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.

Systemic pseudallescheriasis in a patient with acute myelocytic leukemia.

Presented is a case of widely disseminated systemic pseudallescheriasis in a 41 year old male with acute myelocytic leukemia. The immediate cause of death appeared to be due to an extensive invasion of the lungs which showed massive intra-alveolar hemorrhages, congestion, mycotic thrombi, and multiple fungal lesions in all lobes. Pseudallescheria boydii was diagnosed histopathologically by virtue of its characteristic conidia present in miliary lesions throughout a wide range of host's tissues, including the brain and the thyroid. Three antemortem blood specimens cultured during the patient's final hospital stay were positive for the fungus. It was concluded the fungemia was responsible for the rapid and widespread dispersion of P. boydii in this debilitated patient who was granulocytopenic and immunosuppressed.

Effect of Hickman catheters on the self-esteem of patients with leukemia.

Hickman right atrial catheters are useful in providing prolonged access for chemotherapy. Their presence does alter body image, however, and the maintenance of catheter patency during periods of outpatient care demands patient cooperation and participation. To determine whether the alterations in body image and life-style brought about by catheter insertion would have a negative effect upon the self-esteem of patients with acute leukemia, "purpose-in-life" testing was done prospectively in two groups of patients treated over a 30-day period with and without right atrial catheters. No significant alterations in self-esteem were noted during the study period in response to the use of Hickman catheters. The results suggest that Hickman catheters can be used as needed to improve venous access in patients with acute leukemia, without fear that this will adversely affect self-esteem.

Ototoxicity and pharmacokinetically determined dosages of amikacin in granulocytopenic cancer patients.

Pharmacokinetic principles were used to determine amikacin doses for granulocytopenic cancer patients on empirical antibiotic regimens, and audiometry was used to determine the effect of this treatment on auditory acuity. Patients received ticarcillin 300 mg/kg/day plus amikacin, or moxalactam 8 g/day plus amikacin, in a blinded study. Amikacin doses were calculated to achieve a peak serum concentration (one hour after infusion) of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml. Baseline audiometry was conducted, and follow-up audiometry was done on completion of the antibiotic therapy. A decrease of greater than or equal to 20 db at any frequency in one or both ears was considered indicative of ototoxicity. Of 201 patients on the empirical antibiotic protocol, 55 had courses of treatment that could be evaluated. Ototoxicity not attributable to any other drug or disease process occurred in 10 patients. There were no significant differences related to age, weight, daily dose, or total dose between patients who developed ototoxicity and those who did not. Peak and trough amikacin concentrations were not significantly different between groups. More women than men developed ototoxicity. Duration of therapy for the ototoxic group was longer, and there was a trend for those with abnormal initial audiograms to develop further evidence of impairment. The significant risk factor for auditory toxicity was the combination of duration of aminoglycoside therapy and total dose per kilogram. Pharmacokinetically calculated doses of amikacin did not result in a higher incidence of auditory toxicity than reported in previous studies.

Comparison of standard versus pharmacokinetically adjusted amikacin dosing in granulocytopenic cancer patients.

The capabilities of two pharmacokinetic amikacin dosing methods were evaluated and compared with the standard amikacin dosage recommended by the manufacturer. Study patients participated in two consecutive prospective randomized double-blind trials of empiric antibiotic therapy for febrile episodes during granulocytopenia. Patients in study 1 received amikacin at a dosage of 15 mg/kg per day in four divided doses in combination with either ticarcillin or piperacillin. Patients in study 2 received either ticarcillin or moxalactam in combination with amikacin. Amikacin dosages in study 2 were adjusted to achieve a 1-h-postinfusion concentration of approximately 25 micrograms/ml and a trough concentration of approximately 8 micrograms/ml. Initial amikacin dosage requirements were established based on the lean body weight and estimated renal function of the patient. If amikacin serum concentrations were not within acceptable ranges, further dosage adjustments were made by using patient-specific pharmacokinetic parameters. The median 1-h-postinfusion concentration of amikacin in study 1 was 13.0 micrograms/ml, with a median trough concentration of 6.1 micrograms/ml. In study 2 the median 1-h-postinfusion concentration was 20.8 micrograms/ml, with a median trough of 6.4 micrograms/ml. Patients in study 2 required a mean dosage of 29.4 mg/kg per day. The incidence of amikacin-induced nephrotoxicity was not increased despite the substantial increase in dosage. Ototoxicity was not evaluated in study 1, but the incidence of ototoxicity in study 2 (17%) exceeded the incidence observed in a previous amikacin-plus-ticarcillin trial in which patients received 15 mg of amikacin per kg per day.

How many loci on the X-chromosome of Drosophila melanogaster can mutate to recessive lethals?

The sensitivity of the sex-linked recessive lethal test is due to the fact that a very large number of loci are included i the mutation study. From extensive studies on the spontaneous sex-linked recessive lethal frequency and spontaneous specific locus mutation rates, it is possible to derive an estimate of the number of loci included in the recessive lethal test. The average number derived from three estimates on male and female germ cells is 563 loci. A second independent approach derives from published data which analyzed short regions of he genome and the proportion of loci within these regions which mutate to lethality. This analysis suggests that 830 loci are potentially lethal mutables. We describe the reasons for concluding that 600 to 800 loci of the approximately 1,000 loci on the X-chromosome are involved in the X-linked recessive lethal test.