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A randomized prospective study comparing pefloxacin to teicoplanin in the treatment of gram-positive infections in cancer patients was prematurely terminated because of the emergence of pefloxacin resistance associated with oxacillin resistance in Staphylococcus aureus and coagulase-negative staphylococci. Among 56 patients evaluated for efficacy (26 pefloxacin and 30 teicoplanin) and infected with bacteria susceptible to both antibiotics, the clinical cure and eradication rates were similar for pefloxacin (80.5% and 77.3% respectively) and teicoplanin (66.6% and 52.2% respectively). The relapse rates (15% and 10% for pefloxacin and teicoplanin respectively) and the overall mortalities within 1 month (42% and 31%) were similar.

Data concerning 40 patients hospitalized in a cancer center and Salmonella infection were analyzed. Hematological malignancy was present in 24 patients (60%) and solid tumor in 14 patients (35%). Among the predisposing factors, antineoplastic chemotherapy was the most frequent (60%) followed by antacid use (47.5%), corticosteroids (37.5%), granulocytopenia below 500 neutrophils/microliters (15%), surgery (10%) and splenectomy (2.5%). Bacteremia was the most frequent clinical syndrome accounting for 42.5% of the patients. Focal infection, enteritis and carrier state accounted for the remaining 30%, 20% and 7.5% respectively. Salmonella typhimurium and S. dublin represented 65% of the isolates, with clear association between serotype dublin and bacteremia. All S. dublin isolates were resistant to chloramphenicol. Among dublin and typhimurium serotypes, 20% the isolates were resistant to the traditional antibiotics used in salmonellosis (ampicillin, chloramphenicol, cotrimoxazole). All strains were susceptible in vitro to cephalosporins. The frequency of relapse was 15% and the overall mortality (within 30 days) attributed to Salmonella infection was 15%.

Seventy-five episodes of clinically relevant anaerobic bacterial bacteremia observed in cancer patients were reviewed. Gastrointestinal (22.7%), hematological (22.7%) and female genital tract (18.6%) cancers were the most common underlying malignant diseases. Among 84 strains of strict anaerobic bacteria recovered in the 75 patients, gram-negative rods were isolated in 49 patients (58.3%), gram-positive rods in 29 patients (34.5%) and gram-positive cocci in 6 patients (8%). Bacteroides spp. and Clostridium spp. were the most frequent pathogens (85.7%). Twenty-one episodes of bacteremia were polymicrobial, aerobic gram-positive cocci being the most frequently associated pathogens. When identified, the primary sites were the gastrointestinal tract (40%), the female genital tract (17.3%), skin and soft tissue (14.6%), the oropharynx (12%) and the lower respiratory tract (6.7%). The source remained unknown in 7 cases (9.3%). The overall survival (evaluated 10 days after the occurrence of bacteremia) was 82.5%. There was no difference in mortality between patients with monomicrobial and polymicrobial bacteremia. Pulmonary complications were more frequent in patients with fatal outcome in comparison to patients who survived. The mortality rate of the patients adequately treated was 10.3% compared to 41% for the patients not treated or treated inadequately (P = 0.016, chi 2).

A total of 1051 bacteremic episodes (782 patients) were prospectively recorded in 10 cancer centers (9 French, 1 Belgian), with: patient's age (mean 53, range 1-89 years), underlying cancer, neutropenia (< 1000 neutrophils/microliters; 233), signs and symptoms, type of i.v. line (percutaneous central: 534; peripheral: 228; central implanted: 304), treatment, blood culture system, number of positive blood culture bottles/total obtained, time to growth. Of all episodes, 23.2% occurred within 48 h of admission. The patients were receiving systemic antibiotics at sampling (on AB) in 34.6% of cases. The 1147 pathogens isolated (86 polymicrobial) were: E. coli (10.7%), Klebsiella-Enterobacter-Serratia (6.1%), other enterobacteriaceae (2.2%), Pseudomonas aeruginosa (4.8%), other nonfermenters (4.7%), coagulase-negative staphylococci (CNS, 40.8%), Staphylococcus aureus (9.9%), streptococci (5.4%), enterococci (2.2%), anaerobes (3.4%), yeasts (3.5%), and other bacteria (6.9%). The CDC (Centers for Disease Control) criteria (1988) were used to assess significance: group 1: pathogenic species (616 episodes; 59%); group 2: clinical signs and isolation of a "contaminant" species (47; 4.5%); group 3: as in group 2 with an i.v. line and empiric antibiotic treatment (181 episodes including 176 CNS; 17%); group 4: non-significant (207 episodes including 203 CNS; 20%). Groups 1-3, in which the episodes were considered to be significant (844 episodes; 80%) were compared with non-significant episodes (Fisher). Significant differences (P < or = 0.05) were seen in time to growth (median growth within 24 h vs 48 h), fever (86% vs 54%), chills (40% vs 3%), hypotension (10% vs 2%), septic shock (9% vs 1%), polymicrobial etiology (10% vs 0.5%), and initiation of empiric antibiotic treatment (71% vs 4%). Bacteremic episodes of CDC groups 1, 3 and 4 were further studied in episodes with a single isolate as a doubtful clinical significance (482 episodes) and episodes with > or = 2 bottles positive of probable clinical significance (569 episodes; 54%). In group 1 (218 doubtful, 398 probably significant episodes) significant differences were seen in chills (36% vs 52%), shock (7% vs 13%), polymicrobial (8% vs 17%), initiation of empiric antibiotic treatment (60% vs 72%); in group 3 (87 doubtful, 94 probably significant) in time to growth delay; in group 4 (177 doubtful, 30 probably significant) in proportion with implanted catheter (26% vs 52%), fever (62% vs 10%), and time to growth. This study confirms the predominant role of Gram-positive cocci in bacteremia occurring in cancer patients.

Fifty-one episodes of bacteraemia due to Pseudomonas species other than Pseudomonas aeruginosa occurring between 1980 and 1990 in a Belgian cancer centre were reviewed. This corresponded to an incidence of 0.62/1000 admissions, or 1.5% of all bacteraemic episodes. Twenty-nine episodes, each with several positive blood culture sets were considered clinically significant, including six patients belonging to a well-documented outbreak of pseudobacteraemia with Xanthomonas maltophilia and associated with contaminated blood sampling tubes. The respiratory tract was the source in six (20.7%), an infected intravenous catheter in 10 (34.5%) and the source was unknown in seven (24.1%). Seven patients died from infection (24.1%). Twenty-three episodes with a single positive blood culture set were considered clinically not significant, although four of them were considered significant by the Centers for Disease Control (CDC) criteria because of the presence of symptoms and specific antibiotic treatment being administered. None of the patients with a single isolate died from infection despite the fact that 17 of 22 did not receive an effective antimicrobial agent. All isolates were susceptible to co-trimoxazole.

Eighty-two episodes of bacteremia due to streptococci (including the genus Enterococcus) in 78 patients hospitalized at Institut Jules Bordet between 1986 and 1988 were reviewed. The incidence ranged from 5.5 to 7.6 per 1,000 admissions (16% of all bacteremias). Enterococcus faecalis, Streptococcus sanguis, and Streptococcus mitis were the most prevalent isolates, followed by Streptococcus angionosus, Streptococcus salivarius, and large colony-forming beta-hemolytic species (A, B, C, and G). Twenty-one episodes were polymicrobial. One-half of the patients had solid tumors, and one-half had hematologic malignancies. Forty-two patients were neutropenic (less than 1,000 polymorphonuclear neutrophils/microL). Only 15 episodes were acquired outside the hospital, and 11 episodes were breakthrough bacteremias. Twenty patients died within 1 month of the onset of streptococcal bacteremia. Five patients, two of whom were neutropenic, had fatal adult respiratory distress syndrome. The source of bacteremia remained undetermined in 35.4% of the episodes; the oral mucous membrane and the gastrointestinal tract were the most frequently recognized associated sites of infection. No unexpected antimicrobial resistance was observed except in two penicillin-resistant strains, one S. mitis and one E. faecium. No relation between peak or trough serum bactericidal titers and outcome could be demonstrated.

Amphotericin B concentration was measured by high-pressure liquid chromatography (HPLC) and by bioassay in tissues of 11 cancer patients who died from infection and/or their underlying disease after having received amphotericin B entrapped into sonicated liposomes (ampholiposomes). These concentrations were compared to those measured in 28 patients who had only received the commercially available preparation of amphotericin B-Na deoxycholate complex (Fungizone). The fungistatic and fungicidal titres of the tissue homogenates were also evaluated using two strains of Candida spp. and one strain of Cryptococcus neoformans to determine the bioactivity of amphotericin B incorporated in our liposomes. Tissue concentrations varied with the tested tissues and were correlated with the total dose of amphotericin B administered whether given as amphotericin B-Na deoxycholate or ampholiposomes. Amphotericin B concentrations measured by bioassay in tissue methanolic extracts reached 58-81% of concentrations measured by HPLC, whereas only 15-41% was recovered from the unextracted homogenates. Fungicidal titres were seldom measured in tissues, but fungistatic titres were observed and were linearly correlated with amphotericin B concentration measured by HPLC. These results were similar for the patients who received only amphotericin B-Na deoxycholate and for those who received both preparations (amphotericin B-Na deoxycholate and ampholiposomes). Our results suggest that the tissue distribution of amphotericin B is not significantly modified by the type of preparation (deoxycholate complex or liposomes) and that most of the tissue-bound amphotericin B is not bioactive. However, higher daily doses of amphotericin B can be administered safely when incorporated in liposomes and therefore high tissue concentrations may be obtained more rapidly with ampholiposomes than with amphotericin B-Na deoxycholate.

The pharmacologic parameters and toxicity of netilmicin (6 mg/kg/day) given once daily (qd) or thrice daily (tid) for the treatment of urinary tract infections were studied in a randomized prospective study of 60 cancer patients. The overall efficacy was 96%. Nephrotoxicity, assessed by the measure of urinary excretion of phospholipids, was lower for the patients receiving the qd regimen than for those receiving the tid regimen. Elevation of serum creatinine (20% over baseline) occurred in one patient receiving the qd regimen and in three receiving the tid regimen. Cochleotoxicity, assessed by pure-tone audiometry (250 to 18,000 Hz) occurred in one patient receiving the qd regimen and none receiving the tid regimen. Concentrations in sera were measured on days 1 and 5. No significant accumulation was observed in either group. Median serum bactericidal titers, expressed as reciprocal values (percentage of the sera with a titer greater than or equal to 8), were measured against 25 test organisms in samples collected 6 h after the administration of netilmicin and were, for the qd group, 16 (82%) against members of the family Enterobacteriaceae and less than 2 (8%) against Pseudomonas aeruginosa, and for the tid group, 4 (57%) against members of the Enterobacteriaceae and less than 2 (0%) against P. aeruginosa. The rate of killing in serum was rapid (2 to 3 log in 2 h against P. aeruginosa; 3 to 5 log in 2 h against members of the Enterobacteriaceae) and correlated with the sampling time and hence the concentration in serum of netilmicin. The duration of the postantibiotic effect in serum depended also on the strain and the sampling time of the serum.

In a prospective randomized study, 100 episodes of fever (greater than 38 degrees C) and granulocytopenia (less than 1000/microliters) in cancer patients were empirically treated with ceftazidime (2 g every 8 h) plus teicoplanin (400 mg every 8 h on day 1; 400 mg every day thereafter) or ceftazidime (2 g every 8 h) plus amikacin (500 mg every 8 h). Bacteraemia, clinically documented infection and possible infection were documented in seven, 11 and 19 patients treated with ceftazidime plus teicoplanin and in 11, four and 17 patients treated with ceftazidime plus amikacin. Overall, the response rate was similar in the two groups of patients as was the need for treatment modifications and the rate of death. For documented Gram-positive bacteraemia, the response rate was 2/5 patients treated with ceftazidime plus teicoplanin and 2/7 with ceftazidime plus amikacin; for documented Gram-negative bacteraemia, the response rate was 1/2 and 3/4 patients respectively. No breakthrough bacteraemia was observed. Tolerance was excellent, although renal toxicity (elevation of serum creatinine) was observed in three patients treated with ceftazidime plus teicoplanin and in none allocated to ceftazidime plus amikacin.

Granulocytopenia is the leading alteration of the natural host defense mechanisms, whether caused by an underlying disease or associated with anticancer chemotherapy and radiation therapy. Severe granulocytopenia predisposes to septicemia which is now more often due to Gram positive than to Gram negative bacteria. The empiric therapy of febrile episodes with rapidly bactericidal antibiotics has dramatically modified the prognosis of septicemia. The optimal treatment remains controversial although the usual regimen include both a cephalosporin (or a large spectrum penicillin) with an aminoglycoside. The empiric treatment with a specific anti-Gram positive antibiotic such as vancomycin does not modify prognosis, adds significant side-effects and increases the cost. Monotherapy has been associated with the need for treatment modification in 30-80% of the episodes depending on the type of infection (fever of unknown origin, clinically or microbiologically documented infection). The patients who remain febrile despite adequate antibacterial empiric treatment beneficiate of an empiric antifungal treatment. Care should be taken about the recent emergence of vancomycin-resistant Staph. haemolyticus, Corynebacterium JK and non-JK, and non-aeruginosa pseudomonas (only susceptible to cotrimoxazole). More fungal infections are observed with a significant emergence of non-albicans Candida, dermatophytes and filamentous fungi (P. boydii, Fusarium, ...) associated with disseminated infections.

Twenty-eight episodes of Streptococcus pneumoniae bacteremia occurring in 27 cancer patients hospitalized in the Institut Jules Bordet between July 1979 and April 1985 were reviewed. Ten patients had hematological malignancies and 17 had solid tumors (in 7 cases, of the lung). Forty-four per cent of the patients were neutropenic (less than 1000/microliters) and 36% of the patients were in septic shock. In 36% of the patients no clinical source of S. pneumoniae bacteremia could be found. Seventy-nine (21% patients) received empirical antibiotic treatment containing a beta-lactam. Two patients who did not receive any empirical treatment died within 12 hours. Overall, 11/27 patients died within the first week, and 8/27 died within the first three days. Mortality in neutropenic patients was not different from that in non-neutropenic patients. In comparison with a similar study performed previously in our institution, there was no difference in incidence, type of patient, source of bacteremia, or mortality.

One hundred twenty-nine 111In-oxine-labeled leukocyte scintiscans have been performed in 117 patients with cancer in order to diagnose localized infectious disease. Of the 115 contributive scans, 40 were in patients with localizing signs, whereas in 75 fever of unknown origin constituted the indication for this examination. The overall specificity of the method was 95.4%, the overall sensitivity 86%, and the global accuracy 91.3%. In 10 cases with localizing signs, the 111In-oxine granulocyte scintigram allowed exclusion of the diagnosis of infection, whereas in 17 instances without localizing signs, a focal infectious process was demonstrated. Heterologous donor leukocytes were used successfully in five instances. With the exception of accumulation of label at the site of an osteolytic metastasis in one case, no uptake was observed in primary or secondary tumors. It is concluded that 111In-oxine-labeled leukocytes constitute a valuable tool in the diagnosis and localization of infection in patients with malignant disease.

We have studied amphotericin B concentrations in tissues of 13 cancer patients who died after having received 75 to 1,110 mg (total dose) of amphotericin B-deoxycholate for suspected or proven disseminated fungal infection. Amphotericin B concentrations were measured by high-pressure liquid chromatography (HPLC) and by bioassay, the latter being done on tissue homogenates as well as on tissue methanolic extracts. The fungistatic and fungicidal titers of the tissue homogenates were also tested against three strains of Candida albicans and one strain of Aspergillus fumigatus. Tissue concentrations of amphotericin B measured by HPLC varied with the tested tissues as well as with the total dose of amphotericin B-deoxycholate administered and ranged from 0.4 to 147.1 micrograms/g. A mean of 38.3% (range, 23.0 to 51.3%) of the total dose was recovered by HPLC from all of the tested organs. Bioassay of tissue methanolic extracts reached 58 to 81% of the concentration measured by HPLC, whereas only 15 to 41% was recovered from the homogenates. Overall, 27.5% of the total dose was recovered from the liver, 5.2% was recovered from the spleen, 3.2% was recovered from the lungs, and 1.5% was recovered from the kidneys. The median concentration in bile was 7.3 micrograms/ml, suggesting that biliary excretion could contribute to amphotericin B elimination to an estimated range of 0.8 to 14.6% of the daily dose. Fungicidal titers were seldom measured in tissues, but fungistatic titers were observed and were linearly correlated with amphotericin B concentration measured by HPLC. In conclusion, only a small proportion of the amphotericin B administered as amphotericin B-deoxycholate to patients seems diffusible and bioactive.

The practical procedures of digestive tract decontamination and prophylaxis of bacterial infection in granulocytopenic patients are debated. Fluoroquinolones are active against Gram-negative bacilli and have few side-effects. Pefloxacin was administered prophylactically to patients with cancer and granulocytopenia. None of them developed Gram-negative septicaemia, but 2 cases of streptococcal septicaemia were observed. The drug was well tolerated by all patients except one. Studies are currently in progress to try to reduce the incidence of septicaemia caused by Gram-positive cocci, using pefloxacin combined with penicillin.

The aim of the study was to assess the incidence and clinical significance of Clostridium difficile in patients in our cancer center. Over a period of seven consecutive months, 557 stools samples obtained from 156 hospitalized cancer patients (37 leukemic patients receiving oral antimicrobial prophylaxis and 119 patients from whom a stool sample was sent to the laboratory) were analyzed for the presence of Clostridium difficile. Clostridium difficile and/or its toxin was recovered from 13 (35%) of the 37 patients receiving oral antimicrobial prophylaxis, and from 15 (12%) of the other 119 patients (p less than 0.05). Isolation of Clostridium difficile was associated with diarrhoea in 13 (46%) of 28 patients but specific treatment was initiated only in 7 (25%) of the 28 patients in whom Clostridium difficile was isolated. The wide distribution of the serotypes identified in our patients does not suggest an epidemic situation in our hospital.

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.