Prevalence of antibodies to Rickettsia conorii in human beings and dogs from Catalonia: a 20-year perspective.

The incidence of Mediterranean spotted fever (MSF) in Catalonia (Spain) has decreased in the last two decades. The prevalence of antibodies to Rickettsia conorii in human beings and dogs in the region of Vallès Occidental (Catalonia) was assessed by indirect immunofluorescence, and the results compared with those obtained in a similar study from 1987. Nineteen (5·0%) out of 383 human serum samples had antibodies to R. conorii. This seroprevalence was significantly lower (11·5%) (P = 0·003) than that recorded in the 1987 survey. Forty-two out (42·0%) of 100 canine serum samples had antibodies to R. conorii. A high proportion of the studied dogs (91·0%) were receiving anti-tick treatment, mainly with permethrin-imidacloprid spot-on (Advantix, Bayer, Germany). The current canine seroprevalence was not significantly different from that recorded in the 1987 survey (36.9%). In conclusion, this study shows a significant decrease in the prevalence of antibodies to R. conorii in the human population of Catalonia in the last 20 years, which corresponds with a decrease in the number of cases of MSF. We suggest that the widespread use of anti-tick treatment in dogs could limit the introduction of ticks to humans due to a reduction of infestation duration in dogs, thus contributing to the decrease in MSF incidence.

The impact of time on the systemic inflammatory response in pneumococcal pneumonia.

The aim of our study was to analyse the impact of time from onset of symptoms on the systemic cytokine concentrations in patients with pneumococcal pneumonia. Adults with severe pneumococcal pneumonia were prospectively included. At admission, vital signs, time from onset of pneumonia symptoms and circulating levels of C-reactive protein (CRP), serum amyloid A (SAA), tumour necrosis factor (TNF)-alpha, and interleukin (IL)-1beta, IL-6, IL-8, IL-10 and IL-1ra were recorded. 32 patients were included; 13 patients had <48 h of evolution and 19 patients had been sick for >48 h. The group with a longer time of evolution presented higher plasmatic levels of TNF-alpha (19.1+/-8.5 versus 35.5+/-26 pg.mL(-1)), fibrinogen (6+/-1.8 versus 9+/-2); CRP (130+/-85 versus 327+/-131) and SAA (678+/-509 versus 984+/-391). Concentrations of TNF-alpha were associated with the presence of bacteraemia, initial blood pressure <90 mmHg and with a lower oxygen saturation at admission. Likewise, TNF-alpha levels were correlated with concentrations of IL-1beta (r = 0.49), IL-6 (r = 0.41) and IL-8 (r = 0.40). In pneumococcal pneumonia, patients with a longer time of evolution presented with higher levels of pro-inflammatory cytokines and a higher expression of acute phase proteins, suggesting a sustained release of pneumococcal antigens over time.

Single-dose antibiotic prophylaxis in patients at high risk for infection in biliary surgery: a prospective and randomized study comparing cefonicid with mezlocillin.

The usefulness of antibiotic prophylaxis in biliary surgery is well established. When antibiotic prophylaxis is not used, wound infection rates after biliary surgery range from 10% to 25%. With antibiotic prophylaxis, the rates can be reduced to less than 5%. Three questions are still controversial: Do all patients undergoing biliary surgery require antibiotic prophylaxis? What is the ideal antibiotic for use in biliary surgery? What should be the duration of antibiotic prophylaxis? In this study we prospectively evaluated the efficacy of a single dose of antibiotic prophylaxis in biliary surgery, administered to patients at high risk for infection, in a trial comparing cefonicid (a cephalosporin with a long half-life) with mezlocillin (a broad-spectrum ureidopenicillin).

Meningococcal meningitis with 'normal' cerebrospinal fluid.

A prospective study was made of all patients with normal CSF counts and positive cultures for Neisseria meningitidis diagnosed in "El Vallés" County, Barcelona between January 1987 and December 1990. Meningococcal meningitis was documented in 82 patients, eight of whom (seven children, five boys and two girls with a mean age of 5.6 +/- 3.3 years, and a 69-year-old male patient) had no apparent CSF abnormalities in the initial lumbar puncture. At the time of admission all patients had fever (mean 39.1 degrees C) of 10.8 +/- 5.6 hour duration and petechial rash which had been present for a mean of 3.6 +/- 3.3 hours. Signs of meningeal irritation were not found. A 4-month-old infant with symptoms of circulatory collapse, intracranial hypertension and impairment of consciousness subsequently died of septicemia in 48 hours. Group B N. meningitidis was isolated in six cases (reduced penicillin-susceptibility in two cases) and group C N. meningitidis in the remaining two (reduced penicillin-susceptibility in one case). Patients without pleocytosis did not differ in a statistically significant fashion from the patients with high pleocytosis in the duration of temperature, and petechial rash, leukopenia, positive blood culture and fatal outcome.

[Characterization of Haemophilus influenzae's resistance to ampicillin]. / Caracterización de la resistencia de Haemophilus influenzae a la ampicilina.

BACKGROUND: The resistance of Haemophilus influenzae to ampicillin is nearly always dependent on plasmid-mediated betalactamase production. The betalactamase type most frequently identified was TEM-1; type ROB has occasionally been identified. The presence of plasmid-mediated betalactamase has been studied in H. influenzae strains moderately susceptible or resistant to ampicillin. METHODS: The test used in the detection of the presence of betalactamase was nitrocefin hydrolysis; the enzyme type was identified by analytic isoelectric focusing; the codifying gene of this betalactamase was identified by hybridisation with a TEM-1 probe labeled with digoxigenine. Strains studied were 110, obtained during the period 1987 to 1989 and isolated from four Hospitals of the Vallés area of Barcelona. RESULTS: Enzyme production was detected in 105 of 110 strains studied; TEM-1 type betalactamase was identified in 108 and positive hybridisation was obtained in these strains with the TEM-1 probe. CONCLUSIONS: Nitrocefin hydrolysis is a reliable test for the detection of betalactamase production, although it may be unable to detect it (falses negatives) when the production is low. The only betalactamase type identified was TEM-1. The frequency of the strains with non-enzymatic resistance was 1.8%.

[Bacteremia caused by vancomycin-resistant Enterococcus faecalis. Report of 2 cases]. / Bacteriemia por Enterococcus faecalis resistente a vancomicina. A propósito de dos casos.

The rising concern about nosocomial bacteremia due to vancomycin-resistant E. faecalis in Spanish hospitals. Retrospective review of the medical records of two patients with nosocomial bacteremia due to E. faecalis resistant to vancomycin. Both patients (a 78 years-old male and a 65 years-old female) were admitted in two separate hospital units. None of them had been previously treated with vancomycin, and both patients had severe underlying diseases. The two strains isolated showed high-level vancomycin and teicoplanin resistance, although they were sensitive to daptomycin. No other strain with high level glycopeptide antibiotic resistance was isolated in the hospital during the following 23 months. This occasional resistance to glycopeptides among enterococci has been shown also in other Spanish hospitals. The increasing incidence of penicillin and aminoglycoside resistance among enterococci in our environment could have a practical impact, either for the clinical laboratory and/or for therapeutic decisions in patients with infections due to this microorganism.

[Prospective study of the invasive strains of Streptococcus pneumoniae isolated in 16 hospitals in Cataluna, Spain]. / Estudio prospectivo de las cepas invasivas de Streptococcus pneumoniae aisladas en 16 hospitales de Cataluña durante 1996. Grupo de Microbiólogos de Hospitales Comarcales de Cataluña.

BACKGROUND: The increasing penicillin resistance rates of Streptococcus pneumoniae led us to review the strains isolated from usually sterile sources during 1996 in 16 hospitals of Cataluña. METHODS: A card was designed for the prospective collection of patients' data. Susceptibility to penicillin, cefotaxime and erytromicin, as well as serotypes, were studied. RESULTS: 237 S. pneumoniae strains were isolated from patients aged from one month to 95 years (19% younger than 5 years), 9.7% of adult patients being HIV antibodies carriers. Global penicillin resistance was of 35.4% (27.4% with minimal inhibitory concentration [MIC] between 0.1 and 1 microgram/ml and and 8.0% > 1 microgram/ml), but it was only of 25% in strains causing meningeal infections, and of 34.1% in those involved in respiratory processes. Paediatric patients less than five years old had a higher resistance rate (47.7%), as well as octagenarian ones (44.7%), but HIV+ patients had a lower rate (30.4%). 12.2% of strains (10% of meningeal ones) showed some degree of cefotaxime resistance but only five of them (none from meningeal origin) reached a MIC of 2 micrograms/ml. Global erythromicin resistance was 17.7% (17.1% in strains causing respiratory infections). Prevalent serotypes were 6, 9 and 14. CONCLUSIONS: The high percentage of strains, mainly from paediatric patients, with diminished penicillin, cefotaxime and erythromicin susceptibility among those causing meningitis and respiratory infections, alerts of possible therapeutic failures if empiric treatments are established in infections produced by this microorganism. For this reason, nowadays it is necessary the routine study of the susceptibility of all pathogen strains of pneumococci. Most strains (208 out of 216) causing invasive disease in our area belong to serotypes covered by the present 23-valent vaccine.

[Spontaneous mononucleosis caused by cytomegalovirus in the immunocompetent adult]. / Mononucleosis espontánea por citomegalovirus en el adulto inmunocompetente.

BACKGROUND: The first Spanish series of spontaneous infectious mononucleosis (IM) by cytomegalovirus (CMV) in immunocompetent adults is reported. METHODS: Patients whose clinical manifestations, physical exam, analysis and serology were compatible with acute CMV infection from 1984 to 1993 were retrospectively reviewed. RESULTS: Thirty patients with a mean age of 36 years fulfilled the diagnostic criteria. All presented fever, alone or associated with other symptoms, with a mean duration of 18 days, which persisted over 3 weeks in 36%. Physical exam showed lymph node enlargement (50%), hepatomegaly (33%), splenomegaly (20%) and was normal in 8 patients (26%). Mean leukocyte count was 9.75 x 10(9) (+/- 4.63 x 10(9) with more than 50% lymphomonocytic cells in 22 patients (76%) and reactive lymphocytes, principally from the outset, although this was observed on days 2 and 60 in 11 cases (36%). LDH, ASAT and ALAT were moderately elevated and ESR was normal. Serologic diagnosis was established from IgM (13%) seroconversion or positive IgM in the two samples with IgG four-fold increase (23%), as well as the presence of positive IgM and invariable high IgG in both determinations (26%) or all IgM positive titers in a single sample (36%). CONCLUSIONS: Infectious mononucleosis by cytomegalovirus is an infrequently diagnosed disease which should be considered in any young patient with fever despite a little demonstrative initial physical exam absence of atypical lymphocytes or a lack of diagnostic serology.

[Penicillin-resistant pneumococci and the empirical use of penicillins in the treatment of community-acquired acute pneumonia]. / Neumococos resistentes a penicilina y uso empírico de penicilinas en el tratamiento de la neumonía aguda extrahospitalaria.

The prevalence of penicillin-resistant pneumococci in our environment has raised questions about the effectiveness of penicillin as empiric treatment for community-acquired pneumonia cases. We followed prospectively all patients with community-acquired pneumonia from February 1989 through January 1990. We also reviewed retrospectively the treatment and evolution of all patients with confirmed pneumococcal pneumonia diagnosed between January 1988 and January 1990. A total of 115 patients with probable pneumococcal pneumonia were prospectively followed-up. Seventy-nine were treated with penicillin (benzyl- and aminopenicillin), and the remaining patients with macrolides, cephalosporin drugs or both. Five patients died (4%). There is no significant differences between mortality in penicillin-treated patients (2 cases) when compared to patients with other treatments (3 cases). Twenty-three patients have confirmed pneumococcal pneumonia. Among them, 8 (24%) had penicillin-resistant pneumococci (5 strains with MIC: 0.12-1 microgram/ml; 3 strains with MIC: 2 micrograms/ml). No differences were recorded regarding demographic data, predisposing conditions, underlying diseases, severity of pneumonia or the outcome of treatment between penicillin and non-penicillin treatment groups. Also, no differences were seen in clinical response and mortality when patients with pneumonia due to penicillin-resistant pneumococci treated with penicillin were compared to the ones treated with other drugs. In two patients, initially treated with erythromycin, progression of the pneumonia was recorded. Erythromycin resistant pneumococci (MIC greater than 8 micrograms/ml) were recovered from transthoracic needle biopsy. Both patients recovered well when beta-lactam antibiotics were prescribed.(ABSTRACT TRUNCATED AT 250 WORDS)

[Fluoroquinolone and aminoglycoside resistance in chromosomal cephalosporinase-overproducing gram-negative bacilli strains with inducible beta-lactamase]. / Resistencia a fluorquinolonas y aminoglucósidos en cepas hiperproductoras de cefalosporinasa cromosómica de bacilos gramnegativos con betalactamasa inducible.

INTRODUCTION: The increasing prevalence of stable derepressed mutants over-producers of type I chromosomal cephalosporinase in inducible Enterobacteriaceae and Pseudomonas aeruginosa challenges the adequacy of third generation cephalosporins in the empirical treatment of certain nosocomial infections. We sought to determine the frequency of stable over-producers of type I enzyme and their associated resistance to fluoroquinolones and aminoglycosides. METHODS: Disc-diffusion and MIC determinations to extended-spectrum beta-lactams, imipenem, ciprofloxacin and gentamicin were performed in all cell isolates of inducible enteric bacteria (Enterobacter spp., Citrobacter spp., Serratia spp., Morganella morganii, Providencia spp.) and P. aeruginosa collected during the period of study (1992-1993). RESULTS: A total of 1,426 isolates of inducible enteric bacteria and P. aeruginosa were studied. Each one represented a single patient. Among the 511 isolates of enteric bacteria 15.1% of strains were found to be stable derepressed mutants (Serratia 2.2%; Morganella spp., 3%; Providencia and Proteus 3%; Citrobacter spp., 10%; Enterobacter spp., 23.6%); among the 916 P. aeruginosa isolates studied, 9.2% were stable over-producers. Among Citrobacter, Providencia and Proteus spp., 53.1% of stable over-producers were resistant to ciprofloxacin versus 20.2% of non-over-producers (p < 0.01); in P. aeruginosa, 35.3% of over-producers were resistant to gentamicin versus 25.0% in non-over-producers (p < 0.01). CONCLUSION: The prevalence of stable derepressed mutants is high among enteric bacteria and P. aeruginosa with type I inducible beta-lactamase. These strains frequently exhibit resistance to fluoroquinolones and aminoglycosides, reducing considerably the available therapeutic options.

Accuracy of an enzyme immunoassay for the detection of Helicobacter pylori in stool specimens in the diagnosis of infection and posttreatment check-up.

OBJECTIVE: The aim of this study was to assess the reliability of a newly developed enzyme immunoassay for Helicobacter pylori-specific antigen detection in stools (HpSA) compared to other standardized diagnostic techniques such as histology (H), rapid urease test (RUT) and 13C-urea breath test (UBT) to diagnose H. pylori infection and to evaluate its usefulness in determining H. pylori status after treatment. METHODS: One hundred eighty-eight patients referred to our department for upper gastrointestinal endoscopy were included. H. pylori infection was confirmed in all patients by HpSA test in stools, RUT, UBT, and H. Patients were defined as positive for H. pylori if RUT and UBT or H were positive. A total of 142 symptomatic patients received eradication treatment and were reassessed 6 wk after therapy; for 70 of these patients, stool samples were also collected at 24 h and 6 months after finishing eradication treatment. In the posttreatment follow-up, UBT was used as gold standard. RESULTS: The sensitivity of HpSA test for the diagnosis of H. pylori infection using a cut-off value of 0.130 was 89.5% and its specificity 77.8%. This specificity was lower than that obtained with UBT, H, and RUT. In the early follow-up the sensitivity of HpSA test was null. At 6 weeks and at 6 months post-treatment its sensitivity was 70.4% and 50% and its specificity was 81.6% and 79.3%, respectively. CONCLUSIONS: The HpSA stool test, using a cut-off value of 0.130, may be useful for the primary diagnosis of H. pylori infection, with sensitivity similar to that obtained with other standard tests, but with less specificity. HpSA test is not useful for early monitoring of treatment efficacy. At 6 wk and at 6 months posttreatment, HpSA test lacks accuracy as compared to UBT for evaluating the outcome of the eradication treatment.

Prospective epidemiological study of invasive Haemophilus influenzae disease in adults.

The incidence and characteristics of invasive Haemophilus influenzae disease were studied in 43 adult patients admitted to the acute care hospitals in El Vallés County (Barcelona, Spain) between January 1987 and June 1992. The annual incidence of Haemophilus influenzae disease was 1.2 per 100,000 inhabitants. Pneumonia occurred in 24 patients, meningitis in five, intraabdominal infections in three, obstetric infections in two, epiglottitis in two and cellulitis in one. In six patients the source of infection was unknown. Ten (23%) of the infections were hospital acquired. Underlying conditions were diagnosed in 30 (70%) patients. Nontypeable Haemophilus influenzae strains predominated in all adult age groups. Sixty-one percent of type b and 34% of nontypeable strains were ampicillin resistant (p = 0.08). Multiple antibiotic resistance was also high among type b (53%) and nontypeable (18%) strains. The mortality rate was significantly higher in patients with pneumonia, bacteremia from an unidentified focus or shock at presentation.

Ciprofloxacin and trimethoprim-sulfamethoxazole versus placebo in acute uncomplicated Salmonella enteritis: a double-blind trial.

The role of ciprofloxacin and trimethoprim-sulfamethoxazole (TMP-SMZ) was evaluated in empiric treatment of uncomplicated Salmonella enteritis in a comparative, double-blind trial. Patients were randomized to receive ciprofloxacin (500 mg), TMP-SMZ (160/800 mg), or placebo orally twice daily for 5 days. There were 65 evaluatable patients with acute, uncomplicated, culture-confirmed Salmonella enteritis. Duration of diarrhea, abdominal pain, or vomiting and time to defervescence were not significantly different for patients treated with ciprofloxacin, TMP-SMZ, or placebo; there also were no significant differences with respect to full resolution of symptoms for ciprofloxacin versus placebo (point estimate, 0.2 days; 95% confidence interval [CI], -0.5 to 0.9 days) or for TMP-SMZ versus placebo (point estimate, 0.2 days; 95% CI, -1.0 to 0.6 days). The rate of clearance of salmonellae from stools was not significantly different among the groups.

[Hip prosthesis infection: diagnostic approach and treatment of 27 cases]. / Infección de prótesis de cadera: aproximación diagnóstica y tratamiento de 27 episodios.

BACKGROUND: Preoperative diagnosis of hip prosthesis infection (HPI) is difficult. There is no therapeutic option which is completely effective and without risk. The aim of this study was to evaluate a diagnostic approach and therapeutic strategy in a group of patients with HPI. PATIENTS AND METHODS: A retrospective study of 27 episodes of HPI diagnosed by anatomopathologic and/or microbiologic examination of surgical samples was performed. RESULTS: Twenty-three patients with 27 episodes of HPI out of a total of 24 hip prosthesis (HP) were treated. The infection was early in 15 episodes. The etiologic agents were plasmocoagulase negative staphylococcus (NSP) in 11 cases, P. aeruginosa in 8, S. aureus in 5, Enterococcus sp. in 2 and miscellaneous in the remaining cases. In 2 cases the infection was polymycrobial. Following a mean follow period of 22.6 +/- 15.2 months, 13 out of the 14 patients in whom the prosthesis was withdrawn were cured (in 4 a second prosthesis was implanted), one out of 6 in those in whom the prosthesis remained in situ following debridement, and 2 out of 3 episodes in whom reimplantation was performed over time. The withdrawal of the prosthesis was significantly greater than debridement in the treatment of early infection (p < 0.001). The total mean length of postoperative antibiotherapy was 48.2 +/- 17 days. No differences were observed in the oral versus parenteral treatment (p = 0.22), and nor was prognosis worse in those treated for less than 42 days. CONCLUSIONS: The authors' experience suggests that attempts to save a hip prosthesis in early infection usually fail. In addition to prosthesis withdrawal or implantation of another prosthesis, six weeks of postoperative antibiotic therapy, which may be oral route, appear to be sufficient.

Predictive factors for invasive disease due to penicillin-resistant Streptococcus pneumoniae: a population-based study.

A prospective population-based study was carried out to determine predictive factors associated with penicillin-resistant pneumococcal invasive disease. A total of 374 patients (250 males and 124 females; mean age, 50.3 +/- 27 years) with invasive pneumococcal infection were admitted to one of the five hospitals in El Vallés County (an industrial area with 800,000 inhabitants in the province of Barcelona, Spain) over a period of 5 years. Of the 374 episodes, 21 (5.6%) were due to highly penicillin-resistant pneumococci and 67 (17.9%) to intermediately penicillin-resistant pneumococci. Multivariate analysis showed a statistically significant association between infection with intermediately penicillin-resistant pneumococci and an age of 0-4 years (odds ratio [OR] = 5.3; 95% confidence interval [CI] = 2.2-12.6), the presence of an immunosuppressive underlying disease (OR = 3.0; 95% CI = 1.5-6.0), and the previous use of beta-lactam antibiotics (OR = 2.1; 95% CI = 1.0-4.5). Infection with highly penicillin-resistant pneumococci was associated only with the previous use of beta-lactam antibiotics (OR = 5.9; 95% 95% CI = 2.2-15.8). Highly resistant strains were of serotypes 6, 9, 14, 15, 19, and 23, of which all but serotypes 9 and 15 are included in the newly formulated conjugated vaccine.

Randomized clinical trial comparing two one-week triple-therapy regimens for the eradication of Helicobacter pylori infection and duodenal ulcer healing.

OBJECTIVE: One-week triple therapy has been shown to be effective in Helicobacter pylori eradication and duodenal ulcer healing. However, the optimal therapeutic combination has not yet been identified. Bismuth-containing regimens have the advantage of requiring only one antibiotic. It has been suggested that high doses of omeprazole improve the bactericidal efficacy of antimicrobial regimens against H. pylori. We evaluated the efficacy of two 1-wk triple-therapy regimens for H. pylori eradication and duodenal ulcer healing. METHODS: On an intention-to-treat basis, 182 patients with H. pylori-associated duodenal ulcer were randomized. Group OCB patients (n = 91) were given omeprazole 40 mg b.i.d., clarithromycin 500 mg b.i.d., and colloidal bismuth subcitrate 120 mg q.i.d. for 7 days. Group OCA patients (n = 91) were treated with omeprazole and clarithromycin at the same doses plus amoxicillin 1 g b.i.d., also for 7 days. Endoscopies were performed at entry and at 4 wk after the end of treatment. The presence of H. pylori was assessed by urease test, histology, Gram stain, and culture. No patient received follow-up treatment. RESULTS: H. pylori eradication rates achieved in the OCB and OCA groups were similar whether by intention-to-treat (82.4% vs 88.9% ;p = 0.21) or per protocol analysis (83.3% vs 89.9%; p = 0.19). Duodenal ulcer healing rates also were the same for OCB and OCA in intention-to treat (91.2% vs 91.1%) and per protocol analysis (92.2% vs 92.1%), respectively (p = 0.98). CONCLUSIONS: High rates of H. pylori eradication and duodenal ulcer healing were obtained with both short-treatment regimens, which were safe and well-tolerated. Colloidal bismuth subcitrate seems to be a good alternative to amoxicillin in the triple-therapy combination with omeprazole and clarithromycin. The omeprazole dose does not seem to play a major role in H. pylori eradication in these therapeutic combinations.

[Neonatal infection by Streptococcus agalactiae. Multicenter study in the area of Barcelona, Spain]. / Infección neonatal por Streptococcus agalactiae. Estudio multicéntrico en el área de Barcelona.

BACKGROUND: Streptococcus agalactiae or streptococcus group B (SGB) is the main etiologic agent of early neonatal sepsis. A multicenter study was performed with the aim of determining the incidence and characteristics of this disease in our medium and contribute the design of an adequate prevention protocol. METHODS: Ten hospitals and two primary health care centers were implicated in the study; 103 microbiology confirmed episodes of SGB neonatal sepsis (blood and/or LCR positive) were reported from 1994 to 1996. RESULTS: The incidence of early SGB neonatal sepsis was 1.48/1,000 live births with a mortality of 8.7%. The cultures, for detecting the state of the SGB carrier were performed in only 26 (25%) of the patients. At least one of the factors described for risk of perinatal SGB infection was observed in 46% of the mothers, with the most frequent being prolonged amniorrhea (26%), intrapartum fever (17%), and early delivery (14%). At the time of delivery only 10.7% of the mothers received endovenous antibiotherapy. CONCLUSIONS: From these results the following recommendations have been made: a) detection of SGB carriers by the systematic practice of blood cultures in the last weeks of gestation and b) the administration of intrapartum antibiotic prophylaxis in both early births (< 37 weeks) and in all the SGB carriers should be undertaken. With these measures we aim to decrease the neonatal infections by streptococcus group B.

Early and delayed consolidation chemotherapy significantly improves the outcome of children with intermediate risk acute lymphoblastic leukemia. Final results of the prospective randomized PETHEMA ALL-89 TRIAL.

BACKGROUND AND OBJECTIVES: To evaluate the impact of early and delayed consolidation chemotherapy on the outcome of children with acute lymphoblastic leukemia (ALL) stratified according to risk groups. DESIGN AND METHODS: From 1989 to 1994, 195 children (< or = 15 years old) diagnosed as having ALL (ALL-L3 excluded) in 15 Spanish hospitals entered the prospective, randomized PETHEMA ALL-89 trial. Patients were stratified into low-risk (LR), intermediate-risk (IR) and high-risk (HR) groups according to their initial features and the rate of response to induction therapy. LR-ALL patients were randomized to receive or not early consolidation chemotherapy (C-1). After receiving C-1, IR patients were randomized to receive or not delayed consolidation chemotherapy (C-2). HR patients received C-1 and C-2 chemotherapy. Standard maintenance chemotherapy was administered to all patients for 2 years. High doses of intravenous methotrexate and 12 triple intrathecal doses were given as prophylaxis against central nervous system (CNS) disease. RESULTS: The mean (and standard deviation) age was 6 (4) years and 120 patients were males. Fourteen patients had early pre-B-ALL, 149 common or pre-B-ALL, and 32 T-ALL. Complete remission (CR) was attained in 189 patients (97%), 11 of whom (6%) had a slow response. Risk group stratification after CR was: LR 89, IR 50 and HR 56 patients (including a subset of 26 patients at very high risk). Ten-year event-free survival (EFS) and overall survival (OS) probabilities for the whole series were 58% (95% CI: 52-64%) and 69% (61-77), respectively, with a median follow-up of 8.7 years. Dividing the patients according to risk group, the 10-year EFS and OS probabilities in the LR group were 71% (63-79) and 86% (80-92), respectively; in the IR group 69% (57-81) and 76% (64-88), respectively, and in the HR group 30% (18-42) and 44% (32-57), respectively. For LR patients receiving C-1, EFS and OS were 79% (57-92) and 90% (82-98), respectively, versus 62% (48-76) and 66% (51-81) in patients not receiving C-1 (p= 0.06). For IR patients, EFS and OS were significantly improved in those receiving early and delayed consolidation (EFS 87% (74-88) vs. 52% (41-70), and OS 92% (87-97) vs. 61% (51-71)(p=0.036). Prognostic factors for EFS identified in multivariable analyses were: age >10 years in the LR group (OR 3.5, 95% CI 1.3-9.5, p=0.01), and treatment with C-2 in IR patients (OR 5.0, 95% CI 1.4-17.8, p=0.01). The CNS relapse rate was 4% for all the series (including the HR subset). Tolerance to treatment was good. INTERPRETATION AND CONCLUSIONS: In this study, early consolidation seemed to improve the prognosis of children with LR-ALL, but differences in EFS were not significant. Delayed consolidation had a favorable influence on the outcome of IR-ALL. CNS preventive treatment without cranial irradiation was effective in all the groups of ALL patients.