Penicillin-resistant Pneumococcal Infections Research Articles

Role of conjugative elements in the evolution of the multidrug-resistant pandemic clone Streptococcus pneumoniaeSpain23F ST81.

Streptococcus pneumoniae is a human commensal and pathogen able to cause a variety of diseases that annually result in over a million deaths worldwide. The S. pneumoniae(Spain23F) sequence type 81 lineage was among the first recognized pandemic clones and was responsible for almost 40% of penicillin-resistant pneumococcal infections in the United States in the late 1990s. Analysis of the chromosome sequence of a representative strain, and comparison with other available genomes, indicates roles for integrative and conjugative elements in the evolution of pneumococci and, more particularly, the emergence of the multidrug-resistant Spain 23F ST81 lineage. A number of recently acquired loci within the chromosome appear to encode proteins involved in the production of, or immunity to, antimicrobial compounds, which may contribute to the proficiency of this strain at nasopharyngeal colonization. However, further sequencing of other pandemic clones will be required to establish whether there are any general attributes shared by these strains that are responsible for their international success.

Pneumococcal Resistance in the Postvaccine Era

Temime, Laura PhD; Guillemot, Didier MD, PhD; Boëlle, Pierre-Yves PhD Author Information

Spanish primary healthcare physicians' knowledge of resistance of respiratory germs and antimicrobial treatment in acute bronchitis

Objectives: To determine what Spanish primary healthcare physicians consider the rates of pneumococcal resistance to be, the type of antimicrobial treatment they would prescribe on suspicion of high resistance and ascertain in which cases of acute bronchitis these physicians would initiate antibiotic treatment.Methods: A cross-sectional, observational study was performed with a questionnaire distributed to 1368 physicians on their opinion on the degree of resistance of pneumococci to penicillins and macrolides in Spain. They were also asked which treatment they would recommend in penicillin-resistant pneumococcal infection and to indicate their degree of agreement regarding the use of antibiotics in different clinical situations of acute bronchitis.Results: 843 physicians completed and returned the questionnaire, a response rate of 59.1%. Of the 750 physicians who answered the question concerning pneumococcal resistance, 312 stated resistance to be>30% (41.6%) while only 90 felt it to be<15% (12%). 153 physicians reported resistance to macrolides to be>30% (23%). In cases with suspicion of penicillin-resistant pneumococci, the clinicians stated they would prescribe quinolones (321, 40.3%) and macrolides (251, 31.5%). Of the 784 physicians who answered the questions on bronchitis, 662 preferred antibiotic therapy in acute bronchitis with purulent sputum (84.6%), 610 on uncertain diagnosis (77.8%), 569 in patients with fever over 38 °C (72.6%) and 210 on patient request (26.8%).Conclusion: Primary healthcare physicians in Spain are more concerned about pneumococcal resistance to penicillins than to macrolides although 35% of the strains isolated are resistant to the latter while only 10% are resistant to aminopenicillins. Furthermore, many physicians believe macrolides to be effective against pneumococcal infections. Despite their lack of efficacy in the treatment of acute bronchitis, many physicians prescribe antibiotics, mainly in cases with purulent expectoration, thus justifying the high consumption of antimicrobial agents in this disease.

Knowledge of pneumococcal resistance rates in Spain by family doctors

To know the knowledge of Spanish physicians related to pneumococcal resistance rates in an a country known to be one of the places with higher pneumococcal resistance rates and to know as well the choice of antibiotics in cases of suspected high penicillin-resistant pneumococcal pneumonia. A cross-sectional survey was set out in November during the Spanish Conference on Medicine Family held in Donosti (Basque). All the participants who filled up a questionnaire were given a present at the Aventis Pharma's stand at the Conference. They were asked about the perception of resistance rates of Streptococcus pneumoniae towards penicillins and macrolides in Spain and whether they agreed on using macrolides and quinolones in cases of suspected high penicillin-resistant pneumococcal infections. 843 family doctors filled up the questionnaire and 35 inquiries were dropped out because of illegibility or non responses. Out of 750 doctors who answered the question about the pneumococcal resistance towards penicillins, 312 stated to be greater than 30% (41.6) and only 90 thought to be less than 15% (12%). However, 153 doctors stated that pneumococcal resistance to macrolides was greater than 30% (23%) and 28 greater than 45% (4.2%). Respondents prefer the use of penicillins in patients with community-acquired pneumonia (344, 42.6%) but were reluctant to prescribe them in case of pneumonias suspected to be caused by resistant pneumococci (82, 10.3%). In these cases family doctors prefer the use of macrolides (251, 31.5%) and quinolones (321, 40.3%). Family doctors are aware of high resistance patterns but they think that higher pneumococcal resistance rates are reported towards penicillins than to macrolides; however, 30% of the Spanish pneumococcal strains isolated are currently resistant to macrolides and only 5% are highly resistant to penicillins. They also think that penicillin still is the first antibiotic choice in pneumococcal infections unless a resistant pneumococcus is suspected. Surprisingly, in suspected penicillin-resistant pneumococcal pneumonias too many doctors recommend the prescribing of macrolides instead of quinolones.

Impact de la résistance bactérienne sur les infections graves

Since many years, the antimicrobial resistance increases as well as for community-acquired as for nosocomial infections. Antibiotic-resistant pneumococci are neither more nor less virulent susceptible strains. Except for immunocompromised patients, the outcome of penicillin-resistant pneumococcal infections have been similar to those in patients who are infected by susceptible ones. Current levels of S. pneumoniae resistance to penicillin and cephalosporin are not associated to an increase in mortality in children with meningitis if adequate doses of antibiotics are given. Because empiric therapy has changed, antibiotic resistance has not been associated with increased mortality. This statement can be extended to Meningococcus, for which 32 to 50 % of the strains have a decreased susceptibility to penicillin. For nosocomial infections, S. aureus is the main studied pathogen. Several studies report that in patients with severe diseases (bacteremia or pneumonia) methicillin resistance of S. aureus had no significant impact on patient outcome after adjustement for different confounders. The main risk factor for mortality is the severe underlying diseases rather than the resistance as well for methicillin -resistant S.aureus, as for vancomycin resistant enterococci, Klebsiella with extended spectrum beta lactamase and Enterobacters. Recommendations for controlling epidemiologic surveillance, using barrier precautions and limiting the use of antibiotics as well in the hospital as in the community must be undertaken.

Penicillin-ResistantStreptococcus pneumoniaein Metropolitan New York Hospitals: Case Control Study and Molecular Typing of Resistant Isolates

During the 4-month period from January to April, 1998, 476 patients with Streptococcus pneumoniae infections were detected in 12 metropolitan New York hospitals and 112 penicillin-resistant (PRP) isolates (24%) were identified in 11 institutions. A case control study of 100 patients with penicillin-resistant and susceptible pneumococci from four of the widely dispersed hospitals revealed a high incidence of underlying medical illnesses in adult patients (74%), a preponderance of patients with pneumonia (63%), and a majority of patients who had underlying risk factors for pneumonia or invasive disease (51%). In this limited case control study, no difference was noted between cases and controls regarding known risk factors for penicillin-resistant pneumococcal infections. The percentage of single-patient PRP isolates varied among individual hospitals but the mean percentages of PRP from the four participating University Medical Centers and seven community hospitals were similar: 26% and 22% respectively. By E-test, 60% and 26% were high-level penicillin and ceftriaxone resistant, respectively. Pulsed-field gel electrophoresis identified 26 chromosomal macrorestriction patterns among the 103 PRP isolates available for analysis, but almost half (50 isolates or 48%) of these belong to two drug-resistant internationally spread clones, SP(23)-1 and SP(9/14)-3, that were detected in all hospitals and were recovered from invasive and noninvasive sites in both children and adults.

Susceptibility of Streptococcus pneumoniae and Haemophilus influenzae to cefditoren, and provisional interpretive criteria

In vitro cefditoren antimicrobial activity was tested by broth microdilution and disk diffusion methods against 300 Streptococcus pneumoniae and 299 Haemophilus influenzae isolates. MICs were also determined for three comparison drugs. The MICs of cefditoren were very comparable to those of cefotaxime against both species. If penicillin-resistant pneumococci are to be considered not susceptible to cefditoren, the tentative MIC breakpoints for cefditoren of ≤ 0.25 μg/ml for susceptible and ≥ 1.0 μg/ml for resistant could be selected. With these breakpoints, all penicillin-susceptible pneumococci were cefditoren-susceptible, as were 85% of penicillin-intermediate strains. Provisional zone diameter breakpoints would be ≥ 26 mm for susceptible and ≤ 20 mm for resistant. If penicillin-resistant pneumococcal infections are shown to clinically respond to cefditoren therapy, then a susceptible MIC breakpoint of ≤ 1.0 μg/ml would be appropriate, with a corresponding zone diameter breakpoint of ≥ 21 mm. A susceptible MIC breakpoint of ≤ 0.5 or ≤ 1.0 μg/ml is appropriate for H. influenzae, but lack of correlation between cefditoren MICs and disk diffusion zone diameters when testing H. influenzae leads us to make no recommendations at this time regarding cefditoren disk tests for H. influenzae.

BACTERIAL RESISTANCE AND ANTIBIOTIC USE IN THE EMERGENCY DEPARTMENT

Antibiotic resistance among bacteria that are commonly encountered in the pediatric emergency department is a fact of nature. New antibiotics will provide some help, but probably only temporarily. Vaccine strategies seem to provide the best answer to resistance, and many physicians eagerly await the conjugated pneumococcal vaccines, which we can only hope to be as successful as the H. influenzae type b vaccines. Vaccines against other resistant organisms are likely further off. At this point, a major goal must be to limit the prevalence of antibiotic resistance. In considering this goal, two complementary strategies are key. The first is to avoid antibiotics in situations in which they are unlikely to provide benefit, such as for colds, URIs, and bronchitis. The second is to use narrow-spectrum antibiotics as much as possible to minimize selective pressure. Emerging evidence shows that these strategies can be effective. In a day-care center in Omaha, Nebraska, Boken et al showed that nasopharyngeal carriage of highly resistant S. pneumoniae decreased dramatically among attendees when antibiotic use decreased. In Iceland, a nationwide campaign that resulted in decreased antibiotic use was followed by a decrease in the incidence of penicillin-resistant pneumococcal infections from 20.0% to 16.9% and a decrease in the rate of carriage of resistant pneumococci among day-care-center attendees from 49% to 15%. In Finland, erythromycin resistance in Group A streptococci recovered from pharyngeal and pus samples had reached 13% in 1990. National guidelines that recommended a reduction in the use of erythromycin and other macrolide antibiotics in the treatment of outpatients with respiratory and skin infections were instituted, and by 1996, macrolide antibiotic consumption had decreased by 50%, with a similar 50% decrease in frequency of erythromycin-resistant isolates. In the absence of such national strategies, it is incumbent on physicians treating infections on a daily basis in the emergency department to consider carefully the judicious use of antibiotics.

Nosocomial Penicillin-Resistant Pneumococcal Infections at a Midwestern University Hospital

We analyzed 333 isolates of Streptococcus pneumoniae from adult inpatients over a continuous 30-month period. Twenty-five percent of isolates were resistant to penicillin, and 18% of tested strains were not susceptible to ceftriaxone. For 29 (15%) of 199 evaluable patients, S pneumoniae was isolated from a culture first obtained >48 hours after admission, and chart review satisfied our case definition for nosocomial infection. S pneumoniae isolates were penicillin-resistant in 14 of 29 nosocomial and 34 of 170 community-acquired cases (odds ratio, 3.73; 95% confidence interval, 1.53-9.15; P=.01).

Nosocomial penicillin-resistant pneumococcal infections at a Midwestern university hospital.

We analyzed 333 isolates of Streptococcus pneumoniae from adult inpatients over a continuous 30-month period. Twenty-five percent of isolates were resistant to penicillin, and 18% of tested strains were not susceptible to ceftriaxone. For 29 (15%) of 199 evaluable patients, S pneumoniae was isolated from a culture first obtained >48 hours after admission, and chart review satisfied our case definition for nosocomial infection. S pneumoniae isolates were penicillin-resistant in 14 of 29 nosocomial and 34 of 170 community-acquired cases (odds ratio, 3.73; 95% confidence interval, 1.53-9.15; P=.01).

Is Streptococcus pneumoniae a nosocomially acquired pathogen?

Streptococcus pneumoniae is most prominently a major cause of community-acquired infections of the respiratory tract, central nervous system, and bloodstream, but there is an increasing interest in its role in the epidemiology of hospital-acquired infections. Penicillin-resistant pneumococcal strains appeared 3 decades ago and now are present worldwide, often displaying multiple resistance due to antibiotic selective pressure. Horizontal spread can cause either sporadic cases or hospital outbreaks, primarily in younger children and elderly patients. Pneumococcal transmission from one patient to another can be documented by polymerase chain reaction or pulsed-field gel electrophoresis typing. Nosocomial acquisition of infection, along with pediatric age, previous hospitalization, and previous beta-lactam therapy, are the main risk factors significantly associated with penicillin-resistant pneumococcal infections. Nosocomial acquisition also is associated with higher mortality from pneumococcal disease. The importance of penicillin resistance as a risk factor significantly associated with higher mortality from pneumococcal infection is found in some studies, but not in others. Mortality from pneumococcal pneumonia is approximately the same for human immunodeficiency virus (HIV)-infected patients without acquired immunodeficiency syndrome (AIDS) as for HIV-negative subjects, but it is significantly higher in AIDS patients. Penicillin-resistant strains are involved in the vast majority of hospital outbreaks, whether presenting as clinically manifest infection or a simple colonization. Pneumococcal vaccination is recommended universally in order to lower the incidence of invasive infection, although a number of problems can limit its effectiveness.

Risk factors for penicillin-resistant systemic pneumococcal infections in children.

The purpose of this study was to identify risk factors that may differentiate children who develop systemic infections with resistant strains of Streptococcus pneumoniae from those who develop penicillin-susceptible pneumococcal infections. A retrospective case-controlled study was performed of all patients with positive blood and/or cerebrospinal fluid isolates for S. pneumoniae over a 13 1/2-month period. Patients with penicillin-susceptible strains of S. pneumoniae were compared with those with penicillin-resistant infections in terms of age, race, gender, diagnosis, underlying conditions, antibiotic therapy within 1 month prior to systemic infection, treatment, and outcome. Sixty-nine patients with systemic pneumococcal infections were identified over the study period. Nine (13%) of these patients had infection with a penicillin-resistant isolate. Six of these patients were infected with a relatively resistant strain (MIC 0.1-1.0 microgram/mL) while three were infected with a fully resistant strain (MIC > or = 2.0 micrograms/mL). There was no difference between the two groups in terms of age, race, gender, underlying diagnosis, treatment, or outcome. Sixty-seven percent of the patients who developed a penicillin-resistant pneumococcal infection had received antibiotics in the month prior to systemic illness versus 4% of those infected with a penicillin-susceptible strain (P < 0.0000097). In conclusion, when compared with children who develop systemic infection with a penicillin-susceptible strain of S. pneumoniae, children who develop infection with a penicillin-resistant strain are significantly more likely to have received antibiotics within 1 month prior to their illness.

Emerging infectious diseases and insensible bacillus infectious diseases. Insensible bacillus infectious disease. Penicillin resistant pneumococcal infection.

Emerging infectious diseases and insensible bacillus infectious diseases. Insensible bacillus infectious disease. Penicillin resistant pneumococcal infection.

Invasive pneumococcal disease: clinical features, serotypes, and antimicrobial resistance patterns in cases involving patients with and without human immunodeficiency virus infection.

We reviewed 153 episodes of invasive pneumococcal disease involving 147 hospitalized patients with and without human immunodeficiency virus (HIV) disease to examine and compare epidemiologic and clinical features, capsular serotypes, and antibiotic susceptibility patterns. HIV infection was the most common risk factor for invasive pneumococcal disease. Pneumococcal disease in HIV-infected individuals was characterized by the greater frequency with which pneumonia was the source of bacteremia (90% vs. 63%) (P < .01) and an increased recurrence rate (15% vs. < 1%) (P < .01). The overall mortality rate was 12% and did not vary by HIV serostatus. Capsular-type data were available for 149 episodes; 90% of the types were among those found in the polyvalent pneumococcal vaccine. The four most common capsular types causing invasive disease were 14, 6b, 9v, and 22f; capsular type 9v was significantly more common among HIV-infected patients (P < .01). Penicillin-resistant isolates were identified in 7.2% of all cases, and their presence did not vary by HIV status; 20% of isolates from cerebrospinal fluid were resistant. The majority of the resistant isolates were of capsular type 9v. Given the worldwide increase in both HIV and penicillin-resistant pneumococcal infections, better preventative and therapeutic strategies are greatly needed.

Do we need to treat otitis media?

Otitis media is a common pediatric problem. It is well established that over half of infants and children with acute otitis media may have spontaneous recovery. Since it is difficult to predict the course (self-limited versus serious disease) all the children with acute suppurative otitis media need to be treated with antibiotics. Amoxicillin is still the initial antibiotic of choice. There are several alternate antibiotics available with activity against beta-lactamase positive bacteria. These agents have no advantage over amoxicillin in infections due to penicillin resistant pneumococci. Recent use of beta-lactam antibiotics and/or attendance in a day care where there is frequent use of antibiotics are predisposing factors for penicillin resistant pneumococcal infection. In such cases after tympanocentesis, higher dose of amoxicillin, clindamycin or intramuscular ceftriaxone should be considered. Secretory otitis media does not need to be treated with antibiotics unless the patient is in high risk group. Prophylactic use of antibiotics should be actively discouraged. Influenza and pneumococcal vaccination (2 years or older) should be encouraged in children with recurrent episodes of acute otitis media. Breast feeding should be encouraged.

Antibiotic-resistant pneumococcal infection in children with sickle cell disease in the United States.

The purpose of this report is to examine the increasing problem of antibiotic-resistant pneumococcal infection in children with sickle cell disease in the United States. In this retrospective review, 16 children with sickle cell disease and penicillin-resistant pneumococcal invasive infection were identified. They had a median age of 2 years (range 1-15) and were treated in Memphis, Dallas, Los Angeles, and five other cities between 1987 and early 1995. At presentation, patients frequently had high fever (> or 40.0 degrees C in 75%) and a toxic appearance (44%). Meningitis was present initially in two and diagnosed on days 4 and 5 in two. All were treated with an intravenous cephalosporin and nine received vancomycin. The clinical course was variable: two died within 36 h of presentation. In 20-86% of cases the organisms were resistant to cephalosporins, chloramphenicol, trimethoprim/sulfamethoxazole, erythromycin, and clindamycin; none were resistant to vancomycin. (a) The increasing prevalence of antibiotic-resistant Streptococcus pneumoniae infection in the United States poses special problems for patients with sickle cell disease. (b) Prompt antibiotic susceptibility testing of pneumococcal isolates should be performed. (c) Initial antibiotic management for patients suspected of sepsis/meningitis should include intravenous cephalosporin and vancomycin. (d) No alternative to penicillin prophylaxis is currently available. (e) An effective conjugated pneumococcal vaccine is needed.

Effect of replacing cefotaxime with ceftizoxime in a hospital where penicillin-resistant pneumococcal disease is prevalent.

Ceftizoxime and cefotaxime demonstrate very similar activities in vitro against a broad range of bacteria. To reduce costs, our hospital pharmacy implemented an automatic substitution policy whereby ceftizoxime was dispensed and administered whenever cefotaxime was ordered. This policy was modified when penicillin-resistant Streptococcus pneumoniae isolates were found to be markedly less susceptible to ceftizoxime than to cefotaxime, of concern considering the prevalence and virulence of this pathogen. We compared clinical findings among 179 adult patients treated with ceftizoxime for any indication during the substitution months with 200 patients treated with cefotaxime during the previous year. The ceftizoxime group had a shorter mean length of stay, which paralleled a hospital-wide trend toward more efficient discharge planning. After adjusting for this trend, we observed no significant difference in duration of study drug, number of other intravenous antibiotics, likelihood of receiving additional antibiotics after study drug completion, or patient survival. Fortuitously, no penicillin-resistant pneumococcal infections were documented in ceftizoxime-treated patients. This study suggests that cefotaxime and ceftizoxime are comparable. The choice of one versus the other may be dictated by price, provided ceftizoxime is not used for proven or suspected penicillin-resistant pneumococcal infections.

Meningitis in a Canadian Adult due to High Level Penicillin-Resistant, Cefotaxime-IntermediateStreptococcus pneumoniae

Invasive penicillin-resistant pneumococcal (PRSP) infections are increasing worldwide. In Canada, the incidence of penicillin resistance among Streptococcus pneumoniae isolates is estimated at greater than 6%. In Quebec, only one case of PRSP meningitis has been reported and involved an infant. An adult patient is described who presented with meningitis caused by high level penicillin-resistant, cefotaxime-intermediate S pneumoniae.

Effects of combination of benzylpenicillin and fosfomycin on penicillin-resistant Streptococcus pneumoniae.

The in vitro activity of benzylpenicillin in combination with fosfomycin against 51 clinical isolates of penicillin-resistant Streptococcus pneumoniae [minimal inhibitory concentrations (MICs) of benzylpenicillin > or = 0.5 mg/liter] was investigated. The fractional inhibitory concentration (FIC) index using the checkerboard method ranged from 0.38 to 0.75 (mean: 0.63). A synergy was also demonstrated in the killing curve on S. pneumoniae TW-1303 (MIC of benzylpenicillin, 2 mg/liter; MIC of fosfomycin, 32 mg/liter: FIC index, 0.38). Fosfomycin inhibited the production of all penicillin-binding proteins (PBP) except PBP 2B of S. pneumoniae TW-1303 and it decreased that of PBP 2B when it was combined with benzylpenicillin. These results suggest that the combination of benzylpenicillin and fosfomycin could be considered as the alternative treatment of penicillin-resistant pneumococcal infections.

Treatment of respiratory infections due to Streptococcus pneumoniae in an era of rising penicillin resistance

Summary For the most part, pathogens commonly involved in acute respiratory infections have not changed substantially over the last decade. Streptococcus pneumoniae and Haemophilus influenzae are the leading cause of these infections. However, penicillin resistance among S. pneumoniae has been rising rapidly with most recent reports indicating resistance rates of 70 % in Hungary, 50 % in Spain, 50 % in France, and 20–30 % in the US. The growing impact of penicillin resistance among pneumococci in antimicrobial prescribing habits cannot be overestimated. High risk pediatric patients for acquiring penicillin resistant pneumococcal infection include : 1) children in day care; 2) children receiving multiple courses of antimicrobials; 3) children receiving prophylactic antimicrobials. Amoxicillin is currently the most frequently prescribed antimicrobial for the treatment of respiratory infections in children. However, the increasing resistance rate among important, virulent pathogens brings this routine into question, although, some authorities contend that amoxicillin and/or penicillin may remain effective in the treatment of relatively penicillin resistant pneumococci. Newer alternative antimicrobial agents are being used with increasing frequency for empiric treatment of acute respiratory bacterial infections in children. Parameters for selecting among the newer alternatives include : 1) in vitro activity against likely pathogens; 2) proven clinical efficacy; 3) low frequency of adverse events; 4) once or twice a day dosing; 5) palatability in oral suspension; and 6) reasonable cost. Against penicillin-resistant pneumococci, three agents have thus far gained the most attention : cefuroxime axetil, cefprozil, and cefpodoxime proxetil. The cost of antibiotic failure must be assessed to include loss of time from work/school for the parent/child for unsuccessful first time therapies. It is essential that local bacterial resistance patterns be monitored in individual communities. Clinical efficacy trials are necessary to assess if alternatives to amoxicillin will show greater efficacy in management of penicillin-resistant pneumococcal respiratory infections in children.