Hypersensitivity reactions to teniposide (VM-26): an analysis.

An analysis of hypersensitivity reactions to teniposide was approached using three methods: investigator survey, adverse drug reaction analysis, and literature search. By the survey method, hypersensitivity incidence was 6.5% with the majority of the reactions (82%) occurring in brain tumor or neuroblastoma patients. By the second method, 43 cases of hypersensitivity that were reported to the National Cancer Institute (NCI) between January 1983 and October 1985 were analyzed in detail. Reaction onset was unpredictable according to the number of drug doses. The majority of the patients (65%) experiencing the reaction had neuroblastoma or brain tumors, and these patients also tended to react earlier in the course of drug administration than those with hematologic malignancies. Clinical presentation was not correlated with the patient's diagnosis. All patients recovered. However, only six of 13 were successfully rechallenged with the drug. The third approach, the literature search, provided information on 82 hypersensitivity reactions among 2,250 patients (3.6% incidence). Forty-five percent of these reactions were linked to neuroblastoma or brain tumor patients. The analysis of hypersensitivity to teniposide by these three methods provides insight into the true incidence of hypersensitivity reactions in the general patient population. The frequency of the reactions is substantially higher in patients with neuroblastoma and brain tumors. This population should be considered for future trials of aggressive prophylactic therapy.

Phase I trial of N-methylformamide (NMF, NSC 3051).

N-methylformamide (NMF) is a polar-planar solvent with both cytotoxic and differentiating activity in preclinical models; it also acts as a radiosensitizer. We treated 17 patients with 18 courses of NMF on a schedule of six weekly doses, administered on a rapid intravenous infusion, which were escalated from 875 to 2,000 mg/m2/wk. The predominant toxicity was a dose-related syndrome of fatigue, malaise, nausea, and anorexia, which was reflected by a decrease in performance status (Karnofsky) of greater than or equal to 20% in six of ten patients who received doses greater than or equal to 1,500 mg/m2/wk. Other gastrointestinal toxicities included moderate vomiting and mild diarrhea. Reversible increase of liver enzymes occurred in six of ten patients at doses greater than or equal to 1,500 mg/m2/wk. The maximum tolerated dose on this schedule is 1,500 mg/m2/wk; the dose recommended for phase II studies is 1,125 mg/m2/wk. Future studies of this regimen in a combined modality setting are planned.

Cisplatin nephrotoxicity: a summary of preventative interventions.

Nephrotoxicity is usually the dose-limiting toxicity associated with cisplatin therapy. Frequently the nephrotoxicity is mild and reversible. However, it is both dose-related and cumulative and may become life-threatening and irreversible at higher dosages. Many interventions such as vigorous hydration, osmotic or loop diuretics, and alterations of infusion times have been evaluated in the hope of ameliorating this serious toxicity, and are summarized. More recently, hypertonic NaCl 0.9% has been reported to decrease the incidence of cisplatin nephrotoxicity. In addition, newer platinum analogs are currently undergoing clinical trials to ascertain if they retain the antitumor properties of cisplatin but produce less toxicity.

Combination antiemetic therapy in the control of chemotherapy-induced emesis.

Severe nausea and vomiting are frequent complications of cancer chemotherapy. Historically, single-agent antiemetic therapy frequently has been less than optimal. Because multiple sites of emetogenic activity may be involved in chemotherapy-induced nausea and vomiting, many investigators are now using combinations of antiemetics in an effort to block multiple receptor sites. Several preliminary studies using combinations of antiemetic agents that have shown encouraging results are summarized.

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.

Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions.

Piperacillin sodium is a beta lactam antibiotic with a broad range of antibacterial activity that includes gram-negative bacilli, gram-positive cocci (except penicillinase-producing S. aureus) and anaerobic pathogens such as Clostridium difficile, and Bacteroides fragilis. Piperacillin inhibits many of the members of the Enterobacteriaceae, including Klebsiella sp and Pseudomonas, at lower concentrations than required for carbenicillin and ticarcillin. Piperacillin sodium is administered by intramuscular and intravenous injection and is widely distributed throughout body fluids and tissues. Like other newer penicillins, piperacillin is excreted by both renal and biliary mechanisms. The primary route of elimination is by glomerular filtration, which results in high urinary concentrations of the unchanged compound. Piperacillin has been approved for patients with serious infection caused by susceptible strains of specific organisms in intra-abdominal, urinary tract, gynecologic, lower respiratory tract, skin and skin structure, bone and joint, and gonococcal infections and septicemia. As with other penicillins, piperacillin has a low frequency of toxicity. The usual dose of piperacillin in adults with serious infections with normal renal function is 3-4 g every 4-6 hr as a 20-30 min infusion, with a maximum dose of 24 g per day. It is stable in most large volume parenteral solutions. Less serious infectins (requiring smaller dosages) may be treated by intramuscular injection; however, no more than 2 g should be given at any one injection site. Overall, piperacillin has a greater degree of activity than other penicillins. Evidence from prospective studies indicates that piperacillin is a highly effective agent for the treatment of patients with infections caused by susceptible organisms.

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.

Review of amsacrine, an investigational antineoplastic agent.

The pharmacology, chemistry, pharmacokinetics, clinical studies, and adverse effects of amsacrine, an investigational antineoplastic agent, are reviewed. Amsacrine's mechanism of action is not clearly understood, although the drug is known to inhibit DNA synthesis. As an investigational NCI "Group C" agent, amsacrine is available to physicians for the treatment of adult patients with refractory acute nonlymphocytic leukemia (ANLL) under an established protocol. Following intravenous administration, amsacrine has a biphasic plasma clearance. It is extensively metabolized by the liver to inactive compounds that are excreted in the bile. Phase I studies indicated that amsacrine was potentially effective in patients with solid tumors and acute leukemias. Patients with solid tumors could tolerate much lower doses of amsacrine than leukemia patients because of dose-limiting bone-marrow suppression in the former. In Phase II studies, amsacrine appeared effective in treating the acute leukemias, with response rates of 31% and 23% for acute lymphocytic leukemia and ANLL, respectively. Patients with other types of cancers have not responded to amsacrine therapy. Frequently occurring adverse effects of amsacrine include leukopenia and thrombocytopenia in patients with solid tumors; nausea, vomiting, and diarrhea; mucositis in patients receiving higher doses (leukemia patients); alopecia; hepatotoxicity; and phlebitis. The clinical usefulness of amsacrine appears limited to treatment of the acute leukemias. Studies of combination therapies that include amsacrine are currently underway and should further define the therapeutic role of amsacrine.

Empiric antibiotic therapy for suspected infection in granulocytopenic cancer patients: a comparison between the combination of moxalactam plus amikacin and ticarcillin plus amikacin.

Moxalactam is a new cephalosporin with a broad spectrum of activity which includes Pseudomonas aeruginosa in addition to Klebsiella species Escherichia coli, and Staphylococcus aureus. Moxalactam was combined with amikacin (M + A) compared to ticarcillin plus amikacin (T + A) in a prospective, randomized double-blind trial of empiric therapy for febrile episodes among granulocytopenic cancer patients. One hundred and ninety-one epidoses were evaluated; T + A, 93 episodes and M + A, 98 episodes. Median granulocyte count of initiation of therapy was less than 100/microliters. Overall response rates were good. In the T + A group, 21 of 29 (72 percent) microbiologically documented infections, including seven of 14 (50 percent) bacteremias, and 24 of 27 (89 percent) clinically documented infections improved. In the M + A group, 20 of 28 (71 percent) microbiologically documented infections, including 11 of 18 (61 percent) bacteremias, and 25 of 25 (96 percent) clinically documented infections resolved. Adverse effects were minimal and equivalent in both groups. Hypokalemia (decrease in serum potassium of greater than 11 mEq/liter from baseline) occurred in 14 of the 93 episodes in the T + A group and in 10 of the 98 episodes in the M + A group with decline in mean serum potassium level of 0.5 and 0.4 mEq/liter respectively. Nephrotoxicity (increase in serum creatinine greater than 0.04 mg/dl) occurred in only one patient in the T + A group and in two patients in the M + A group. Moxalactam plus amikacin has a broader in vitro spectrum, is as effective, and is no more toxic than ticarcillin plus amikacin as empiric therapy for febrile granulocytopenic cancer patients.

Piperacillin or ticarcillin plus amikacin. A double-blind prospective comparison of empiric antibiotic therapy for febrile granulocytopenic cancer patients.

Piperacillin plus amikacin was compared in a prospective randomized double-blind trial with our standard regimen of ticarcillin plus amikacin as empiric therapy of fever in patients with granulocytopenia. Profound persistent granulocytopenia (fewer than 100/microliter polymorphonuclear leukocytes without any rise during therapy) was present in 60 percent of the patient trials in both treatment groups. Of 38 microbiologically and clinically documented infections treated with piperacillin plus amikacin, 22 (58 percent) showed improvement. Of 34 microbiologically and clinically documented infections treated with ticarcillin plus amikacin, 19 (56 percent) showed improvement. There was no difference in response between groups according to the site of infection or infecting pathogen. Toxicity was minimal, with an equivalent incidence of immediate reactions, nephrotoxicity and superinfection. Patients receiving ticarcillin plus amikacin became colonized with more resistant gram-negative bacilli (17) than did those receiving piperacillin plus amikacin (3). Despite the monosodium structure of piperacillin, hypokalemia was not reduced for patients who received piperacillin plus amikacin. Although piperacillin has a wider in vitro antibacterial spectrum than ticarcillin, the clinical efficacy and toxicity of the combination of piperacillin plus amikacin were similar to those of ticarcillin plus amikacin as empiric therapy.

A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia.

Fifty-three profoundly granulocytopenic patients with relapsed acute leukemia who were undergoing reinduction chemotherapy were prospectively randomized to receive either trimethoprim-sulfamethoxazole plus nystatin or gentamicin plus nystatin for prevention of infections. The acquisition of new organisms per patient during the total study period was similar in both groups. Thirty-five symptomatic infections (five of which were bacteremias) occurred in patients receiving trimethoprim-sulfamethoxazole plus nystatin, whereas 31 infections (eight bacteremias) occurred in patients receiving gentamicin plus nystatin. Four deaths related to infection occurred in patients taking trimethoprim-sulfamethoxazole, and eight occurred in patients taking gentamicin. We conclude that trimethoprim-sulfamethoxazole plus nystatin was approximately as effective as gentamicin plus nystatin for prophylaxis against infection in relapsed acute leukemia. Furthermore, side effects were fewer and compliance was better with trimethoprim-sulfamethoxazole plus nystatin.

Potential of mezlocillin as empiric single-agent therapy in febrile granulocytopenic cancer patients.

Mezlocillin was used as an initial empiric antibiotic therapy for febrile (> 101 degrees F, ca. 38.33 degrees C) granulocytopenic (< 1,000/microliter) cancer patients. Patients known to be colonized with an organism resistant to 100 micrograms of mezlocillin per mol were excluded. The initial 25 cases (23 patients) received intravenous mezlocillin, 260 mg per kg per day in six divided doses; the mean 1-h-postinfusion serum level was 69 micrograms/ml. Because of the low serum level, the next 25 cases (22 patients) received 450 mg/kg per day, also in six divided doses, resulting in a mean 1-h-postinfusion serum level of 161 micrograms/ml. Both dosage regimens provided similar efficacy. Combined results show that 11 of 21 microbiologically documented infections and 7 of 13 clinically documented infections improved. Instances of bacteremia (number of cases in parentheses) were caused by Pseudomonas aeruginosa (two), Staphylococcus epidermidis (two), Clostridia perfringens (one), and Bacillus species (one); only one case improved. A rise in granulocyte count to > 500/microliters, a serum bactericidal activity of greater than or equal to 1:8 against the infecting pathogen, or both were indicators of a good therapeutic response. Despite exclusion of patients known to be previously colonized with mezlocillin-resistant organisms, 7 of 23 pathogens required a minimal concentration of greater than or equal to 100 micrograms of mezlocillin per ml for inhibition. In addition, surveillance cultures from 18 cases showed resistant organisms colonizing the gingiva, rectum, or both. Side effects of mezlocillin were minimal and included pseudoproteinuria, asymptomatic transient rise in bilirubin, and easily reversible kypokalemia. Mezlocillin, a new semisynthetic penicillin with little toxicity, was found to be inadequate as a single-agent empiric antibiotic therapy for febrile, granulocytopenic cancer patients.

Meperidine for the treatment of shaking chills and fever.

Meperidine hydrochloride was evaluated in a prospectively randomized double-blind study for its effectiveness in stopping shaking chills occurring with amphotericin B infusions. Seven patients were randomized on multiple occasions for a total of 19 reactions. In the meperidine group, nine of nine reactions stopped within 30 minutes of the administration of meperidine, with a mean cessation time of 10.8 minutes. The placebo group had a mean time of 37.4 minutes to cessation of reactions with three of ten reactions subsiding spontaneously. The mean dose of meperidine hydrochloride for cessation of reaction was 45 mg. The comparisons between meperidine and placebo for cessation of reaction within 30 minutes and the mean time to cessation of reaction were significantly different. Side effects with meperidine were minimal and less severe than the shaking chills and fever seen with amphotericin B infusions. Meperidine can eliminate these reactions more effectively and more rapidly than simply discontinuing the amphotericin B.

Comparative auditory toxicity of aminoglycoside antibiotics in leukopenic patients.

The incidence of auditory toxicity resulting from therapy with ticarcillin (T) (12 g/sq m/day) in combination with gentamicin (G) (200 mg/sq m/day), amikacin (A) (600 mg/dq m/day), or netilmicin (N) (280 mg/sq m/day) was compared. Before administration of these antibiotic combinations to febrile, granulocytopenic patients, baseline audiograms were determined by a pharmacist using a portable audiometer. The before-therapy audiograms for 32 patients receiving T and G, 29 receiving T and A, and 29 receiving T and N were compared with the audiograms after the completion of therapy. The mean length of therapy was seven days. Two patients (6.2%) receiving T and G, one (3.4%) receiving T and N, and one (3.4%) receiving T and A developed auditory toxicity with bilateral decreases of at least 20 decibels at one or more frequencies. The incidence of auditory toxicity secondary to aminoglycoside exposure was low, and the relative auditory toxicity among the three aminoglycosides appeared to be similar.

Randomized trial of empiric antibiotic therapy with ticarcillin in combination with gentamicin, amikacin or netilmicin in febrile patients with granulocytopenia and cancer.

A randomized trial of ticarcillin plus gentamicin (group 1), ticarcillin plus amikacin (group 2) and ticarcillin plus netilmicin (group 3) as empiric antibiotic therapy in patients with granulocytopenia and cancer was carried out at the Baltimore Cancer Research Center. The response rate for all infections was 97 per cent in group 1, 91 per cent in group 2 and 95 per cent in group 3. Patients with bacteremias showed improvement in 93 per cent (group 1), 78 per cent (group 2) and 82 per cent (group 3) of cases. All failures were among patients with gram-negative bacteremias. Both antibiotic susceptibility of the bacteremic organism and granulocyte recovery correlated with patient improvement. Nephrotoxicity and ototoxicity were rare and were not significantly different in three groups of patients. Therefore, ticarcillin plus gentamicin, ticarcillin plus amikacin and ticarcillin plus netilmicin appear to be equally efficacious and minimally toxic in this patient population. Excellent over-all results can be expected with these combinations provided the etiologic agent is susceptible.

Role of vancomycin as a component of oral nonabsorbable antibiotics for microbial suppression in leukemic patients.

A total of 38 adult patients with acute leukemia who were undergoing remission induction chemotherapy in regular patient rooms were randomly allocated to one of two oral nonabsorbable antibiotic regimens for infection prophylaxis (gentamicin, vancomycin, and nystatin [GVN] or gentamicin and nystatin [GN]) to evaluate whether vancomycin was a necessary component. The patient population in both groups were comparable. Tolerance to GVN was less than GN but compliance was approximately equal (>85% in both groups). Patients receiving vancomycin demonstrated greater overall alimentary tract microbial suppression; however, acquisition of potential pathogens was approximately equal in both groups. The incidence of bacteremia, as well as the overall incidence of infection as related to the number of days at various granulocyte levels, was also approximately equal in both groups. Group D Streptococcus species were poorly suppressed by GN compared with GVN, although no patient developed an infection with these organisms. Colonization by newly acquired gram-negative bacilli was significantly less in the GN group (GN, 3 colonizations; GVN, 13 colonizations; P < 0.01). It is concluded that vancomycin may be safely eliminated from the GVN regimen provided microbiological data is monitored to detect resistant organisms.

Audit of the de Haen Drugs-In-Use Drug Information System.

An audit of 100 abstracts from the de Haen Drugs-In-Use Drug Information System was conducted to determine the reliability of this drug information source. The original article was reviewed and compared with the information contained on the corresponding de Haen card. The card was audited for accuracy, completeness and judgment of abstraction. Forty-six cards contained at least one error. A total of 66 errors were observed: 47 involved errors of accuracy, 15 involved errors of completeness and 4 involved errors in judgment. The subscriber is urged to use the de Haen abstracts as a means of literature access only, and not as a primary source of drug information.

Infection in acute leukemia patients receiving oral nonabsorable antibiotics.

During a 20-month period all acute nonlymphocytic patients (87 patient trials) receiving cytotoxic chemotherapy were placed on an oral nonabsorbable antibiotic regimen consisting of gentamicin, vancomycin, and nystatin in addition to an intensive program of infection prevention aimed at reducing exogenously acquired and body-surface potential pathogens. Although side effects of anorexia, diarrhea, and nausea were common, gentamicin-vancomycin-nystatin was ingested 80% of the study time. Microbial growth in gingival and rectal cultures was substantially reduced. The incidence of bacteremias and other serious infections was low. Pseudomonas aeruginosa, other gram-negative bacilli, and Candida species caused few infections along the alimentary canal, whereas infections of the skin (especially Staphylococcus aureus) were not reduced compared with those occurring in former years. A total of the 104 acquired gram-negative bacilli were gentamicin resistant; 5 subsequently caused infection. Thus, despite certain definite drawbacks, the use of oral nonabsorbable antibiotics to suppress alimentary tract microbial flora in combination with other infection prevention techniques in granulocytopenic cancer patients has proven feasible and tolerable and has been associated with a low order of life-threatening infections.