To evaluate the prognostic factors in adult cancer patients with pneumococcal bacteremia, describe episode features and the phenotypic characteristics of the isolated strains. We evaluated the episodes in patients admitted to a cancer hospital between 2009 and 2015. The outcomes were defined as 48 h mortality and mortality within 10 days after the episode. The variables evaluated were: age, sex, ethnicity, ECOG, Karnofsky score, SOFA, cancer type, metastasis, chemotherapy, radiotherapy, neutropenia, previous antibiotic therapy, community or healthcare-acquired infection, comorbidities, smoking, pneumococcal vaccination, infection site, presence of fever, polymicrobial infection, antimicrobial susceptibility, serotype and treatment. 165 episodes were detected in 161 patients. The mean age was 61.3 years; solid tumors were the most prevalent (75%). 48 h and 10-day mortality were 21% (34/161) and 43% (70/161) respectively. The 48 h mortality- associated risk factors were SOFA and polymicrobial bacteremia; 10-day mortality-associated risk factors were fever, neutropenia, ECOG 3/4, SOFA and fluoroquinolones as a protective factor. Pneumococcal bacteremia presented high mortality in cancer patients, with prognosis related to intrinsic host factors and infection episodes features. Fluoroquinolone treatment, a protective factor in 10-day mortality, has potential use for IPDs and severe community-acquired pneumonia in cancer patients.

Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data

Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27­0·37]) and 82% at 8 weeks (0·18 [0·14­0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Pública de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

Effect of 10-valent pneumococcal conjugate vaccine on nasopharyngeal carriage of Streptococcus pneumoniae and Haemophilus influenzae among children in São Paulo, Brazil

In March 2010, Brazil introduced the 10-valent pneumococcal conjugate vaccine (PCV10) in the routine infant immunization program using a 4-dose schedule and catch-up for children <23 months. We investigated PCV10 effect on nasopharyngeal carriage with vaccine-type Streptococcus pneumoniae (Spn) and non-typeable Haemophilus influenzae (NTHi) among children in São Paulo city. Cross-sectional surveys were conducted in 2010 (baseline) and 2013 (post-PCV10). Healthy PCV-naïve children aged 12­23 months were recruited from primary health centers during immunization campaigns. Nasopharyngeal swabs were collected and tested for Hi; for Spn, all baseline and a stratified random sample of 400 post-PCV10 swabs were tested. We compared vaccine-type Spn and NTHi carriage prevalence pre-/post-PCV10, and used logistic regression to estimate PCV10 effectiveness (1-adjusted odds ratio 100%). Overall 501 children were included in the baseline and 1167 in the post-PCV10 survey (including 400 tested for Spn). Spn was detected in 40.3% of children at baseline and 48.8% post-PCV10; PCV10 serotypes were found in 19.8% and 1.8% respectively, representing a decline of 90.9% (p < 0.0001). Carriage of vaccine-related serotypes increased (10.8­21.0%, p < 0.0001), driven primarily by a rise in serotype 6C (1.8­11.2%, p < 0.0001); carriage of serotypes 6A and 19A did not significantly change. PCV10 effectiveness (4 doses) against vaccine-type carriage was 97.3% (95% confidence interval 88.7­99.3). NTHi prevalence increased from 26.0% (130/501) to 43.6% (509/1167, p < 0.0001); PCV10 vaccination seemed significantly associated with NTHi carriage, even after adjusting for other known risk factors. Carriage with PCV10 serotypes among toddlers declined dramatically following PCV10 introduction in São Paulo, Brazil. No protection of PCV10 against NTHi was observed. Our findings contribute to a growing body of evidence of PCV10 impact on vaccine-type carriage and highlight the importance of PCV10 as a tool to reduce the burden of pneumococcal disease in Brazil and globally

Serotypes of carriage and invasive isolates of Streptococcus pneumoniae in Brazilian children in the era of pneumococcal vaccines.

Nasopharyngeal carriage of Streptococcus pneumoniae is a key factor in the development of invasive disease and the spread of resistant strains within the community. A single nasopharyngeal swab was obtained from 648 unvaccinated children aged <5 years, either healthy or with acute respiratory tract infection or meningitis, during the winters of 2000 and 2001. The overall pneumococcal carriage rate was 35.8% (95% CI 32.1-39.6). The pneumococcal serotypes found most frequently in the nasopharynx were 14, 6B, 6A, 19F, 10A, 23F and 18C, which included five of the seven serotypes in the currently licensed seven-valent conjugate vaccine (PCV7); serotypes 4 and 9V were less common. Serotypes 1 and 5 were isolated rarely from the nasopharynx. A comparison of 222 nasopharyngeal isolates with 125 invasive isolates, matched for age and time to the carrier isolates, showed a similar prevalence of penicillin non-susceptible pneumococci (PNSp) (19.8% and 19.2%, respectively). PNSp serotypes were similar (6B, 14, 19F, 19 A, 23B and 23F) for carriage and invasive disease isolates. The coverage of PCV7 for carriage isolates (52.2%) and invasive isolates (62.4%) did not differ significantly (p 0.06); similarly, there was no significant difference in PCV7 coverage for carriage isolates (34.5%) and invasive isolates (28.2%) of PNSp. These data suggest that PCV7 has the potential to reduce pneumococcal carriage and the number of carriers of PNSp belonging to vaccine serotypes.

Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine in Brazilian elderly.

Serum antibodies specific for the capsular polysaccharides of Streptococcus pneumoniae provide protection against invasive pneumococcal infection. In Brazil, this vaccine has been used for people over 65 years with clinical risk to develop pneumococcal infection since 1999. We evaluated the immune response of 102 elderly subjects (75.5% females and 24.5% males) with a mean age of 71 years, and 19 young healthy adults (63.2% females and 36.8% males) with a mean age of 27 years. The elderly study group consisted of outpatients who received follow-up care in the Geriatric Department of General Hospital, Faculty of Medicine, University of São Paulo. None had acute illness at the time of vaccination. Both groups were immunized with one intra-deltoid injection with 0.5 ml of a 23-valent pneumococcal polysaccharide vaccine. The total IgG specific antibody concentrations to capsular polysaccharides 1, 3, 5, 6B, 8, and 14 were determined against pre- and 1-month post-vaccination sera. All samples were analyzed according to the second-generation pneumococcal polysaccharide ELISA protocol. We observed that the pneumococcal polysaccharide vaccine evoked consistent antibody increase for serotypes 1, 5, 6B, 8, and 14 (geometric mean concentration increase of 2.46 in the elderly and 2.84 in the young adults). Otherwise, we observed no increase in antibody concentration for serotype 3 in both groups.

Immunogenicity of a 23-valent pneumococcal polysaccharide vaccine in Brazilian elderly

Serum antibodies specific for the capsular polysaccharides of Streptococcus pneumoniae provide protection against invasive pneumococcal infection. In Brazil, this vaccine has been used for people over 65 years with clinical risk to develop pneumococcal infection since 1999. We evaluated the immune response of 102 elderly subjects (75.5 percent females and 24.5 percent males) with a mean age of 71 years, and 19 young healthy adults (63.2 percent females and 36.8 percent males) with a mean age of 27 years. The elderly study group consisted of outpatients who received follow-up care in the Geriatric Department of General Hospital, Faculty of Medicine, University of São Paulo. None had acute illness at the time of vaccination. Both groups were immunized with one intra-deltoid injection with 0.5 ml of a 23-valent pneumococcal polysaccharide vaccine. The total IgG specific antibody concentrations to capsular polysaccharides 1, 3, 5, 6B, 8, and 14 were determined against pre- and 1-month post-vaccination sera. All samples were analyzed according to the second-generation pneumococcal polysaccharide ELISA protocol. We observed that the pneumococcal polysaccharide vaccine evoked consistent antibody increase for serotypes 1, 5, 6B, 8, and 14 (geometric mean concentration increase of 2.46 in the elderly and 2.84 in the young adults). Otherwise, we observed no increase in antibody concentration for serotype 3 in both groups.

Immune response to native NadA from Neisseria meningitidis and its expression in clinical isolates in Brazil

A mAb against the NadA protein from Neisseria meningitidis strain 3006 (serosubtype B : 2b : P1.2 : P5.2,8) demonstrated strong bactericidal activity against Brazilian epidemic serogroup B strain N44/89 (B : 4,7 : P1.19,15 : P5.5,7) and a serogroup C strain, IMC 2135 (C : 2a : P1.5,2), but not against another serogroup C strain, N1002/90 (C : 2b : P1.3 : P5.8). The immunogenicity of native NadA in an outer-membrane vesicle (OMV) preparation was also tested. Serum from mice immunized with OMV from serogroup B strain N44/89, which contains the NadA protein, showed bactericidal activity against serogroup B and C strains possessing NadA. In dot-blot analysis of 100 serogroup B and 100 serogroup C isolates from Brazilian patients, the mAb to NadA recognized about 60% of the samples from both serogroups. The molecular mass of the NadA protein from strain N44/89 determined by mass spectrometry was 37 971 Da and the peptide sequences were identical to those of NadA from N. meningitidis strain MC58.

Evolution of Streptococcus pneumoniae serotypes and penicillin susceptibility in Latin America, Sireva-Vigía Group, 1993 to 1999. PAHO Sireva-Vigía Study Group. Pan American Health Organization.

BACKGROUND: Since 1993 the Pan American Health Organization has coordinated a surveillance network with the National Reference Laboratories of Argentina, Brazil, Chile, Colombia, Mexico and Uruguay aimed at monitoring capsular types and antimicrobial susceptibility of Streptococcus pneumoniae causing invasive disease in children <6 years of age. METHODS: The surveillance system included children 6 years of age and younger with invasive disease caused by S. pneumoniae. The identification, capsular typing and susceptibility to penicillin of the isolates were conducted using a common protocol, based on standard methodologies. RESULTS: By June, 1999, 4,105 invasive pneumococcal isolates had been collected mainly from pneumonia (44.1%) and meningitis (41.1%) cases. Thirteen capsular types accounting for 86.1% of the isolates (14, 6A/6B, 5, 1, 23F, 19F, 18C, 19A, 9V, 7F, 3, 9N and 4) remained the most common types during the surveillance period. Diminished susceptibility to penicillin was detected in 28.6% of the isolates, 17.3% with intermediate and 11.3% with high level resistance. Resistance varied among countries and increased during this period in Argentina, Colombia and Uruguay. Serotypes 14 and 23F accounted for 66.6% of the resistance. CONCLUSION: These surveillance data clearly demonstrate the potential impact of the introduction of a conjugate vaccine on pneumococcal disease and the need for more judicious use of antibiotics to slow or reverse the development of antimicrobial resistance.

Three-year assessment of methicillin-resistant Staphylococcus aureus clones in Latin America from 1996 to 1998.

Four hundred ninety-nine methicillin-resistant Staphylococcus aureus (MRSA) isolates recovered from 1996 to 1998 from 22 hospitals in five countries of Latin America-Argentina, Brazil, Chile, Uruguay and Mexico-were examined for antimicrobial susceptibility and clonal type in order to define the endemic clones in those hospitals. The hybridization of ClaI restriction digests with the mecA- and Tn554-specific DNA probes combined with pulsed-field gel electrophoresis of chromosomal SmaI digests (ClaI-mecA::ClaI-Tn554::PFGE clonal types) documented not only the predominance and persistence of the Brazilian clone (XI::B::B) in Brazil (97%) and Argentina (86%) but also its massive dissemination to Uruguay (100%). Moreover, a close relative of the Brazilian clone (XI::kappa::B) was highly represented in Chile (53%) together with a novel clone (47%) (II::E'::F) resistant to pencillin, oxacillin, ciprofloxacin, chloramphenicol, clindamycin, erythromycin, and gentamicin. A unique clonal type (I::NH::M) was detected in Mexico among pediatric isolates and was resistant to penicillin, oxacillin, and gentamicin only. This study clearly documented the very large capacity for geographic expansion and the persistence of the Brazilian clone, contributing not only to the increasing uniformity of the MRSA in South America but worldwide as well.

Community acquired pneumonia among pediatric outpatients in Salvador, Northeast Brazil, with emphasis on the role of pneumococcus.

Pneumonia is one of the leading causes of hospitalization and death among children in developing countries, and mortality due to pneumonia has been associated with S. pneumoniae infection. This investigation was designed to describe the antimicrobial susceptibility and serotype patterns of pneumococcal strains recovered from the blood of children with community-acquired pneumonia (CAP) and to assess the clinical findings of pneumococcal bacteremic patients with pneumonia. In a 26 month prospective study, blood cultures were obtained as often as possible from children (<16 years of age) diagnosed with CAP in two emergency rooms. Antimicrobial drug susceptibility tests and serotyping were performed when pneumococcus was identified. We studied 3,431 cases and cultured blood samples from 65.5% of those. Pneumococcus was recovered from 0.8% of the blood samples. The differences in age, somnolence, wheezing and hospitalization among children with and without pneumococcal bacteremia were statistically significant. Pneumococcal bacteremia was age-related (mean 1.63 +/- 1.55; median 0.92) and associated with somnolence and hospitalization among children with CAP. One strain was recovered from pleural fluid. Penicillin resistance was detected in 21.0% (4/19) of the strains at an intermediate level, whereas 63.0% of the strains were resistant to trimethoprim-sulfamethoxazole. The most common serotypes were 14 and 6B, and these serotypes included the resistant strains. Eight of our 18 isolates from blood were of types included in the heptavalent conjugate pneumococcal vaccine, recently licensed in the USA.

[Nasopharyngeal colonization and antimicrobial resistance of Streptococcus pneumoniae isolated from children with acute rhinopharyngitis] / Colonização e resistência antimicrobiana de Streptococcus pneumoniae isolado em nasofaringe de crianças com rinofaringite aguda.

OBJECTIVE: To determine the prevalence and risk factors for nasopharyngeal colonization by, and to evaluate antimicrobial susceptibility of Streptococcus pneumoniae strains in children with acute rhinopharyngitis. METHODS: We collected nasopharyngeal swab specimens from 400 children aged 3 months to 5 years and with clinical status of acute rhinopharyngitis from June 16, 1997 to May 20, 1998 at the outpatient clinics of two hospitals in the city of São Paulo. Nasopharyngeal specimens were collected pernasally using a calcium alginate swab and plated immediately after collection onto trypticose soy agar with 5% sheep blood and garamicin 5 mcg/ml. Penicillin susceptibility was determined by oxacillin 1 mcg disk screening test and the minimal inhibitory concentration by the E-test. RESULTS: Pneumococci were recovered from 139 children, indicating a colonization prevalence of 35%. The risk factors analyzed indicated that the colonization was more prevalent in children attending day-care centers, children with siblings younger than 5 years, and children with recent use of antimicrobial agents. The prevalence of penicillin non-susceptible strains was of 16 % (20 strains). All strains were intermediately resistant (0.1mcg/ ml

Antibiotic resistance in Streptococcus pneumoniae in six Latin American countries: 1993-1999 surveillance.

The impact of invasive pneumococcal invasive disease is increased by the emergence of antibiotic resistance. We report regional and temporal variations in antibiotic resistance for 4,105 invasive Streptococcus pneumoniae isolates collected from Latin American children <5 years, between 1993 and 1999. Reduced susceptibility to penicillin was detected in 1,182 isolates (28.8%); 36% of these were resistant (> or = 2 microg/ml), including 12.6% with MIC > or = 4 microg/ml, occurring primarily in serotypes 14 and 23F. Reduced susceptibility to third-generation cephalosporins was detected in 12.1% of the collection. Mexico had the highest proportion of reduced susceptibility to penicillin (51.6%) and to third-generation cephalosporins (22%), whereas Brazil had the lowest at 20.9% and 0.7%, respectively. Isolates cultured from patients with pneumonia were more likely to have reduced susceptibility to third-generation cephalosporins than isolates from patients with meningitis (p < 0.0001). Susceptibility to trimethoprim-sulfamethoxazole, chloramphenicol, erythromycin, and vancomycin was tested by disk diffusion for 2.899 isolates. Reduced susceptibility was observed for 45.6%, 11.5%, 6.9%, and 0%, respectively. Thirty-one percent of the strains were resistant to > or = 2 drugs. High levels of antibiotic resistance in Latin America emphasize the need for the development of and adherence to rational antibiotic use guidelines. On-going surveillance will monitor the impact of these programs.

Haemophilus influenzae resistance in Latin America: systematic review of surveillance data.

Haemophilus influenzae is a relevant cause of morbidity and mortality among children under 5 years of age in the developing world. In Latin America, H. influenzae type b (Hib) conjugate vaccine and surveillance of H. influenzae antimicrobial susceptibility have been implemented in recent years. We have undertaken a systematic review and a pooled analysis on H. influenzae antimicrobial resistance, including reports of 15 Latin America countries over a 10-year period (1990-2000). We have found that 450 (21.4%) of 2,100 invasive isolates were beta-lactamase producers compared to 145 (14.5%) of 998 isolates of noninvasive isolates (p < 0.05). Ampicillin resistance was detected among 783 (21.9%) of 3,577 invasive isolates compared to 111 (17.2%) of 646 noninvasive strains (p < 0.05). In contrast, 568 (41.9%) of 1,355 noninvasive strains were trimethoprim-sulfamethoxazole (TMP-SMX) resistance against 241 (26.9%) of 897 invasive ones (p < 0.05). Therefore, TMP-SMX resistance was more common in nonsterile fluids than in sterile fluids. Over time, rates of beta-lactamase-producing strains were stable in Brazil and Mexico, whereas rates of TMP-SMX resistance were increasing in Brazil. It is predictable that following the Hib immunization, Latin America countries will be faced with increased nontypeable H. influenzae infection. Although standing by the nontypeable H. influenzae vaccine, in this novel epidemiological scenario of post-Hib vaccination in Latin America settings there is a need to improve H. influenzae resistance monitoring to guide clinicians to choose efficacious antimicrobial therapy.

Decreased point prevalence of Haemophilus influenzae type b (Hib) oropharyngeal colonization by mass immunization of Brazilian children less than 5 years old with hib polyribosylribitol phosphate polysaccharide-tetanus toxoid conjugate vaccine in combination with diphtheria-tetanus toxoids-pertussis vaccine.

A protective herd effect has been described after susceptible populations of children are vaccinated with conjugate Haemophilus influenzae type b (Hib). Hib carriage was studied in children aged 6-24 months attending day care centers in two cities in southern Brazil (Curitiba and Porto Alegre). In Curitiba, routine immunization with Hib polyribosylribitol phosphate polysaccharide-tetanus toxoid conjugate vaccine (PRP-T) in combination with diphtheria-tetanus toxoids-pertussis vaccine (PRP-T/DTP) has been offered since September 1996; DTP vaccine alone is routinely given in Porto Alegre. Children in Porto Alegre (n=643) were 8 times less likely to have received adequate Hib vaccination and 4 times more likely to be Hib carriers than children in Curitiba (n=647; i.e., point prevalence of oropharyngeal colonization, 4.8% vs. 1.2%). Point prevalence of carriage with non-type b or other nontypeable Hi was similar in children of both cities. There was a vaccination effect on carriage rates in children who received a primary 3-dose series, independent of the booster dose, suggesting that a booster may be unnecessary to induce population protection.

Fatal group A Streptococcal toxic shock-like syndrome in a child with varicella: report of the first well documented case with detection of the genetic sequences that code for exotoxins spe A and B, in São Paulo, Brazil.

A previously healthy seven-year-old boy was admitted to the intensive care unit because of toxaemia associated with varicella. He rapidly developed shock and multisystem organ failure associated with the appearance of a deep-seated soft tissue infection and, despite aggressive treatment, died on hospital day 4. An M-non-typable, spe A and spe B positive Group A Streptococcus was cultured from a deep soft tissue aspirate. The criteria for defining Streptococcal toxic shock-like syndrome were fulfilled. The authors discuss the clinical and pathophysiological aspects of this disease as well as some unusual clinical findings related to this case.

First confirmed case of a vancomycin-resistant Enterococcus faecium with vanA phenotype from Brazil: isolation from a meningitis case in São Paulo.

The importance of enterococci as a nosocomial etiologic agent is well documented; however, enterococci are also capable of causing a variety of community-acquired infections. Vancomycin resistance in a clinical Enterococcus isolate was first reported in 1986, and since then vancomycin-resistant enterococci (VRE) have been reported world-wide. This report describes a case of E. faecium with the VanA phenotype, isolated from meningitis in Sao Paulo, Brazil. Two E. faecium strains were isolated. One strain showed VanA phenotype, and the molecular characterization of the VanA gene was confirmed by polymerase chain reaction. The other strain was susceptible to vancomycin and teicoplanin. The authors would like to call the attention of the scientific community to this first identification of a VRE case in Sao Paulo, Brazil.

Determination of trimethoprim-sulfamethoxazole resistance in Streptococcus pneumoniae by using the E test with Mueller-Hinton agar supplemented with sheep or horse blood may be unreliable. The Pneumococcal Study Group.

An international, multicenter study compared trimethoprim-sulfamethoxazole MICs for 743 Streptococcus pneumoniae isolates (107 to 244 isolates per country) by E test, using Mueller-Hinton agar supplemented with 5% defibrinated horse blood or 5% defibrinated sheep blood, with MICs determined by the National Committee for Clinical Laboratory Standards broth microdilution reference method. Agreement within 1 log2 dilution and minor error rates were 69.3 and 15.5%, respectively, on sheep blood-supplemented agar and 76.9 and 13.6%, respectively, with horse blood as the supplement. Significant interlaboratory variability was observed. E test may not be a reliable method for determining the resistance of pneumococci to trimethoprim-sulfamethoxazole.