trimethoprim--sulfamethoxazole-drug-combination and Agranulocytosis

Gram-negative infections in neutropenic patients originate frequently from the gut flora. Attempts to decrease the incidence of these infections have utilized several regimens for gastrointestinal decontamination, of which some have proven to be clinically useful. Orally administered nonabsorbable antibiotics (aminoglycosides, polymyxins) can decrease the incidence of gram-negative sepsis during neutropenia, but, with the possible exception of netilmicin, tolerance to these agents is generally poor, and compliance is low. Trimethoprim-sulfamethoxazole has been used widely for the prophylaxis of infections in neutropenic patients. Clinical results with this agent have been conflicting, as its efficacy is clearly related to epidemiological patterns of resistance of the pathogens in the population under study. More recently, the quinolones, which are well tolerated by patients and are presently active on most strains of Enterobacteriaceae, have been associated with a virtual eradication of gram-negative infections in neutropenic patients. These results have been paralleled by an increase in the frequency of gram-positive infections, which, fortunately, cause an incidence of mortality that is much lower than that seen in gram-negative sepsis. The fact that the quinolones are absorbed systemically might help to explain their efficacy in chemoprophylaxis during neutropenia. This paper discusses the chemoprophylaxis of gram-negative infection during neutropenia in the light of theoretical concepts such as 'colonization resistance', 'selective decontamination', and 'bacterial translocation'.

Topics: Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Drug Therapy, Combination; Gram-Negative Bacteria; Humans; Neutropenia; Quinolones; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Agranulocytosis; Anti-Infective Agents; Bacterial Infections; Child; Drug Combinations; Humans; Immune Tolerance; Neoplasms; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Drug Combinations; Hematologic Diseases; Humans; Infection Control; Neoplasms; Patient Isolation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Blood Transfusion; Clinical Trials as Topic; Drug Combinations; Environment, Controlled; Granulocytes; Humans; Neoplasms; Patient Isolation; Premedication; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Several prospectively randomized trials have shown that the administration of prophylactic oral nonabsorbable antibiotics may be beneficial in decreasing the incidence of infection in granulocytopenic patients, whereas others have not. Intolerable nausea and vomiting have prevented the prolonged use of these agents in some studies. Discontinuation of therapy while patients are still granulocytopenic has carried the risk of life-threatening infections, often with aminoglycoside-resistant gram-negative organisms. The benefit of selective decontamination with trimethoprim/sulfamethoxazole used prophylactically remains controversial. The use of trimethoprim/sulfamethoxazole may also be associated with the development of resistant, potentially pathogenic, organisms or prolonged neutropenia. These regimens do not appear to be indicated when patients are anticipated to be neutropenic for less than three weeks. Even in patients with prolonged neutropenia, the risks of such treatment must be weighed against potential benefits.

Topics: Acute Disease; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Colistin; Drug Combinations; Environment, Controlled; Gentamicins; Humans; Leukemia; Neoplasms; Nystatin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Topics: Agranulocytosis; Anti-Bacterial Agents; Antisepsis; Bacterial Infections; Drug Combinations; Humans; Immunosuppression Therapy; Infection Control; Infections; Mycoses; Nalidixic Acid; Parasitic Diseases; Patient Isolation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Virus Diseases

Fifty-three granulocytopenic patients were studied in a randomized trial comparing trimethoprim-sulfamethoxaxole (ST) alone with ST + ciprofloxacin (CPFX) for prevention of bacterial infections. Seventeen febrile episodes occurred in 24 patients receiving ST alone, and 9 febrile episodes occurred in 29 patients receiving ST + CPFX. ST + CPFX was significantly effective than ST alone (p < 0.005). Although ST alone was effective to prevent infections in moderately granulocytopenic patients, it could not prevent infections in severely granulocytopenic patients whose minimal granulocyte count was less than 250/microliters during prophylactic treatment. In contrast, ST + CPFX was effective in severely as well as in moderately granulocytopenic patients. Clinically significant adverse reactions were not observed in both regimens. These results suggest that combination with ST and CPFX is more efficacious than ST alone for the prevention of bacterial infections in granulocytopenic patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Ciprofloxacin; Drug Therapy, Combination; Female; Hematologic Diseases; Humans; Immunocompromised Host; Male; Middle Aged; Pregnancy; Trimethoprim, Sulfamethoxazole Drug Combination

Despite widespread use of trimethoprim-sulfamethoxazole (TMP-SMZ) for prophylaxis in neutropenic patients, questions remain regarding its efficacy, toxicity, the risk of selection of resistant isolates, and the relation of its activity to selective decolonization vs. the attainment of direct inhibitory levels within blood and tissues. We evaluated the effect of TMP-SMZ (160/800 mg orally every 12 hours) in 42 adult granulocytopenic patients (< 100 absolute neutrophils/mm3, mean duration 13.3 days) undergoing chemotherapy for acute leukemia at 11 participating Veterans Administration Medical Centers in a randomized, double-blind, placebo-controlled trial. No significant differences in survival, frequency of bacteremia, overall infections, use of systemic antimicrobial therapy, or adverse effects, including myelosuppression, were observed between patients receiving TMP-SMZ vs. those receiving placebo. All patients acquired trimethoprim-resistant organisms. Concentrations of trimethoprim in serum were significantly lower before febrile episodes than when patients were afebrile. These results suggest that the purported activity of TMP-SMZ may be related to the serum concentration achieved. Moreover, the results highlight the need for additional study of the value of antibiotic prophylaxis in neutropenic patients.

Topics: Acute Disease; Adult; Agranulocytosis; Bacterial Infections; Double-Blind Method; Female; Humans; Leukemia; Male; Middle Aged; Prospective Studies; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

230 leukaemic patients were entered into a randomised, prospective, multicentre trial of either ciprofloxacin (1 g/day) or co-trimoxazole (1920 mg/day) plus colistin (800 mg/day) for the prevention of infection during granulocytopenia. Bacteraemia due to resistant gram-negative rods occurred only in the co-trimoxazole-colistin group though both regimens were effective for selective gastrointestinal tract decontamination. However, there were fewer patients without any infective complications (31% vs. 18%: P = 0.02), fewer febrile days [mean (S.D.) 5.9 (1.1) vs. 8.2 (1.4): P = 0.0242], a lower proportion of infective events (0.9 (0.16) vs. 1.2 (0.18): P = 0.005) and fever occurred later (median 19 vs. 14 days: 0.025 less than P less than 0.05) in the co-trimoxazole-colistin group. The choice of prophylactic regimen therefore appears to depend upon whether or not protection against gram-negative infection is required or better systemic prophylaxis overall.

Topics: Administration, Oral; Adolescent; Adult; Aged; Agranulocytosis; Ciprofloxacin; Colistin; Drug Therapy, Combination; Female; Gram-Negative Bacterial Infections; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Premedication; Prospective Studies; Trimethoprim, Sulfamethoxazole Drug Combination

In a controlled randomized study among 48 patients undergoing 75 courses of aggressive antileukemic therapy, it was shown that cotrimoxazole was less effective than penicillin G in preventing septicemia due to viridans streptococci. Both antibiotics were given intravenously. During 35 episodes of chemotherapy in the group of patients on penicillin G only, one patient developed a streptococcal bacteremia; this contrasted with bacteremia and septicemia in seven patients during 40 episodes in the group on cotrimoxazole. In three of these seven patients, septicemia was associated with respiratory failure and it was the cause of death in one. Both aerobic gram-negative rods and streptococci which caused infection despite cotrimoxazole prophylaxis were resistant to cotrimoxazole. Side effects such as hypersensitivity and favorable or unfavorable interaction with the oral selective decontamination regimen were similar for the two drugs, with the exception of colonization with Candida spp, which occurred more often in patients on cotrimoxazole than in patients on penicillin.

Topics: Agranulocytosis; Antineoplastic Agents; Bacteremia; Drug Hypersensitivity; Drug Interactions; Drug Resistance, Microbial; Humans; Length of Stay; Leukemia; Penicillin G; Streptococcal Infections; Streptococcus; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Twenty-four cancer patients with diffuse interstitial pneumonitis (DIP) were randomized to undergo an open lung biopsy (OLB) within 8 hours of presentation (12 patients) or to receive empiric antimicrobial therapy (ET) with trimethoprim-sulfamethoxazole (TMP-SMX) erythromycin for a minimum of 4 days (12 patients). Patients whose condition deteriorated underwent an OLB on day 4. Eight of 12 patients (67%) having OLB survived versus 10 of 12 (83%) receiving ET (P = .64). Morbidity occurred in nine of 12 (75%) having OLB versus eight of 12 (67%) receiving ET (P = 1.0). Concurrently, there were 14 additional cancer patients with DIP who were not randomized (nine refused, three had a coagulopathy contraindicating surgery, two were excluded by primary care physicians) and who were comparable demographically to the randomized group. Two received OLB and 12 ET. Combining the randomized and nonrandomized groups, eight of 14 (57%) having an initial OLB survived versus 18 of 24 (75%) of ET-treated patients (P2 = .19). Results of the OLB were seven Pneumocystis carinii pneumonia (PCP), five nonspecific pneumonitis (NSP), one cytomegalovirus, and one lymphoma. Results of OLB led to discontinuation of antibiotics in three patients. Of the 24 ET patients, eight failed to improve by day 4 and had an OLB. Results were two NSP, two PCP, two cancer, one blastomycosis, and one Candida pneumonia. Complications were seen in 10 of 14 (72%) initial OLB patients versus 14 of 24 (58%) patients on the ET arm (P = .65). When the complication rate between patients receiving only empiric antibiotics was compared with all patients having an OLB (initially or on day 4), the difference was greater in patients undergoing OLB (37% v 72%, respectively) (P2 = .14). ET with TMP-SMX plus erythromycin and broad spectrum antibiotics in granulocytopenic patients appeared to be as successful and potentially less toxic than an OLB in this study. Although the number of patients in this study was small, these data suggest that a trial of empiric antibiotic management may be reasonable in cancer patients presenting with DIP, especially if they are nonneutropenic.

Topics: Adult; Agranulocytosis; Biopsy; Diagnosis, Differential; Drug Therapy, Combination; Erythromycin; Female; Humans; Male; Middle Aged; Neoplasms; Pneumonia, Pneumocystis; Prospective Studies; Pulmonary Fibrosis; Random Allocation; Trimethoprim, Sulfamethoxazole Drug Combination

The efficacy of ofloxacin in preventing infection in neutropenic patients following cytotoxic chemotherapy was evaluated and was compared with that of co-trimoxazole. A total of 102 patients with hematological malignancies were randomly selected to receive either co-trimoxazole or ofloxacin. All patients were monitored for compliance, occurrence of infection, and drug-related side effects. A surveillance culture of a rectal swab was performed regularly. A total of 25 of the 52 patients (48%) who received co-trimoxazole and 11 of the 50 patients (22%) who received ofloxacin developed fever during the study period (P less than 0.025). Gram-negative bacteremia occurred in nine patients in the co-trimoxazole group (17%) but in only one patient (2%) in the ofloxacin group (P less than 0.05). No patient in either group had documented gram-positive bacterial or Pneumocystis carinii infection. Poor performance status was the only identifiable factor associated with an increased incidence of bacteremia. The surveillance study showed that significantly fewer bacterial strains were resistant to ofloxacin than to co-trimoxazole and that acquisition of resistance to co-trimoxazole was more commonly observed than was acquisition of resistance to ofloxacin. Significantly more patients had skin rashes following co-trimoxazole than ofloxacin treatment (P less than 0.05). Ofloxacin was superior to co-trimoxazole in preventing infection in this population of neutropenic patients.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Antineoplastic Agents; Bacterial Infections; Child; Female; Gram-Negative Bacteria; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Neutropenia; Ofloxacin; Trimethoprim, Sulfamethoxazole Drug Combination

The efficacy and safety of norfloxacin were compared with those of placebo, vancomycin-polymyxin, and trimethoprim-sulfamethoxazole (TMP/SMX) for prophylaxis of bacterial infections in granulocytopenic patients. The study results showed that norfloxacin treatment, which was well tolerated and not associated with any serious systemic adverse effects, prevented acquisition of gram-negative bacillary organisms. Fewer norfloxacin-treated patients (38 of 108 patients, or 35 percent) experienced microbiologically documented infections compared with patients receiving placebo (27 of 40 patients, or 68 percent), vancomycin-polymyxin (16 of 30 patients, or 53 percent), or TMP/SMX (14 of 28 patients, or 50 percent). Gram-negative bacteremia developed in five of 108 norfloxacin-treated patients (5 percent), compared with 17 of 40 placebo-treated patients (43 percent), five of 30 treated with vancomycin-polymyxin (17 percent), and one of 28 patients treated with TMP/SMX (4 percent). The incidence of gram-positive bacteremia was similar in all study groups and was not affected by norfloxacin or any other oral prophylactic antibiotics. These results suggest that norfloxacin is both safe and effective for the prevention of serious gram-negative bacillary infections in granulocytopenic patients. More effective prophylaxis of gram-positive bacterial infections, however, is needed.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Bacterial Infections; Drug Combinations; Drug Therapy, Combination; Humans; Middle Aged; Mycoses; Norfloxacin; Polymyxins; Random Allocation; Sepsis; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Eighty-four cancer patients at risk of infection because of neutropenia were randomized to receive nalidixic acid as an alternative to trimethoprim-sulfamethoxazole (TMP-SMX) for infection prophylaxis. Infections were documented significantly earlier and more often among patients who entered the trial with neutrophil counts of less than 0.1 X 10(9)/liter. TMP-SMX recipients experienced fewer microbiologically documented infections and bacteremias and were free of infection for a higher proportion of days with severe neutropenia (less than 0.1 X 10(9)/liter) than nalidixic acid recipients. Gram-negative bacillary and Staphylococcus aureus infections accounted for the major differences. Although the majority of aerobic gram-negative bacilli were eliminated from the feces after 1 week of prophylaxis with either agent, TMP-SMX was proved superior to nalidixic acid in this regard and was associated with acquired drug resistance by gram-negative bacilli less frequently. Both agents selected for colonization and subsequent infection by gram-positive cocci. Our data suggest that prophylaxis is most likely to be effective if administered to patients for at least 1 week before they become severely neutropenic. Nalidixic acid used as a single agent in doses of 4 g daily, however, cannot be recommended as an alternative to TMP-SMX for infection prophylaxis in neutropenic cancer patients.

Topics: Agranulocytosis; Antineoplastic Agents; Bacteria; Bacterial Infections; Clinical Trials as Topic; Drug Administration Schedule; Drug Combinations; Humans; Intestines; Microbial Sensitivity Tests; Mycoses; Nalidixic Acid; Neoplasms; Neutropenia; Random Allocation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The clinical and microbiologic efficacy of trimethoprim alone and trimethoprim/sulfamethoxazole for infection prevention was evaluated in 75 patients during 92 episodes of granulocytopenia. Ultimately, 60 patients were evaluable during 77 episodes of granulocytopenia, 36 episodes in the trimethoprim group and 41 episodes in the trimethoprim/sulfamethoxazole group. The incidence of infection was higher in the trimethoprim group (50 percent) than in the trimethoprim/sulfamethoxazole group (39 percent), but this did not reach statistical significance. Trimethoprim did not appear to be as protective as trimethoprim/sulfamethoxazole when the granulocyte count was less than 100/mm3. In patients receiving trimethoprim/sulfamethoxazole, aerobic gram-negative bacilli cleared from fecal surveillance cultures more often and new aerobic gram-negative bacilli were acquired less often than in those receiving trimethoprim alone (p less than 0.05). More myelosuppression was observed among patients receiving trimethoprim/sulfamethoxazole (p less than 0.001). These observations suggest that trimethoprim alone may not be optimal for preventing colonization and infection in granulocytopenic patients and that combination with other agents may be necessary to increase the spectrum of activity. Trimethoprim/sulfamethoxazole itself may predispose toward an increased risk of infection by prolonging myelosuppression.

Topics: Adult; Agranulocytosis; Bacteria; Bacterial Infections; Clinical Trials as Topic; Drug Combinations; Feces; Female; Humans; Male; Mycoses; Nystatin; Premedication; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Blood Transfusion; Clinical Trials as Topic; Drug Combinations; Environment, Controlled; Granulocytes; Humans; Neoplasms; Patient Isolation; Premedication; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Several prospectively randomized trials have shown that the administration of prophylactic oral nonabsorbable antibiotics may be beneficial in decreasing the incidence of infection in granulocytopenic patients, whereas others have not. Intolerable nausea and vomiting have prevented the prolonged use of these agents in some studies. Discontinuation of therapy while patients are still granulocytopenic has carried the risk of life-threatening infections, often with aminoglycoside-resistant gram-negative organisms. The benefit of selective decontamination with trimethoprim/sulfamethoxazole used prophylactically remains controversial. The use of trimethoprim/sulfamethoxazole may also be associated with the development of resistant, potentially pathogenic, organisms or prolonged neutropenia. These regimens do not appear to be indicated when patients are anticipated to be neutropenic for less than three weeks. Even in patients with prolonged neutropenia, the risks of such treatment must be weighed against potential benefits.

Topics: Acute Disease; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Colistin; Drug Combinations; Environment, Controlled; Gentamicins; Humans; Leukemia; Neoplasms; Nystatin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Of 545 patients expected to develop prolonged neutropenia and randomized to received trimethoprim-sulfamethoxazole (TMP-SMZ) or placebo, 342 were evaluable for occurrence of infection or bacteremia. Some centers used oral nonabsorbable antibiotics in addition. Infection occurred in 64 (39%) of 165 placebo recipients and 46 (26%) of 177 TMP-SMZ recipients (P = .016), whereas bacteremia occurred in 32 (19%) and 22 (12%), respectively (P = .106, difference not significant [NS]). In the 139 patients with acute nonlymphocytic leukemia (ANLL), infection occurred in 35 (55%) of 64 placebo-treated patients and 31 (41%) of 75 TMP-SMZ-treated patients (P = .162, NS), whereas bacteremia occurred in 15 (23%) and 18 (24%; NS), respectively. Excluding patients with ANLL, infection occurred in 29 (29%) of 101 placebo-treated patients and 15 (15%) of 102 TMP-SMZ recipients (P = .038), whereas bacteremia occurred in 17 (17%) and four (4%; P = .005), respectively. Gram-positive cocci were isolated less frequently from TMP-SMZ-treated, bacteremic patients, but more of their isolates were resistant to TMP-SMZ than were those from placebo recipients.

Topics: Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Drug Combinations; Enterobacteriaceae Infections; Granulocytes; Humans; Leukemia; Leukocyte Count; Neutropenia; Sepsis; Staphylococcal Infections; Streptococcal Infections; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Fifty febrile, granulocytopenic allogeneic bone marrow transplant patients receiving prophylactic trimethoprim-sulfamethoxazole were randomized to one of two empirical antibiotic regimens to determine whether a shortened course of empirical therapy was beneficial. Of the 50 patients, 25 received empirical tobramycin and ticarcillin for only 3 days, and 25 were maintained on empirical tobramycin and ticarcillin until they were afebrile and no longer granulocytopenic. Although the incidence of bacterial infections in the two groups was not statistically significantly different, almost twice as many bacterial infections were observed in the group that received the short course of empirical therapy. Furthermore, because of the high incidence of bacterial infection and clinical concerns about occult bacterial sepsis, within 2 weeks of the randomization the overall use of parenteral antibacterial agents was similar in both groups. The incidence of invasive fungal disease and the use of amphotericin B therapy were similar in both groups. The results of this study suggest that little clinical benefit is likely to be seen in bone marrow transplant patients treated with short-course empirical tobramycin and ticarcillin, despite the administration of prophylactic trimethoprim-sulfamethoxazole, and emphasize the need for new strategies to prevent infections with gram-positive and trimethoprim-sulfamethoxazole-resistant gram-negative bacteria in these patients.

Topics: Adolescent; Adult; Agranulocytosis; Anti-Bacterial Agents; Bacterial Infections; Bone Marrow Transplantation; Child; Child, Preschool; Clinical Trials as Topic; Drug Combinations; Female; Humans; Infant; Infusions, Parenteral; Male; Middle Aged; Mycoses; Random Allocation; Sulfamethoxazole; Ticarcillin; Time Factors; Tobramycin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Ketoconazole or miconazole was randomly administered to 42 and 46 neutropenic patients respectively. Of the total number of stool cultures 12% were positive for yeasts in both groups; 4% of the total number of cultures from other sites (nose, throat, skin) were positive in both groups. Candida albicans was the most common isolate, but other fungal species were also identified. No patient developed fungemia; 5/88 patients developed severe oropharyngeal candidiasis while receiving prophylaxis. Among the 21 autopsies performed, 5 cases of pulmonary aspergillosis and 2 local and 1 disseminated candidiasis were demonstrated in 7 patients. Although there was no placebo group of patients in this study, post-mortem data suggest that miconazole or ketoconazole might reduce the incidence of disseminated candidiases in neutropenic patients.

Topics: Agranulocytosis; Antifungal Agents; Candidiasis; Drug Combinations; Female; Humans; Imidazoles; Ketoconazole; Male; Miconazole; Middle Aged; Mycoses; Neoplasms; Neutropenia; Piperazines; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

In an attempt to reduce the incidence of fever and infection, we randomized patients with cancer to receive trimethoprim/sulfamethoxazole plus erythromycin (TMP/SMX + E) versus placebos after each cycle of chemotherapy (no crossover) and to continue until granulocytopenia (polymorphonuclear leukocytes less than 500/mm3) resolved or the patient became febrile. We evaluated 541 episodes (150 patients); 249 episodes (77 patients) with TMP/SMX + E and 292 episodes (73 patients) with placebos. The patients' median age was 17 years. Thirty percent of the patients had leukemia, 23% had lymphoma, and 47% had solid tumors. Compliance with prescribed medication was prospectively rated as excellent in 60.6%, good in 11.7%, poor in 11.1%, and unknown in 16.6%; compliance was better for the placebo group (P = 0.001). The overall incidence of fever or infection was 22.1% for the TMP/SMX + E group versus 26.9% for the placebo group. When only episodes with excellent compliance in which granulocytopenia was documented were compared, the incidence of fever or infection was 18.1% for the TMP/SMX + E group vs 32.2% for the placebo group (P = 0.009), with bacterial infection occurring in 3.8% of the TMP/SMX + E group vs 11.9% of the placebo group (P = 0.019), and unexplained fever in 10.5% of the TMP/SMX + E group vs 19.6% of the placebo group (P = 0.037). Patients with good or poor compliance showed no significant benefit from the TMP/SMX + E, and patients with excellent compliance did best, regardless of whether they were receiving antibiotics or placebos, suggesting that patient compliance is an important independent variable. The incidence of fever or infection was significantly lower for patients with leukemia with excellent compliance who received antibiotics (P = 0.037) than for patients with lymphomas or solid tumors. Oral antibiotic prophylaxis reduced the incidence of fever and infection in some granulocytopenic patients, but the benefit was limited and restricted to patients whose compliance was complete.

Topics: Adolescent; Adult; Agranulocytosis; Bacterial Infections; Child; Child, Preschool; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Therapy, Combination; Erythromycin; Female; Fever; Humans; Infant; Leukemia; Lymphoma; Male; Neoplasms; Patient Compliance; Random Allocation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

It is well known that patients with granulocytopenia due either to bone marrow failure, acute leukemia or its treatment, or as a result of other intensive chemotherapy are at enhanced risk of serious infection. Several approaches have been designed to minimize the risk of infection in these patients by means of suppression of gastrointestinal flora. A retrospective review of infection in febrile neutropenic patients revealed a significant decrease in bacteremia in patients who had received some oral antimicrobial regimen compared with those who did not. In one large series, infection due to the four most common infecting organisms in neutropenic patients (Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Klebsiella species) occurred in 28% of 380 patients receiving some oral antibiotic regimen compared with 44% of 426 receiving no oral prophylaxis. Aminoglycosides alone or in combination with vancomycin or polymyxin and bacitracin and other agents have been utilized in gut decontaminating regimens. More recently, selective decontamination with a variety of oral agents including nalidixic acid, cotrimoxazole, colistin, etc. have been shown to be effective in some trials. Although cotrimoxazole initially was thought to be beneficial in reducing infection and bacteremia in neutropenic patients, the recently completed EORTC trial did not show a significant difference in incidence of infection or bacteremia in acute leukemia patients attendant upon the use of oral trimethoprim-sulfamethoxazole. There was a significant reduction in infections and bacteremia in patients with malignancies other than acute non-lymphocytic leukemia. Thus, there is a need for infection prevention in neutropenic patients but the optimal method for achieving this goal remains to be determined.

Topics: Administration, Oral; Agranulocytosis; Aminoglycosides; Anti-Bacterial Agents; Bacterial Infections; Clinical Trials as Topic; Drug Combinations; Humans; Neutropenia; Nystatin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

Topics: Adult; Agranulocytosis; Child; Clinical Trials as Topic; Drug Combinations; Fever; Humans; Infection Control; Infections; Leukemia; Lymphoma; Neutropenia; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Agranulocytosis; Anti-Bacterial Agents; Anti-Infective Agents; Bacterial Infections; Clinical Trials as Topic; Drug Combinations; Drug Therapy, Combination; Feces; Gentamicins; Humans; Neoplasms; Neutropenia; Pilot Projects; Random Allocation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Vancomycin

A randomized study of intestinal decontamination was undertaken in 68 children with leukemia and solid tumours. Framycetin, colymycin, nystatin, and metronidazole were given in 35 neutropenic episodes in 33 children, while co-trimoxazole and lactobacilli preparation were administered in 35 episodes in 35 children. The diseases, severity of neutropenia, and incidence of infection at entry into study were comparable in the two groups. There was no significant difference in the incidence of infections developing during the phase of neutropenia. The median and range of time required to recover from neutropenia were also not different. Co-trimoxazole and lactobacilli were significantly better tolerated, there being no nausea and vomiting, no refusal to take medication, no dose reduction or change to an alternative regimen. We conclude that co-trimoxazole and lactobacilli preparation improve quality of life during a neutropenic episode and have the additional advantage of being relatively inexpensive.

Topics: Agranulocytosis; Anti-Bacterial Agents; Antifungal Agents; Bacterial Infections; Biological Products; Child; Child, Preschool; Colistin; Drug Combinations; Framycetin; Humans; Lactobacillus; Neoplasms; Neutropenia; Nystatin; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acetaminophen; Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Antirheumatic Agents; Clinical Competence; Diagnostic Errors; Doxepin; Drug Monitoring; Fatal Outcome; Female; Humans; Hydrocodone; Ibuprofen; Indomethacin; Middle Aged; Sulfasalazine; Time Factors; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Anti-Infective Agents; Bacterial Infections; Female; Humans; Male; Middle Aged; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Agranulocytosis; Decision Making; Diagnosis, Differential; Dyspnea; Edema; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Infant, Newborn; Leukopenia; Lung Diseases; Lupus Erythematosus, Systemic; Pregnancy; Pregnancy Complications; Puerperal Disorders; Trimethoprim, Sulfamethoxazole Drug Combination

A comparison has been made of risk estimates for agranulocytosis connected with sulphasalazine and trimethoprim-sulphamethoxazole (T-SM) therapy calculated from data in the Swedish Drug Monitoring System ("spontaneous" reports, sales and prescription information) and a population based case-control study (the IAAAS). The relative risk for agranulocytosis during sulphasalazine treatment was calculated to be 107 and 123 by the spontaneous reporting system and the case-control study, respectively. The corresponding excess risk in both systems was 1.8. For T-SM the relative risk was 17 in the spontaneous reporting system and 12 in the case-control study, while the excess risk calculated for 3 days of treatment was 0.9 in the spontaneous reporting system, and 1.6 for 3 or more days of treatment in the case-control study. It is concluded that the Swedish Drug Monitoring System gives an appropriate estimate of the risk of developing agranulocytosis in association with the two drugs studied.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Case-Control Studies; Drug Monitoring; Female; Humans; Male; Middle Aged; Risk; Sulfasalazine; Sweden; Trimethoprim, Sulfamethoxazole Drug Combination

Following renal transplantation, a patient developed life-threatening granulocytopenia secondary to a specific combination of drugs which are commonly utilized in this setting. Coincident with the depression of granulocytes, an expansion of natural killer cells was seen, which may have been a consequence of immunosuppressive therapy required for allograft retention. Infection with cytomegalovirus may have contributed to both phenomena.

Topics: Adult; Agranulocytosis; Azathioprine; Cimetidine; Cytomegalovirus Infections; Drug Therapy, Combination; Humans; Kidney Transplantation; Killer Cells, Natural; Lymphocytosis; Male; Trimethoprim, Sulfamethoxazole Drug Combination

During the 10-year period 1976-1985, a total of 154 cases of blood dyscrasia were reported in Sweden which were evaluated as having a probable or possible causal relationship with trimethoprim-sulphamethoxazole (T-SM). There were 61 cases of leucopenia (of which 16 had agranulocytosis), 28 cases of thrombocytopenia, and two of non-haemolytic anaemia. There were also 32 cases of bicytopenia and 31 cases of tricytopenia. The median age varied from 38 years in the leucopenia group to 81 years in those with tricytopenia. The overall fatality rate was 17%, ranging from 2% in the group with mild leucopenia to 52% in the group with tricytopenia. In relation to sales and prescription data, the overall incidence of reported T-SM blood dyscrasias was 5.3 per million defined daily doses, and among out-patients the incidence was one case per 18,000 prescriptions. Thus the overall incidence of any blood reaction to T-SM appears to be low. In relation to prescription data, elderly people were overrepresented among the serious reactions.

Topics: Adult; Aged; Aged, 80 and over; Agranulocytosis; Female; Hematologic Diseases; Humans; Incidence; Leukopenia; Male; Middle Aged; Registries; Sweden; Thrombocytopenia; Trimethoprim, Sulfamethoxazole Drug Combination

The risks of agranulocytosis and aplastic anemia in relation to the use of anti-infective drugs were estimated in a population-based case-control study conducted in Europe and Israel. Anti-infective drug use in the 2-week period before the onset of illness was compared between 251 patients admitted to hospital with agranulocytosis and 1271 controls hospitalized for reasons judged to be unrelated to previous use of anti-infective drugs. Anti-infectives significantly associated with agranulocytosis when used for at least 3 consecutive days were trimethoprim/sulfamethoxazole (relative risk, 12; 95% confidence interval, 3.9 to 40) and macrolides (infinity). The relative risk estimate for any use of sulfonamides without trimethoprim was elevated, but not statistically significant (3.6; 0.7 to 18). These estimates took confounding by various factors, in particular the use of other drugs, into account. The estimated excess risks of agranulocytosis attributable to the use of trimethoprim/sulfamethoxazole and macrolides in a 2-week period were 1.6 and 7.1 per million, respectively. Anti-infective use during the 29- through 180-day period before hospital admission was compared between 135 patients with aplastic anemia and 1410 controls. Although relative risk point estimates were elevated for trimethoprim/sulfonamides (2.1), other sulfonamides (2.9), and beta-lactams (1.5), none was statistically significant.

Topics: Agranulocytosis; Anemia, Aplastic; Anti-Bacterial Agents; Anti-Infective Agents; Drug Combinations; Humans; Lactams; Risk Factors; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Anti-Infective Agents; Drug Combinations; Humans; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The correlation of fecal gram-negative bacilli (GNB), neutropenia, and bacteremia was studied in 45 bone marrow transplant recipients. Weekly stool cultures were prospectively monitored for GNB resistant to routine prophylactic and empiric antimicrobial agents. Seven cases of GNB bacteremia occurred in 45 patients described as follows. Twenty-three patients had no fecal or blood GNB. Fifteen patients had fecal GNB and no blood GNB; three of these latter patients had less than or equal to 50/mm3 circulating white blood cells (WBC) at the time of isolation of fecal GNB but two of the three were concurrently receiving appropriate empiric antibiotics. Two patients had blood GNB but no fecal GNB: one patient had a trimethoprim/sulfamethoxazole (TMP-SMZ)-sensitive isolate that would not be detectable in the feces by our methodology and one patient had feces analyzed only after the bacteremic event. Five patients had fecal GNB and blood GNB: one of these patients did not have a fecal sample analyzed prior to bacteremia but the remaining four patients had the same species/antibiogram of GNB isolated from the feces two to three days prior to the detection of bacteremia. Thus, the fecal GNB could have been used to predict the antibiogram of the subsequent blood GNB. In addition, all four of these latter bacteremic patients had less than or equal to 50/mm3 circulating WBC at the time of documented fecal GNB. Thus, bone marrow transplant recipients with fecal GNB coupled with severe neutropenia (less than or equal to 50/mm3 circulating WBC) were more likely to develop bacteremia (P less than 0.02) than were those with fecal GNB and greater than 50/mm3 circulating WBC.

Topics: Adult; Agranulocytosis; Anti-Bacterial Agents; Bone Marrow Transplantation; Child; Drug Combinations; Drug Resistance, Microbial; Feces; Gram-Negative Bacteria; Humans; Immune Tolerance; Neutropenia; Prospective Studies; Sepsis; Sulfamethoxazole; Ticarcillin; Tobramycin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Aged; Agranulocytosis; Anti-Infective Agents, Urinary; Drug Combinations; Female; Humans; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

6 out of 7 patients with severe neutropenia associated with the use of amodiaquine for malaria prophylaxis amodiaquine (400 mg weekly) plus proguanil (200 mg daily); 1 of these patients had also taken cotrimoxazole and another had taken sulphaguanidine. The 7th patient had taken amodiaquine alone, but at a higher dose. A retrospective analysis suggests that the frequency of severe neutropenia complicating amodiaquine taken prophylactically may be as high as 1 in 2000.

Topics: Acute Disease; Adult; Agranulocytosis; Amodiaquine; Drug Combinations; Drug Therapy, Combination; Female; Humans; Leukocyte Count; Malaria; Male; Middle Aged; Neutropenia; Proguanil; Retrospective Studies; Sulfaguanidine; Sulfamethoxazole; Travel; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Chlorides; Drug Combinations; Drug Therapy, Combination; Female; Glycogen Storage Disease Type I; Hematopoiesis; Humans; Ketoconazole; Leukocyte Count; Lithium; Lithium Chloride; Neutropenia; Skin Diseases, Infectious; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Agranulocytosis; Anti-Infective Agents, Urinary; Drug Combinations; Female; Humans; Neutropenia; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Urinary Tract Infections

Topics: Agranulocytosis; Drug Combinations; Drug Resistance, Microbial; Humans; Neutropenia; Risk; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adult; Aged; Agranulocytosis; Bacterial Infections; Drug Combinations; Drug Therapy, Combination; Female; Humans; Leukemia; Lymphoma; Male; Middle Aged; Sulfamethoxazole; Tobramycin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Nystatin, one million units every four hours, was prospectively studied as a prophylactic antifungal agent in 164 neutropenic patients who were not initially colonized by fungi: 104 received nystatin and 60 served as controls. Fungal colonization occurred in 68/104 (65%) nystatin recipients and in 43/60 (71%) controls. However, nystatin significantly reduced multiple body site colonization and persistent oropharyngeal colonization. Despite these alterations in colonization profile, 16/104 (15%) nystatin recipients developed disseminated fungal infections, as compared to 5/60 (8%) control patients (0.5 greater than p greater than 0.1, N.S). Differences in the clinical course of colonized and non-colonized patients were observed. Eighteen of 111 (16%) colonized patients had afebrile clinical courses as compared to 16/53 (30%) non-colonized patients (p less than 0.05). Twenty-nine of 93 (31%) febrile episodes in colonized patients failed to respond to empiric antibiotic therapy as compared to 3/37 (8%) episodes in non-colonized patients (p less than 0.01). Disseminated fungal infections were diagnosed in 19/111 (17%) of colonized patients, as compared to 1/53 (2%) non-colonized patients (p less than 0.02). We conclude that colonized patients are more likely to develop febrile clinical courses, to fail to respond to empiric antibiotic therapy, and to develop disseminated fungal infection. Nystatin altered colonization patterns but did not prevent disseminated fungal infection.

Topics: Adolescent; Adult; Aged; Agranulocytosis; Anti-Bacterial Agents; Drug Combinations; Female; Fever; Humans; Male; Middle Aged; Mycoses; Nystatin; Oropharynx; Prospective Studies; Random Allocation; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination; Yeasts

Topics: Agranulocytosis; Digestive System; Disinfection; Drug Combinations; Drug Resistance, Microbial; Humans; Infection Control; Infections; Sterilization; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The incidence of hematologic abnormalities was evaluated in 120 children with otitis media treated respectively with cotrimoxazole (trimethoprim-sulfamethoxazole) (group 1), cotrimoxazole plus folinic acid (group 2) and amoxicillin (group 3) in therapeutic doses for ten days. Only eosinophilia (an absolute count greater than or equal to 0.5 X 10(9)/l) (group 1 = 10%, 2 = 5%, 3 = 7.5%) and neutropenia (polymorphonuclear neutrophilic leucocyte count less than or equal to 1.5 X 10(9)/l) (group 1 = 35%, 2 = 17.5%, 3 = 13.3%) were noted. Early neutropenia (evident on the 5th day of therapy) occurred in all the treatment groups, thus it is not related to cotrimoxazole administration and in most cases neutrophil count reversed to normal in few days without drug discontinuation. Late neutropenia (evident after 10 days of treatment) appeared only in cotrimoxazole treated children (p less than 0.05). No superimposed bacterial infection was demonstrated in any case. Late neutropenia seems to be strictly related to the sequential blockage of folinic acid metabolism and can be prevented by the concomitant administration of folinic acid.

Topics: Agranulocytosis; Amoxicillin; Child; Child, Preschool; Drug Combinations; Drug Therapy, Combination; Eosinophilia; Female; Folic Acid; Humans; Infant; Male; Neutropenia; Otitis Media; Risk; Sulfamethoxazole; Time Factors; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Agranulocytosis; Child; Drug Combinations; Humans; Leukemia, Lymphoid; Neutropenia; Pulmonary Fibrosis; Sulfamethoxazole; Thrombocytopenia; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

The amikacin-carbenicillin-cotrimoxazole combination was used as an empiric treatment for febrile episodes in patients with acute leukemia and severe granulocytopenia. The choice of drugs was based on the finding in our institute that the majority of infections are caused by gram-negative rods, particularly Pseudomonas, with high percentage of strains resistant to gentamycin and tobramycin. Granulocyte transfusions were given to the patients who did not show satisfactory clinical improvement 48 h after start of antibiotic therapy. There were cures in 84.6% of the febrile episodes treated with this antibiotic combination, including five of eight episodes of microbiologically confirmed bacteremia. Survival after 21 days of antibiotic therapy amounted to 89.1%. Renal toxicity occurred in 10.9% of the episodes treated. The prompt use of this antibiotic combination seems to be a safe and efficacious therapeutic tool for treating these high-risk patients.

Topics: Acute Disease; Adolescent; Adult; Aged; Agranulocytosis; Amikacin; Anti-Bacterial Agents; Bacterial Infections; Carbenicillin; Drug Combinations; Drug Therapy, Combination; Female; Humans; Leukemia; Male; Middle Aged; Sepsis; Sulfamethoxazole; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Adolescent; Adult; Aged; Agranulocytosis; Anti-Bacterial Agents; Cephalothin; Child; Drug Combinations; Drug Therapy, Combination; Female; Fever; Humans; Leukemia; Male; Middle Aged; Sulfamethoxazole; Tobramycin; Trimethoprim; Trimethoprim, Sulfamethoxazole Drug Combination