Reduction in mortality from gram-negative sepsis in neutropenic patients receiving trimethoprim/sulfamethoxazole therapy.

The causes of death were reviewed in 53 patients from two prospective randomized trials on the efficacy of trimethoprim/sulfamethoxazole as prophylaxis of gram-negative bacillary infection in granulocytopenic patients. Twenty-nine deaths occurred in patients treated with TMP/SMX prophylaxis while 24 occurred in patients who served as controls in the first trial. The two groups were similar, with the exception that more patients in the TMP/SMX group had acute leukemia (82 versus 50%; P less than 0.02). Microbiologically documented gram-negative rod infection preceeded death in 8/24 control patients as compared to 2/29 TMP/SMX recipients (P less than 0.02). This decrease in gram-negative related deaths was most pronounced in the patients with acute leukemia. Fatal gram-negative rod infection occurred in 7/12 control leukemic patients as compared to 2/24 TMP/SMX treated patients. Despite the reduction in numbers of gram-negative rod-related deaths, infectious deaths accounted for 16/24 and 15/29 patients in control and TMP/SMX treated patients, respectively. Similar numbers of fungal, viral, and gram-positive bacterial infections occurred in each group. Fever with pulmonary infiltrates but without proven etilogic agents were included in the category of "clinically documented infections;" 6/7 patients with fever and undiagnosed pulmonary infiltrates were in the TMP/SMX group. Prophylactic administration or oral trimethoprim/sulfamethoxazole reduces the frequency of fatal gram-negative rod infections in neutropenic patients.

Effect of liver disease on pharmacokinetics and toxicity of 9-beta-D-arabinofuranosyladenine-5-phosphate.

Plasma levels of 9-beta-D-arabinofuranosyladenine-5'-phosphate (ara-AMP) and its metabolites 9-beta-D-arabinofuranosyladenine (ara-A and 9-beta-D-arabinofuranosylhypoxanthine (ara-Hx) were determined by high-performance liquid chromatography in four patients with chronic active hepatitis positive for hepatitis B surface antigen and eight patients with severe herpesvirus infections and normal liver function. Ara-AMP was given intravenously over a 30-min period in doses ranging from 10 to 30 mg of ara-A equivalent/kg per day. The metabolism of ara-AMP did not differ significantly between the two patient groups. Ara-AMP was quickly converted to ara-A, which was rapidly deaminated to ara-Hx. The mean half-lives of ara-AMP, ara-A, and ara-Hx were 0.14 hr, 0.17 hr, and 3.5 hr, respectively. Thus, ara-AMP is rapidly metabolized and does not act as a depot form of ara-A. Patients with chronic active hepatitis demonstrated increased bone marrow sensitivity to ara-AMP and a musculoskeletal pain syndrome not observed in patients treated for herpesvirus infections.

A prospective controlled investigation of prophylactic trimethoprim/sulfamethoxazole in hospitalized granulocytopenic patients.

Oral trimethoprim/sulfamethoxazole (TMP/SMZ) therapy was investigated in the prophylaxis of infections in granulocytopenia. Hospitalized granulocytopenic patients were allocated at random to receive TMP/SMZ (group 1) or to a control group (group 2). The percentage of febrile granulocytopenic days was significantly reduced in group 1, 19 per cent compared to 39 per cent in group 2 (P less than 0.01). In group 1, there were no bacteremias in 59 episodes of granulocytopenia (909 days). In group 2, there were nine bacteremias in 52 episodes of granulocytopenia (796 days)(P = 0.001). Disseminated candidiasis developed in two patients in each group. Candida occurred in similar numbers in surveillance cultures in both groups; Staphylococcus aureus and Pseudomonas aeruginosa were slightly decreased, and Enterobacteriaceae resistant to TMP slightly increased in group 1. This study suggest that oral prophylactic TMP/SMZ therapy is an effective, well tolerated, easily administered alternative to "gut sterilization" with nonabsorbable antibiotics.

Clinical efficacy and toxicity of netilmicin in the treatment of gram-negative infections.

Netilmicin, a new semisynthetic aminoglycoside antibiotic, was used to treat 41 infections in 38 patients. The outcome of four infections could not be evaluated: two patients received inadequate therapy and two did not have gram-negative infections. Clinical improvement occurred in 36 (97%) of the 37 gram-negative infections, and bacteriologic cure occurred in 30 (86%) of the 35 evaluable infections. Therapeutic serum concentrations of netilmicin were readily achieved by both intramuscular and intravenous routes. Reversible ototoxic effects occurred in 1 (3%) of 35 courses of therapy evaluated, reversible nephrotoxic effects occurred in 5 (14%) of 36 courses and mild reversible alterations in liver function occurred in 3 (19%) of 34 courses. Netilmicin appears to be effective and safe in the treatment of aerobic gram-negative infections.

Prospective comparison of cefoxitin and cefazolin in infections caused by aerobic bacteria.

Intravenous cefazolin and cefoxitin were compared in a prospective randomized trial in infections where the suspected pathogen was expected to be susceptible to both antibiotics. In the cefazolin group (12 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 5, Staphylococcus aureus bacteremia in 1, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefoxitin group (10 patients) the diagnosis was pneumonia in 4, including 2 with pneumococcal bacteremia, soft tissue infection in 4, acute pyelonephritis in 1, and disseminated gonococcal infection in 1. In the cefazolin group receiving an evaluable course of therapy, a good clinical response was seen in 10 of 11 patients, and a bacteriological response was seen in 5 of 7. Cefazolin failed to eradicate S. aureus bacteremia in 1 patient and S. aureus in a skin ulcer of another patient. All 10 cefoxitin patients had good clinical and bacteriological responses, but in 1 patient S. aureus colonization of a postoperative wound recurred after discontinuation of the drug. Side effects in both groups included skin rash, phlebitis, and elevation of the serum alkaline phosphatase. Both cefoxitin and cefazolin appeared effective in infections caused by susceptible aerobic pathogens with the possible exception of S. aureus, although all 11 strains of S. aureus isolated in this study were susceptible in vitro to both antibiotics. Cefoxitin appeared to be equivalent to cefazolin in efficacy and occurrence of side effects.

Granulocytopenia in hospitalized patients: I. Prognostic factors and etiology of fever.

The clinical course of 126 hospitalized patients during 192 episodes of granulocytopenia and fever was studied. Fever was a regular accompaniment of granulocytopenia, occurring in 94 per cent of granulocytopenic episodes. The mean duration of granulocytopenia (less than 1,000/mm3) was 18 days, with fever (temperature greater than 38 degrees C) being present during 44 per cent of those days. Fever was present during 69 per cent of days with a granulocyte count less than 10/mm3. A presumed infection was present in 86 of 128 febrile granulocytopenic episodes in adults and in 19 of 64 febrile granulocytopenic episodes in children. A fungal infection was found in 11 patients; a viral infection in 23 patients. Bacteremia occurred during 44 granulocytopenic episodes with 16.8 bacteremias/1,000 days of granulocytopenia in adults and 12.7 bacteremias/1,000 days in children. The mortality was 33 per cent per granulocytopenic episode in adults and only 8 per cent per episode in children.

Granulocytopenia in hospitalized patients. II. A prospective comparison of two antibiotic regimens in the empiric therapy of febrile patients.

The results of empiric antibiotic therapy in 126 hospitalized patients with fever during 192 episodes of granulocytopenia were studied. Febrile granulocytopenic patients were randomly allocated to receive either carbenicillin, methicillin and gentamicin, or carbenicillin and cephalothin. The response rate for the two antibiotic regimens was similar, 49 (60 per cent) of 81 responded to the former and 42 (54 per cent) of 78 to the latter. The response rate in patients receiving other antibiotics because of specific indications or counterindications was 19 (58 per cent) of 33. Thirty-nine (35 per cent) of 110 patients who responded to initial antibiotic therapy had an increase in circulating granulocytes of one log10 or more compared to only 10 (12 per cent) of 79 nonresponders with such an increase. The mortality rate in adult patients receiving carbenicillin, methicillin and gentamicin was eight (16 per cent) of 51, compared to 18 (37 per cent) of 49 in those receiving cephalothin and carbenicillin (P less than 0.05). The significance of this difference in the initial response rate or mortality rate between patients treated with the two antibiotic regimens when only patients with documented bacterial infection were considered. Patients who responded to their initial antibiotic regimen, and patients for whose fever no explanation was found, had the best prognosis.

Clinical and laboratory study of tobramycin in the treatment of infections due to gram-negative organisms.

Tobramycin, an aminoglycoside antibiotic, was used to treat 52 infections due to gram-negative organisms in 51 patients. Complicated urinary tract infections, bacteremia and pyelonephritis accounted for 80% of the infections. The rate of immediate satisfactory response was 79%. During therapy with tobramycin, resistant organisms emerged in four patients--two Pseudomonas aeruginosa and two Escherichia coli strains. There were four superinfections with tobramycin-resistant Providencia sp. In four seriously ill patients the serum creatinine concentration increased 1 mg/dL or more; in three the increase was transient. No auditory toxicity was noted in the 19 patients in whom serial audiograms were made. In vitro testing of isolates from these patients showed that tobramycin and gentamicin had equal activity against Enterobacteriaceae. Tobramycin was two to four times more active against susceptible P. aeruginosa.

Clinical evaluation of amikacin in treatment of infections due to gram-negative aerobic bacilli.

The efficacy and safety of amikacin were evaluated in 42 patients with infections presumed to be due to gram-negative rods. The dosage of 7.5 mg of amikacin/kg every 12 hr was administered intramuscularly to 32 patients and intravenously to seven patients; three patients with renal impairment were given a modified regimen. The duration of treatment was three to 51 days (mean, 9.6 days). Of 19 patients with acute pyelonephritis, five had positive blood culture results. Ten patients had chronic urinary infection, and isolates of Pseudomonas aeruginosa from four of these patients acquired resistance to amikacin during therapy. Of seven patients with gram-negative bacteremia from sources other than the urinary tract, four showed satisfactory and three had less than optimal responses to therapy with amikacin. Two patients with chronic osteomyelitis or soft tissue infection improved but subsequently relapsed. Two patients with acute febrile illness, in whom the etiologic agent was unidentified, recovered. Serial audiograms revealed no change in 26 of 27 patients; one had a significant deterioration in hearing. A transient rise in the level of serum creatinine was noted in three patients. Serial tests of liver function revealed no abnormalities.

Emergence of gentamicin- and carbenicillin-resistant Pseudomonas aeruginosa in a hospital environment.

Strains of Pseudomonas aeruginosa resistant to either gentamicin or carbenicillin have been noted since their introduction into clinical use. During a 6-month period, twice-weekly cultures were obtained from all patients treated with either gentamicin or carbenicillin and from all patients with a positive culture for P. aeruginosa. Susceptibility testing to gentamicin and carbenicillin and pyocine typing were performed on all isolates. Organisms with a minimal inhibitory concentration greater than 12.5 mug of gentamicin per ml or greater than 100 mug of carbenicillin per ml were defined as resistant. P. aeruginosa was cultured from 238 patients. One patient was initially infected with a gentamicin-resistant isolate. In 11 other patients, serial cultures revealed the emergence of resistance to gentamicin. All but one of these resistant isolates occurred in patients treated with gentamicin. In eight instances the pyocine and/or serological types before and after the change in sensitivity pattern were the same. Gentamicin-resistant P. aeruginosa emerged significantly more often in patients treated with gentamicin than in those who did not receive gentamicin. Carbenicillin-resistant P. aeruginosa emerged in four of 14 patients treated with carbenicillin. Seventeen of the 238 patients were infected de novo with carbenicillin-resistant P. aeruginosa. Carbenicillin-resistant P. aeruginosa emerged significantly more often in patients treated with carbenicillin than in those who did not receive carbenicillin. No evidence was found for in-hospital spread of resistant P. aeruginosa.

A comparison of trimethorprim-sulfamethoxazole with sulfamethoxazole alone in infections localized to the kidneys.

Ninety patients with urinary tract infections were treated in a randomized double-blind study with either a combination of trimethoprim and sulfamethoxazole (TMP-SMX) or sulfamethoxazole alone (SMX). Thirty of 42 patients treated with TMP-SMX were cured by the time of follow-up compared with 26 of 48 treated with SMX alone. Of the 29 patients infected with SMX-resistent organisms, the combination TMP-SMX cured 12 of 17, whereas SMX alone cured 2 of 12. Of the 61 patients infected with SMX-sensitive organisms, TMP-SMX cured 18 of 25; SMX alone cured 24 of 36. In 50 women the infection was found localized to The upper urinary tract by the use of the Fairley bladder washout technique. TMPsmx cured 16 or 24 of these patients with proved upper tract infections and SMX alone cured 11 of 26. Although none of these differences were significant, TMP-SMX appears to be an effective drug combination for the therapy of proved upper tract infection and is also effective in eradicating sulfonamide-resistant organisms.