Biomedical subjects
J C Wade
Publications and source records attributed to J C Wade.
Lack of association between Clostridium difficile toxin and diarrhea in infants.
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Bacillus infections in patients with cancer.
Eighteen febrile patients experienced 24 episodes of Bacillus bacteremias from January 1978 to June 1986. Bacillus species isolated included Bacillus cereus (eight cases), Bacillus circulans (three), Bacillus subtilis (two), Bacillus pumilus (two), Bacillus licheniformis (one), Bacillus sphaericus (one), Bacillus coagulans (one), and six that could not be speciated. Fifteen patients had lymphoma or leukemia and three had breast cancer. Nine patients were neutropenic (polymorphonuclear neutrophil count, less than 1.0 x 10(9)/L), seven patients had a Hickman catheter in place, and 14 had recently received chemotherapy. Twelve of the bacteremic episodes were clinically significant, and four of these 12 involved Hickman catheters. Catheter removal was ultimately necessary in all four patients. Scanning and transmission electron microscopy was performed on one of the removed Hickman catheters and showed Bacillus organisms embedded in a biofilm composed of gram-positive cocci and glycocalyx. Bacillus species were uniformly susceptible to vancomycin, imipenem, and aminoglycosides, with penicillin susceptibilities being variable. Bacillus appears to be another gram-positive organism now being recognized as a bacterial pathogen for compromised hosts. When such infections involve long-term indwelling venous access devices, treatment should include immediate catheter removal as well as antibiotic therapy.
Medicare: ethics versus economics.
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Synergism of the combinations of imipenem plus ciprofloxacin and imipenem plus amikacin against Pseudomonas aeruginosa and other bacterial pathogens.
The combinations of imipenem plus ciprofloxacin and imipenem plus amikacin were investigated for their activity against Pseudomonas aeruginosa and other bacterial pathogens. For imipenem-susceptible P. aeruginosa, synergy of imipenem plus ciprofloxacin and imipenem plus amikacin was observed against 36 and 45% of the strains, respectively. The incidence of synergy against imipenem-resistant isolates of P. aeruginosa was 10% for both combinations. Antagonism was not observed with either combination.
Steady-state pharmacokinetics of imipenem in febrile neutropenic cancer patients.
We ascertained the pharmacokinetics of imipenem in febrile granulocytopenic cancer patients. The values observed were both different from and significantly more variable than those observed in normal volunteers. Free drug concentrations exceeded the MIC for 90% of Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus strains for greater than 6 h. The MIC for 90% of Pseudomonas aeruginosa strains was exceeded for 4 h. Because imipenem induces a 2-h postantibiotic effect in P. aeruginosa, it is promising as single-agent empiric therapy in this setting.
Supportive care: issues in the use of blood products and treatment of infection.
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Monotherapy for empiric treatment of fever in granulocytopenic cancer patients.
Infection remains a major complication of severe granulocytopenia. The administration of empiric antibiotic therapy at the first sign of infection or fever has significantly reduced the sequelae of infection in such compromised patients. Yet, the appropriate composition of the empiric antibiotic regimen continues to be debated. Antibiotic combinations have been the standard approach; multiple studies have confirmed the importance of antibiotic combinations in patients who are profoundly granulocytopenic and have gram-negative rod bacteremia. The presence of a synergistic antibacterial effect and high serum bactericidal activity of the antimicrobial regimen improves the response rate in such severe infectious episodes. However, the occurrence of such infections at certain centers is declining, and the introduction of new, highly active, broad-spectrum beta-lactam antibiotics has raised the question of using a single agent, or monotherapy, as empiric treatment of febrile granulocytopenic cancer patients. Approximately 20 studies have been completed, and although these trials have demonstrated support for this approach, caution must be exercised because of the inconsistent study designs, wide range of response definitions, small patient numbers, and limited frequency of treated documented infections. Therefore, at present, a broad-spectrum antibiotic combination still remains the treatment of choice for empiric therapy of febrile granulocytopenic cancer patients. Carefully designed, prospective, randomized, double-blind trials investigating new approaches, such as monotherapy, must continue.
Trichosporonosis in patients with neoplastic disease.
Trichosporonosis due to Trichosporon beigelii or T. capitatum is an infrequent but potentially fatal invasive fungal infection in cancer patients. We studied epidemiologic, clinical, pathologic, and microbiologic features of this infection during a 7-year period at the University of Maryland Cancer Center. Fifteen patients with involvement by Trichosporon were identified: 5 were infected, 5 were possibly infected, and 5 were colonized but not infected by Trichosporon. Four of the infected patients had trichosporonemia and/or positive skin biopsy cultures as the first evidence of infection. The fifth infected patient had positive marrow and skin biopsy cultures. Serial surveillance cultures of infected patients showed preceding Trichosporon colonization in only 1 of 5 cases. Pulmonary infiltrates in 3 infected patients correlated at postmortem examination with Trichosporon pneumonia. Renal dysfunction marked by proteinuria, hematuria, red blood cell casts and azotemia correlated with widespread glomerular infiltration with the fungus. The five infected patients died of their infection, whereas the 2 possibly infected patients who died succumbed to their underlying illness. Trichosporonemia may have been averted in possibly infected patients because of a shorter median duration of profound (less than 100/microliter) neutropenia (5 days) when compared to that of infected patients (20 days). No environmental source of Trichosporon was found in environmental surveillance cultures of food, air, or inanimate surfaces. In vitro studies of three pathogenic strains showed resistance to 5-fluorocytosine but susceptibility to amphotericin B, ketoconazole, and miconazole. Norfloxacin augmented the in-vitro antifungal activity of amphotericin B. Trichosporon must be considered an opportunistic pathogen that can cause serious infections among patients with cancer.
Adherent microorganisms on lumenal surfaces of long-term intravenous catheters. Importance of Staphylococcus epidermidis in patients with cancer.
Using electron microscopy, we prospectively evaluated how frequently adherent microorganisms colonized silicone rubber intravenous (Hickman) catheters removed from patients with cancer. Thirteen (87%) of 15 catheters had gram-positive cocci in glycocalyx adherent to the surface of the catheter lumen. Fungal elements or gram-negative bacilli were mixed with the gram-positive cocci in the glycocalyx on the lumens of three catheters. A consistent morphologic form was adherent to, and the same species was recovered from, the corresponding catheter for six of 27 organisms causing septicemia during catheterization: four of five Staphylococcus epidermidis bacteremias and the only Staphylococcus aureus bacteremia, and one of five candidemias. Three of these six septicemias were successfully treated without removal of the catheter. Although adherent organisms, particularly S epidermidis, were likely to be present on the surface of the lumen of long-term, indwelling, silicone intravenous catheters, septicemias potentially related to these organisms occurred infrequently (fewer than two per 1000 days of catheter use), and the suspect septicemias could sometimes be treated without removal of the catheter.
Potential of imipenem as single-agent empiric antibiotic therapy of febrile neutropenic patients with cancer.
Infection remains a major cause of morbidity and mortality for the patient with cancer who experiences episodes of severe granulocytopenia. The search continues for new antimicrobial agents with improved efficacy and lower incidence of toxicity. Imipenem is a new carbapenem antibiotic which possesses a broad antibacterial spectrum with excellent activity against Pseudomonas aeruginosa and the other commonly recovered enteric gram-negative bacilli that infect the granulocytopenic patient with cancer. The combination of imipenem plus an aminoglycoside has shown in vitro synergy against P. aeruginosa and Staphylococcus aureus whereas the combination of imipenem plus piperacillin or the extended spectrum cephalosporins have frequently shown antagonism when tested against P. aeruginosa and Serratia marcescens. The use of a P. aeruginosa-infected neutropenic rat model has provided an in vivo system to evaluate the activity of new antibiotics or antibiotic combinations. Monotherapy with imipenem is as effective in this model as any of the currently available synergistic antibiotic combinations. This degree of activity has not been found with other broad-spectrum antibiotics when used alone. Imipenem provides serum bactericidal activity well above a 1:8 dilution for the four most commonly isolated pathogens: P. aeruginosa, Escherichia coli, Klebsiella species, and S. aureus. In addition, imipenem's post-antibiotic effect against P. aeruginosa may be pertinent. Imipenem is a unique antibiotic, with properties that make it well suited for study as monotherapy for fever and suspected infection in granulocytopenic patients with cancer. A prospective randomized, double-blind study comparing imipenem with a control regimen of piperacillin plus amikacin as empiric antibiotic therapy of febrile granulocytopenic patients with cancer is currently underway at the University of Maryland Cancer Center.
Recurrent infection with herpes simplex virus after marrow transplantation: role of the specific immune response and acyclovir treatment.
Herpes simplex virus (HSV) reactivation is common after marrow transplantation, with some patients developing frequent and severe recurrences. Sixty patients were studied to determine both the effect of the specific lymphocyte response to HSV on subsequent recurrences and the effect of acyclovir treatment on restoration of this response. Patients with a positive response after the first HSV recurrence had fewer second recurrences (13 of 28 vs. 18 of 19; P less than .01) and at a longer interval when they did recur (42 vs. 27 days; P less than .0001). Conversely, patients treated with acyclovir had more frequent second recurrences than did those not treated (18 of 21 vs. 13 of 26; P less than .05) and they were at a shorter interval when they did recur (27 vs. 36 days; P = .001). Treated patients also had lower specific lymphocyte responses to HSV. These data confirm the importance of the specific immune response to HSV in the determination of the course of HSV infection after marrow transplant.
Acyclovir treatment of varicella-zoster virus infection in the compromised host.
Forty marrow transplant patients were treated with acyclovir for varicella-zoster virus infection. Median duration of virus positivity and of new lesion formation was 2.1 and 2.2 days, and pustulation , crusting, and healing occurred at medians of 3.5, 8, and 28 days, respectively. Acute pain ceased at a median of 7 days, though seven patients had later recurrence of pain and eight had pain that persisted for more than 28 days. Three patients had recurrence of infection within 4 days after the end of treatment and were successfully treated in each case with a second course of acyclovir. Side effects were minimal. These data compare favorably with published data both from the treatment of normal persons with acyclovir and treatment of normal persons with acyclovir and treatment of immunocompromised patients with vidarabine, and they indicate that acyclovir is safe and effective for the treatment of varicella-zoster virus infection in the severely immunocompromised host.
Oral acyclovir for prevention of herpes simplex virus reactivation after marrow transplantation.
Oral acyclovir was found to be safe and effective for the prevention of herpes simplex virus reactivation after marrow transplantation in a double-blind, placebo-controlled trial. Acyclovir or placebo was administered to 49 patients for 5 weeks beginning 1 week before transplantation: 5 of 24 patients receiving acyclovir developed herpes simplex virus infection during prophylaxis, compared to 17 of 25 patients receiving placebo (p less than 0.01). The median time to first virus reactivation was significantly longer among patients receiving acyclovir (78 days versus 9 days after transplant, p = 0.006). The effect was even more pronounced when the analysis was adjusted for drug compliance: Among patients taking a minimum of 40% of their prescribed drug, acyclovir was 96% virologically effective and 100% clinically effective during the period of administration. Acyclovir use was also associated with significantly more rapid marrow engraftment in patients receiving methotrexate. No virus resistant to acyclovir was isolated. Oral acyclovir provides effective prophylaxis against reactivation of herpes simplex virus among severely immunosuppressed patients able to take orally administered drugs.
Prolonged venous access for chemotherapy by means of the Hickman catheter.
One hundred and six long-term right atrial (Hickman) catheters have been used to establish permanent venous access in 99 patients undergoing prolonged chemotherapy for leukemia and other malignancies at the University of Maryland/Baltimore Cancer Research Center over the 30-month period from November 1978 to May 1981. A uniform technique for insertion, using cannulation of the external or internal jugular vein and atraumatic dissection of the subcutaneous tunnel, has resulted in no episodes of hemorrhage or tunnel infection in the last 55 placements in these high-risk granulocytopenic, thrombocytopenic patients. Twelve catheters have now been in place for over one year, and two catheters have been in place for over two years without apparent ill effects. A low catheter related infection rate is attributed to meticulous adherence to catheter care guidelines, supervised by a single trained and interested nurse.
Acyclovir halts progression of herpes zoster in immunocompromised patients.
We conducted a placebo-controlled, double-blind study of acyclovir therapy for acute herpes zoster in immunocompromised patients. Of the 94 patients enrolled in the study, 52 had localized skin lesions at entry, and 42 had disseminated cutaneous zoster. A one-week course of intravenous acyclovir (1500 mg per square meter of body-surface area per day) halted progression of zoster in both groups, as determined by development or progression of cutaneous dissemination, development of visceral zoster, or proportion of cases deemed treatment failures. Significantly fewer patients treated with acyclovir within the first three days after the onset of exanthem had complications of zoster, as compared with patients treated with placebo (P = 0.02 by Fisher's exact test), but acyclovir also stopped progression of zoster in patients treated after three days of rash (P = 0.05 by Fisher's exact test). Acyclovir recipients with disseminated cutaneous zoster had a significantly accelerated rate of clearance of virus from vesicles, as compared with placebo recipients (P = 0.05 by the Breslow test).
Hepatitis in patients with acute nonlymphocytic leukemia.
Three consecutive groups (University of Maryland Cancer Center protocols 7110, 7405, and 7802) of patients with acute nonlymphocytic leukemia who achieved a complete hematologic remission with similar antileukemic therapy were reviewed for the development of hepatitis. Ninety-four (73 percent) experienced viral hepatitis; eight had type B hepatitis and 86 had non-A/non-B hepatitis. The hepatitis was mild in all patients. Hepatitis secondary to cytomegalovirus, herpes simplex virus, Epstein-Barr virus, or Toxoplasma gondii was not observed. Antibody to type A hepatitis was common, but acute infection could not be substantiated. All cases of type B hepatitis in which the surface antigen could be serotyped were found to have the less frequently observed ayw marker, suggesting a common donor as the source of infection. The median duration of complete remission was longer (p = 0.03) for patients in Group II (protocol 7405) who contracted hepatitis (247 days) compared with patients without hepatitis (125 days). Median overall survival was also longer (p = 0.01) for these patients in whom hepatitis developed (672 days versus 372 days, respectively). No prolongation of complete remission duration or survival could be demonstrated for patients from Group I (protocol 7110) or Group III (protocol 7802) who contracted hepatitis. In patients with hepatitis, the height of transaminase serum bilirubin levels or duration of abnormal results of liver function tests did not correlate with the duration of complete remission or survival. Hepatitis, a common infection in those patients with acute nonlymphocytic leukemia who undergo induction therapy, had an inconsistent effect on the duration of complete remission interval and overall survival.
Selective antimicrobial modulation as prophylaxis against infection during granulocytopenia: trimethoprim-sulfamethoxazole vs. nalidixic acid.
Sixty-two profoundly granulocytopenic patients with acute leukemia undergoing induction chemotherapy were prospectively randomized to receive either trimethoprim-sulfamethoxazole plus nystatin or nalidixic acid plus nystatin for prevention of infection. Patients given trimethoprim-sulfamethoxazole plus nystatin during initial remission induction experienced an increased duration (22.6 vs. 13.6 days) of profound granulocytopenia (less than 100 granulocytes/mm3; P = 0.007). Acquisition of gram-negative bacilli was more frequent among patients treated with nalidixic acid plus nystatin while filamentous fungi were acquired more frequently by patients receiving trimethoprim-sulfamethoxazole plus nystatin (P = 0.05). The median duration of on-study time prior to documentation of first infection was longer for patients receiving trimethoprim-sulfamethoxazole plus nystatin (17 days) than for those receiving nalidixic acid plus nystatin (eight days) (P = 0.0002). Three infection-related deaths occurred among patients receiving nalidixic acid; seven occurred among patients receiving trimethoprim-sulfamethoxazole, five of which were secondary to pneumonia due to Aspergillus flavus. Both of these methods of selective antimicrobial modulation have apparent advantages, but each has disadvantages serious enough to limit their routine use.