Prediction of systemic fungal infection in allogeneic marrow recipients: impact of amphotericin prophylaxis in high-risk patients.

PURPOSE: To identify risk factors that might predict for systemic fungal infections in marrow transplant recipients within the first 100 days and to assess the efficacy of low-dose amphotericin B used as prophylaxis for candidemia and infection with invasive Aspergillus species in patients at risk. PATIENTS AND METHODS: A retrospective analysis of transplant outcomes for 331 allogeneic marrow recipients transplanted between 1983 and 1989 was performed to identify patients who might be at increased risk of fungal infection. Factors analyzed included disease, remission status, transplant regimen, graft-versus-host disease (GVHD) prophylaxis, duration of neutropenia, and development of GVHD. A trial of low-dose amphotericin (5 to 10 mg/d) begun on day +1 and continuing for 2 to 3 months posttransplant was begun in 1987 to evaluate its utility in reducing systemic mycoses. RESULTS: There were 18 episodes of candidemia and 18 systemic mycoses documented by blood or tissue culture or by biopsy. The initiation of high-dose (0.5 to 1 mg/kg/d) corticosteroids early as a component of GVHD prophylaxis in 1986 was identified as the most important risk factor for fungal infections, with a sixfold increase in infections as compared with the previous GVHD regimen (P < .0001); this was despite a significant decrease in the incidence of grade II to IV GVHD (7% v 43%; P = .0001). Low-dose amphotericin B initiated before the start of high-dose corticosteroid GVHD prophylaxis reduced the incidence of fungal infections from 30% to 9% (P = .01) without renal toxicity. Cyclosporine levels were lower in the patients who received amphotericin, leading to an increase in the rate of GVHD to 19% (P = .02). Controlling for GVHD prophylaxis, prolonged neutropenia (P = .00), and grade II to IV GVHD (P = .01) were also identified as risk factors for fungal infection. CONCLUSION: Amphotericin B can be used in low doses as prophylaxis for fungal infections early in the posttransplant course. However, cyclosporine doses need to be monitored to maintain target levels.

Evaluation of the BACTEC 16B medium in a cancer center.

The routine use of the new resin-containing BACTEC 16B (Johnston Laboratories, Inc., Cockeysville, MD) culture medium was evaluated in a population consisting primarily of cancer patients. Of 1,163 paired blood culture sets collected, 652 (56%) were collected in the presence of antimicrobial therapy. Eighty-three aerobic and facultatively anaerobic isolates were recovered from 79 positive blood culture sets. No significant difference could be demonstrated between the 16B and the 6B medium in the group of blood cultures collected from patients not receiving antibiotic therapy at the time of blood collection. In contrast, a significantly greater proportion of isolates (P less than 0.005) was recovered from the 16B medium (96%) than the 6B medium (68%) in the group of blood cultures collected in the presence of antimicrobial therapy. In this group, 43% of the isolates were either detected earlier or recovered solely from the 16B medium.

The value of bronchoalveolar lavage and bronchial washings in the diagnosis of invasive pulmonary aspergillosis.

The objective of this study was to clarify conflicting reports of the sensitivity and specificity of bronchoalveolar lavage or bronchial washings for diagnosing invasive pulmonary aspergillosis. The study was a retrospective review of 300 consecutive patients in a tertiary referral centre subjected to 343 fiberoptic bronchoscopic procedures for the evaluation of pulmonary infiltrates. Classification of paired fungal culture and cytologic examination of bronchoalveolar lavage or bronchial washing fluid according to clinical, radiographic, histological and autopsy evidence of invasive pulmonary aspergillosis. One-hundred and fifteen deaths occurred, with a 58% autopsy rate. A diagnosis of invasive pulmonary aspergillosis was made in 21 immunosuppressed patients with 16 deaths. Bronchoalveolar lavage cytology showed aspergillus in 19 specimens (invasive pulmonary aspergillosis in 16), cultures yielded aspergillus in 41 (invasive pulmonary aspergillosis in ten), with both tests positive in nine. Cytology sensitivity was 64.0%, specificity 99.1%, positive predictive value 84.2%, and negative predictive value 97.2%. Culture sensitivity was 40.0%, specificity 90.3%, positive predictive value 24.4%, and negative predictive value 95.0%. Concordant cytology and culture sensitivity was 32.0%, specificity 99.7%, positive predictive value 88.9%, and negative predictive value 94.9%. In conclusion, when characteristic hyphae are visualized in bronchoalveolar lavage specimens from immunosuppressed patients with compatible clinical data, it is advisable to treat for presumptive invasive pulmonary aspergillosis.

Mechanisms of lipopolysaccharide-induced protection against pseudomonas sepsis in granulocytopenic mice.

The nature of the enhanced resistance to Pseudomonas aeruginosa sepsis induced by type-specific lipopolysaccharide vaccine was examined in a mouse model of cyclophosphamide-induced granulocytopenia. Mice actively immunized with type-specific vaccine survived significantly longer than did nonimmune mice (P less than .002) when challenged 8, 12, or 16 days after immunization. This protection was nonspecific eight days after immunization and specific 12 days after immunization. Passive immunization of mice with specific antibody resulted in significant, though minimal, protection. In contrast, long-term protection was observed when the passive transfer of specific antibody was combined with nonspecific immunization. This observation suggests that the specific protection observed with type-specific active immunization results from the interaction of specific antibody and an immunization-induced nonspecific cellular effector. While no significant effect of immunization on granulocyte counts in peripheral blood was demonstrated, studies of phagocytosis performed with peritoneal mononuclear cells suggest that the macrophage may be the immunization-induced, nonspecific cellular effector.

Brief report: nosocomial infection rates in a cancer treatment center.

This report describes the results of a prospective study of nosocomial infection in 7,714 patients hospitalized during a 24-month period at a cancer treatment center. An overall nosocomial infection rate of 9.3% was observed with site-specific infection rates of 2.6% for urinary tract, 1.9% for surgical wound, 2.2% for bacteremia and 1.9% for respiratory tract infection. Within specific patient groups, the overall nosocomial infection rates observed were: 8.2% in medical patients, 14.9% in surgical patients and 1.5% in pediatric patients. Despite the markedly elevated nosocomial infection rate in surgical patients (P less than 0.001), surgical wound infection rates were not unlike those observed in general hospitals: clean-2.4%, clean contaminated-5.8%, contaminated-13.2%, and dirty-11.8%. These observations provide evidence that institutions which provide medical care predominantly for cancer patients can expect to observe higher nosocomial infection rates than general care hospitals.

Visceral varicella-zoster after bone marrow transplantation: report of a case series and review of the literature.

OBJECTIVES: Infection with varicella-zoster virus after bone marrow transplantation (BMT) is a common cause of morbidity and mortality. Visceral involvement with varicella-zoster may be incorrectly ascribed to graft-versus-host disease, resulting in delayed diagnosis and misguided therapy. METHODS: A 4-yr retrospective chart review was performed to determine the presenting symptoms and clinical outcome of visceral varicella-zoster virus infection in BMT recipients. RESULTS: Ten BMT recipients who subsequently developed visceral varicella-zoster virus infection were identified. The mean age at diagnosis was 40 yr (range 27-56 yr). Primary hematological malignancies were leukemia (N = 7), myelodysplasia (N = 2), and myelofibrosis (N = 1). Bone marrow transplants in affected patients were autologous (N = 2), related allogeneic (N = 5), or matched unrelated allogeneic (N = 3). The mean time interval from BMT to symptomatic visceral varicella-zoster virus infection was 153 days (range 60-280 days). Presenting symptoms included abdominal pain in all patients, nausea (60%), fever > 38 degrees C (60%), vomiting (50%), pneumonitis (50%), skin rash (40%), and diarrhea (30%). All patients had moderately or profoundly elevated aminotransferases and most had elevated pancreatic enzymes (80%). The mean time interval from the development of abdominal pain to the characteristic skin rash and then diagnosis was 6 and 7 days, respectively (range 4-10 and 4-14 days). Active graft-versus-host disease had previously been documented in five of the eight allogeneic BMT recipients. Immunosuppressive medications were increased at the onset of the abdominal pain in seven of these eight patients for suspected exacerbation of graft-versus-host disease. After recognition of varicella infection, antiviral therapy was promptly initiated; despite this, mortality was still 50%. CONCLUSIONS: Visceral involvement with varicella-zoster virus infection can occur as a late complication after both allogeneic and autologous BMT. In these cases, symptoms of severe abdominal pain with associated nausea, vomiting, and diarrhea and elevated liver and pancreatic enzymes preceded the vesicular skin eruption and were confused with graft-versus-host disease. With the increasing application of high-dose chemotherapy followed by stem cell rescue for both hematological and solid tumors, clinicians should be aware of this potentially treatable and often lethal complication.

Evaluation of a quantitative plasma PCR plate assay for detecting cytomegalovirus infection in marrow transplant recipients.

A plasma PCR test, using a nonradioactive PCR plate assay, was evaluated for detection of human cytomegalovirus reactivation. This assay was compared to Southern blotting and found to perform well. As a noncompetitive method of quantitation, it was similar to a competitive method for detecting the number of genome copies per milliliter of plasma in marrow transplant recipients. This is a technically simplified assay with potential for adaptation to automation.

Late cytomegalovirus disease in marrow transplantation is predicted by virus load in plasma.

Late occurrence of cytomegalovirus (CMV) disease after day 100 after bone marrow transplantation has become an increasing problem; whether a quantitative measurement of CMV DNA in plasma by polymerase chain reaction (P-PCR) could be predictive of such disease was investigated. In a prospective study, 117 subjects undergoing allogeneic marrow transplantation were followed for 120 days with weekly CMV blood cultures, with day 35 bronchoalveolar lavage CMV cultures, with weekly CMV P-PCR, and with clinical follow-up for an additional 1-2 years. Despite preemptive ganciclovir, CMV disease occurred in 9% of subjects, with a median time of onset of 176 days. Quantitative CMV P-PCR was associated with the late development of CMV disease (P = .01). Of 43 subjects with positive P-PCR results, 23% developed CMV disease, but no disease occurred in the 74 subjects with negative P-PCR (P < .001), despite the fact that 22% had CMV isolated from lung lavage fluid and 32% had CMV isolated from blood.

Altered gentamicin pharmacokinetics during the perioperative period.

The effect of surgery on the pharmacokinetics of gentamicin sulfate in hospitalized patients was studied. Patients with cancer undergoing surgery of the head and neck were given gentamicin sulfate in doses calculated to achieve peak serum concentrations of 6-8 micrograms/mL and trough concentrations of 1-2 micrograms/mL. Each patient received a loading dose at the time of surgical incision, followed by five maintenance doses at eight-hour intervals. Steady-state peak and trough serum gentamicin concentrations were predicted using a one-compartment open pharmacokinetic model and literature values for volume of distribution (V) and first-order elimination rate constant (k). Serum gentamicin concentrations were measured 0.25 hours before and at 0.5, 3.5, and 6.5 hours after completion of infusion of the second maintenance dose. Peak and trough serum concentrations were obtained by extrapolation from these measured concentrations using weighted, nonlinear least squares regression. Predicted versus measured serum gentamicin concentrations and estimated versus observed values for V and k were compared. Eight men and seven women had evaluable serum gentamicin concentrations. Patients received a mean calculated maintenance dose of 4.4 +/- 0.7 mg/kg/day. Mean extrapolated peak and trough serum gentamicin concentrations were significantly lower than predicted, and observed values of V and k were significantly greater than estimated values. Gentamicin dosages calculated using standard pharmacokinetic variable values may not produce therapeutic concentrations in patients undergoing surgery. Monitoring of serum concentrations with dosage adjustment when indicated is necessary for optimal therapy in these patients.