Roman Pallares

Resistance to Penicillin and Cephalosporin and Mortality from Severe Pneumococcal Pneumonia in Barcelona, Spain

BACKGROUND Penicillin-resistant strains of Streptococcus pneumoniae are now found worldwide, and strains with resistance to cephalosporin are being reported. The appropriate antibiotic therapy for pneumococcal pneumonia due to resistant strains remains controversial. METHODS To examine the effect of resistance to penicillin and cephalosporin on mortality, we conducted a 10-year, prospective study in Barcelona of 504 adults with culture-proved pneumococcal pneumonia. RESULTS Among the 504 patients, 145 (29 percent) had penicillin-resistant strains of S. pneumoniae (minimal inhibitory concentration [MIC] of penicillin G, 0.12 to 4.0 micrograms per milliliter), and 31 patients (6 percent) had cephalosporin-resistant strains (MIC of ceftriaxone or cefotaxime, 1.0 to 4.0 micrograms per milliliter). Mortality was 38 percent in patients with penicillin-resistant strains, as compared with 24 percent in patients with penicillin-sensitive strains (P = 0.001). However, after the exclusion of patients with polymicrobial pneumonia and adjustment for other predictors of mortality, the odds ratio for mortality in patients with penicillin-resistant strains was 1.0 (95 percent confidence interval, 0.5 to 1.9; P = 0.84). Among patients treated with penicillin G or ampicillin, the mortality was 25 percent in the 24 with penicillin-resistant strains and 19 percent in the 126 with penicillin-sensitive strains (P = 0.51). Among patients treated with ceftriaxone or cefotaxime, the mortality was 22 percent in the 59 with penicillin-resistant strains and 25 percent in the 127 with penicillin-sensitive strains (P = 0.64) The frequency of resistance to cephalosporin increased from 2 percent in 1984-1988 to 9 percent in 1989-1993 (P = 0.002). Mortality was 26 percent in patients with cephalosporin-resistant S. pneumoniae and 28 percent in patients with susceptible organisms (P = 0.89). Among patients treated with ceftriaxone or cefotaxime, mortality was 22 percent in the 18 with cephalosporin-resistant strains and 24 percent in the 168 with cephalosporin-sensitive organisms (P = 0.64). CONCLUSIONS Current levels of resistance to penicillin and cephalosporin by S. pneumoniae are not associated with increased mortality in patients with pneumococcal pneumonia. Hence, these antibiotics remain the therapy of choice for this disease.

Risk Factors and Response to Antibiotic Therapy in Adults with Bacteremic Pneumonia Caused by Penicillin-Resistant Pneumococci

We retrospectively studied 24 adults with bacteremic pneumonia (25 episodes) due to penicillin-resistant pneumococci, for which the minimal inhibitory concentrations (MICs) of penicillin G were 0.12 to 8.0 micrograms per milliliter; 79 percent of the strains showed multiple antibiotic resistance. As compared with 48 control patients with bacteremic pneumonia caused by penicillin-sensitive pneumococci, the 24 patients with penicillin-resistant pneumococci had a significantly higher incidence of use of beta-lactam antibiotics during the previous three months (65 vs. 17 percent, P = 0.0008), hospitalization during the previous three months (58 vs. 21 percent, P = 0.0038), nosocomial pneumonia (37 vs. 6 percent, P = 0.0032), episodes of pneumonia during the previous year (29 vs. 4 percent, P = 0.010), and factors on initial presentation that were associated with a poor prognosis (an initially critical condition) (67 vs. 27 percent, P = 0.0030). Their overall mortality rate was significantly higher (54 vs. 25 percent, P = 0.0298). Eleven of 19 episodes of pneumonia due to organisms for which MICs were 0.12 to 2.0 micrograms per milliliter, which were treated with penicillin G (10 episodes) or another beta-lactam agent (9 episodes), resulted in recovery (2 of 10 patients in an initially critical condition recovered, as compared with all of 9 not initially in a critical condition, P = 0.0012). Two patients who had penicillin-resistant pneumococci for which MICs were 4.0 and 8.0 micrograms per milliliter did not respond to ampicillin and ticarcillin therapy, respectively. Our study suggests that pneumonia due to penicillin-resistant pneumococci may occur more often in a population with some identifiable risk factors, and may respond to intravenous high-dose penicillin therapy if MICs are less than or equal to 2 micrograms per milliliter. Cases involving higher resistance may require an alternative antibiotic.

Emergence of Invasive Pneumococcal Disease Caused by Nonvaccine Serotypes in the Era of 7-Valent Conjugate Vaccine

BACKGROUND Little is known about the epidemiology of invasive pneumococcal disease (IPD) after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in Spain and other European countries. METHODS We performed a 10-year prospective study including all children with culture-proven IPD admitted to Sant Joan de Deu Hospital, a childrens center in the southern area of Barcelona, Catalonia, Spain. PCV7 was introduced in June 2001, and the current estimate of PCV7 coverage is 45%-50%. RESULTS Comparing the prevaccine period (1997-2001) with the vaccine period (2002-2006), among children aged <2 years, the rate of IPD increased from 32.4 episodes per 100,000 population to 51.3 episodes per 100,000 population (an increase of 58%; 95% confidence interval, 2%-145%), and among children aged 2-4 years, the rate increased from 11.3 episodes per 100,000 population to 26.5 episodes per 100,000 population (an increase of 135%; 95% confidence interval, 31%-320%). At clinical presentation, the rate of pneumonia and/or empyema among children aged <5 years increased from 3.6 episodes per 100,000 population to 15.1 episodes per 100,000 population (an increase of 320%; 95% confidence interval, 98%-790%). These increased rates of IPD were caused by non-PCV7 serotypes, which represented 38% and 72% of infecting serotypes in the prevaccine and vaccine periods, respectively (P=.001). Penicillin resistance decreased from 48% in the prevaccine period to 27% in the vaccine period (P=.005). In the vaccine period, there was an emergence of previously established virulent clones of non-PCV7 serotypes 1 and 5. There was also an increase in the prevalence of serotypes 19A and 6A expressed with different clonal types, including Spain(23F)-1 and Spain(6B)-2. CONCLUSIONS Since the introduction of PCV7 for children, there has been an emergence of IPD caused by virulent clones of non-PCV7 serotypes that has been associated with significant clinical changes and a decrease in antibiotic resistance.

Nosocomial Staphylococcus aureus bacteremia among nasal carriers of methicillin-resistant and methicillin-susceptible strains

OBJECTIVES To determine the relevance of nasal carriage of Staphylococcus aureus, either methicillin-sensitive (MSSA) or methicillin-resistant (MRSA), as a risk factor for the development of nosocomial S aureus bacteremia during an MRSA outbreak. PATIENTS AND METHODS In this prospective cohort study, 488 patients admitted to an intensive care unit (ICU) during a 1-year period were screened with nasal swabs within 48 hours of admission and weekly thereafter in order to identify nasal S aureus carriage. Nasal staphylococcal carriers were observed until development of S aureus bacteremia, ICU discharge, or death. RESULTS One hundred forty-seven (30.1%) of 488 patients were nasal S aureus carriers; 84 patients (17.2%) harbored methicillin-sensitive S aureus; and 63 patients (12.9%) methicillin-resistant S aureus. Nosocomial S aureus bacteremia was diagnosed in 38 (7.7%) of 488 patients. Rates of bacteremia were 24 (38%) of the MRSA carriers, eight (9.5%) of the MSSA carriers, and six (1.7%) of noncarriers. After adjusting for other predictors of bacteremia by means of a Cox proportional hazard regression model, the relative risk for S aureus bacteremia was 3.9 (95% confidence interval, 1.6-9.8; P = 0.002) for MRSA carriers compared with MSSA carriers. CONCLUSIONS Among ICU patients, nasal carriers of S aureus are at higher risk for S aureus bacteremia than are noncarriers; in the setting of an MRSA outbreak, colonization by methicillin-resistant strains represents a greater risk than does colonization by MSSA and strongly predicts the occurrence of MRSA bacteremia.

Prevalence and prognostic implications of dysphagia in elderly patients with pneumonia

BACKGROUND oropharyngeal dysphagia is a common condition among the elderly but not systematically explored. OBJECTIVE to assess the prevalence and the prognostic significance of oropharyngeal dysphagia among elderly patients with pneumonia. DESIGN a prospective cohort study. SETTING an acute geriatric unit in a general hospital. SUBJECTS a total of 134 elderly patients (>70 years) consecutively admitted with pneumonia. METHODS clinical bedside assessment of oropharyngeal dysphagia and aspiration with the water swallow test were performed. Demographic and clinical data, Barthel Index, Mini Nutritional Assessment, Charlson Comorbidity Index, Fines Pneumonia Severity Index and mortality at 30 days and 1 year after admission were registered. RESULTS of the 134 patients, 53% were over 84 years and 55% presented clinical signs of oropharyngeal dysphagia; the mean Barthel score was 61 points indicating a frail population. Patients with dysphagia were older, showed lower functional status, higher prevalence of malnutrition and comorbidities and higher Fines pneumonia severity scores. They had a higher mortality at 30 days (22.9% vs. 8.3%, P = 0.033) and at 1 year of follow-up (55.4% vs. 26.7%, P = 0.001). CONCLUSIONS oropharyngeal dysphagia is a highly prevalent clinical finding in elderly patients with pneumonia and is an indicator of disease severity in older patients with pneumonia.

Evaluation of vancomycin for therapy of adult pneumococcal meningitis.

The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy.

Changes in antimicrobial resistance, serotypes and genotypes in Streptococcus pneumoniae over a 30-year period

Over the past three decades, antimicrobial resistance in Streptococcus pneumoniae has dramatically increased worldwide. Non-susceptibility to penicillin in S. pneumoniae was first described in Australia in 1967, and later in New Guinea (1974), South Africa (1977), and Spain (1979). Most of these strains showed resistance to multiple antibiotics and belonged to serotypes 6A, 6B, 19A, 19F, and 23F. By the late 1980s and 1990s, the emergence and rapid dissemination of antibiotic-resistant pneumococci was observed in southern and eastern Europe, North America, South America, Africa, and Asia. Great geographical variability, both in serotype distribution and in the prevalence of resistant pneumococci, has been reported. However, the highest rates of resistance to penicillin and erythromycin worldwide were found in serotypes 6B, 6A, 9V, 14, 15A, 19F, 19A, and 23F. The introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in the 2000s and a reduction in antimicrobial use were associated with a significant decline in the incidence of invasive pneumococcal infections and in rates of antibiotic resistance in the USA. However, an increase in the incidence of infections caused by non-PCV7 serotypes, especially multiresistant serotype 19A pneumococci, has been observed in many countries over the last 5 years. The dynamic character of serotypes and antibiotic resistance in S. pneumoniae should be controlled by a policy of prudent antibiotic use and by implementation of the new generation of conjugate vaccines.

Relationship between quinolone use and emergence of ciprofloxacin-resistant Escherichia coli in bloodstream infections.

From 1988 to 1992, 27 of 855 cases of Escherichia coli bacteremia in nonneutropenic adult patients observed at our hospital were due to ciprofloxacin-resistant (CIPRO-R) strains. Eighteen episodes (67%) were community acquired, and nine (33%) were nosocomially acquired. Overall, the rates of E. coli bacteremia caused by CIPRO-R strains increased steadily from 0% in 1988 to 7.5% in 1992 (P < 0.01). There was a statistically significant correlation between the incidence of CIPRO-R E. coli bacteremia and the upward trend in fluoroquinolone (norfloxacin and ciprofloxacin) use in the community (r = 0.974; P = 0.005) as well as in the hospital (r = 0.975; P = 0.005). When we compared the 27 case patients with 54 simultaneous control patients who had ciprofloxacin-susceptible E. coli bacteremia, the case patients more frequently had chronic underlying diseases (71 versus 37%; P = 0.004), urinary tract infection (74 versus 50%; P = 0.03), prior surgery (22 versus 6%; P = 0.02), and prior fluoroquinolone use (63 versus 4%; P < 0.001). A logistic regression analysis identified prior quinolone use as the only independent risk factor for CIPRO-R E. coli bacteremia. In conclusion, our study shows a significant correlation between ciprofloxacin resistance and fluoroquinolone use and indicates that prior fluoroquinolone use seems to be the most important risk factor for CIPRO-R E. coli bacteremia.

Epidemiology of Invasive Pneumococcal Disease among Adult Patients in Barcelona Before and After Pediatric 7-Valent Pneumococcal Conjugate Vaccine Introduction, 1997–2007

BACKGROUND A dramatic decrease in the incidence of invasive pneumococcal disease (IPD) was observed among children and adults in the United States after the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). Little is known about the incidence of IPD after PCV7 licensure in Europe. The objective of this study was to examine changes in the prevalence of IPD among adults in the PCV7 era. METHODS We undertook a prospective study involving adults with IPD who required hospital admission in the southern area of Barcelona, Spain. Three periods were studied: the pre-PCV7 period (1997-2001), the early PCV7 period (2002-2004), and the late PCV7 period (2005-2007). RESULTS A total of 1007 episodes of IPD were observed. Rates of IPD among adults increased from 13.9 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .6) and then to 19.55 episodes per 100,000 population in the late PCV7 period (P < .001). The rates of IPD among adults due to non-PCV7 serotypes increased from 8.4 to 9.7 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .15) and then to 15.3 episodes per 100,000 population in the late PCV7 period (P < .001); IPD due to PCV7 serotypes decreased from 5.6 to 4.9 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .3), then to 4.3 episodes per 100,000 population in the late PCV7 period (P = .056). Among people aged > or = 65 years, IPD due to PCV7 serotypes decreased from 19.5 to 14.6 episodes per 100,000 population between the pre-PCV7 period and the early PCV7 period (P = .13), then to 12.3 episodes per 100,000 population in the late PCV7 period (P = .02). A decrease in the prevalence of antibioticresistant pneumococci in the late PCV7 period was associated with a decrease in the prevalence of multidrugresistant PCV7 clones (Spain(23F)-ST81, Spain(6B)-ST90, and ST88(19F)) and an increase in the prevalence of non-PCV7 antibiotic-susceptible clones (ST306(1), ST191(7F), ST989(12F), and ST433(22F)). CONCLUSIONS Rates of IPD among adults increased in Barcelona in the late PCV7 period, coinciding with a clonal expansion of non-PCV7 serotypes. In contrast, rates of IPD caused by PCV7 serotypes decreased among people aged > or = 65 years, which suggests the development of a herd immunity.

Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci

Of 66 episodes of pneumococcal meningitis seen in Bellvitge Hospital, Barcelona, Spain (January 1981 to June 1987), 15 (23 percent) were due to penicillin-resistant pneumococci [minimal inhibitory concentrations (MICs) of 0.1 to 4 micrograms/ml]. Fifty percent of these strains were also resistant to chloramphenicol. Most were sporadic community-acquired cases. Clinical characteristics were similar in both penicillin-resistant and penicillin-sensitive cases. Those cases with MICs of greater than 1 microgram/ml did not show a response to penicillin therapy. Of nine patients treated with cefotaxime (200 to 350 mg/kg per day) with penicillin G MICs of 0.1 to 4 micrograms/ml and cefotaxime MICs of less than or equal to 0.03 to 1 microgram/ml, seven recovered, one experienced a relapse after 14 days of therapy and the infection was cured with intravenous vancomycin, and one patient died with sterile cerebrospinal fluid. Thus, adults with meningitis due to penicillin-resistant pneumococci may be adequately treated with high doses (around 300 mg/kg per day) of intravenous cefotaxime if MICs of penicillin G are less than or equal to 4 micrograms/ml. Cases with higher resistance may require another antibiotic such as vancomycin.