I.R.O. Novakova

Efficacy of Itraconazole in the Prevention of Fungal Infections Among Neutropenic Patients with Hematologic Malignancies and Intensive Chemotherapy. A Double Blind, Placebo Controlled Study

We studied the efficacy and safety of itraconazole for the prevention of fungal infection in neutropenic patients given cytotoxic chemotherapy for hematologic malignancies. Patients were randomly allocated to receive either itraconazole (200 mg bd) or placebo in addition to oral amphotericin B until the patient either developed fungal infection or had completed antileukemic treatment. Forty six patients (83 neutropenic episodes) treated with itraconazole and 46 placebo treated patients (84 neutropenic episodes) were evaluable. No specific toxicity was noted. Nine fungal infections developed in the itraconazole group, of which four were histologically or microbiologically proven and 15 in the patients given placebo (eight proven) (p < 0.12). All these patients received IV amphotericin B. The incidence of Candida albicans infections tended to be lower in the itraconazole group, but overall, there was no measurable improvement in the prevention of fungal infections and mortality by itraconazole.

Hyperhomocysteinemia and other thrombotic risk factors in women with placental vasculopathy

Objective To investigate coagulation inhibitors and abnormalities of the homocysteine metabolism, which are related to an increased thrombotic risk, as risk factors for placental vasculopathy.

Meloxicam, 15 mg/day, spares platelet function in healthy volunteers.

To study the influence of meloxicam, a cyclooxygenase‐2 (COX‐2) preferential nonsteroidal anti‐inflammatory drug, on serum thromboxane and platelet function in healthy volunteers with use of the maximum recommended daily dosage of 15 mg/day.

Prophylactic effect of recombinant factor VIIa in factor VII deficient patients

Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder associated with a bleeding tendency. We describe three patients with congenital FVII deficiency who have been treated with activated recombinant factor VII (rVIIa). Two patients had novel mutations and were treated prophylactically with 1·2 mg rVIIa two to three times a week. Patients 1 and 2 had a severe bleeding tendency. The frequency and severity of bleeding decreased by treatment with rVIIa compared with similar treatment with plasma‐derived FVII. The third patient with a moderate bleeding phenotype was treated on demand and showed no change in the frequency of bleeding upon treatment with rVIIa or plasma products. The beneficial effect of rVIIa cannot be explained by the rVIIa half‐lives. Pharmacokinetical analysis showed rVIIa activity half‐lives of 35, 50 and 54 min for patients 1, 2 and 3, respectively. In conclusion, prophylactic treatment of FVII deficient patients with rVIIa appears to be applicable, safe and successful, although the mechanism of action remains to be elucidated.

Factor VIII genotype and inhibitor development in patients with haemophilia A: highest risk in patients with splice site mutations

Summary.  The appearance of inhibitory antibodies against factor VIII (FVIII) is the most severe and costly complication of replacement therapy in patients with haemophilia A (HA). To determine the relationship between FVIII genotype and inhibitor development, baseline FVIII activity, genotype and inhibitor development were reviewed in 1104 patients with HA. In patients with severe HA, splicing errors present the highest frequency of inhibitors, ahead of inversion of intron 1 and of intron 22, nonsense mutations and large deletions. The lowest inhibitor frequency in severe HA is found in patients with missense mutations and small deletions/insertions. Subanalyses indicate that nonsense mutations and small deletions/insertions leading to a frameshift in the light chain are associated with a significant higher risk of inhibitor formation than similar mutations occurring in the heavy chain (27% vs. 14%). These mutation types also have a higher frequency of inhibitors when occurring in exons 23–26, where a second FVIII transcript originates, compared with similar mutations in exons 1–22 (28% vs. 17%). These results suggest that complete absence of FVIII because of null mutations, including splice site mutations, or the absence of a second transcript result in an increased risk of inhibitor development.

Diagnosis of factor VIII deficiency

Summary.  The correct diagnosis of factor VIII deficiency and the assessment of severity of the disease are essential for a patient‐tailored treatment strategy. An optimal diagnostic procedure comprises sensitive and specific screening methods and factor VIII activity assays. Different screening reagents show variable characteristics and receiver operator characteristic curves are presented showing the relation between sensitivity and specificity of eleven activated partial thromboplastin time reagents. The details of the three methods for factor VIII activity assay, one‐stage and two‐stage assay and chromogenic assays, are discussed. The chromogenic assay seems to be more sensitive than the one‐stage assay with regard to the detection of severe haemophilia. Discrepant results obtained with one‐stage and two‐stage assays are reviewed and discussed.

Potential Sites of Infection That Develop in Febrile Neutropenic Patients

Three hundred episodes of neutropenia were reviewed for the occurrence of potential sites of infection. Ninety sites (30 per cent) were identified at the onset of fever independent of initial bacteraemia which was encountered in 104 episodes (35%) and predominantly involved Gram-positive cocci. A further 90 sites were recorded involving mainly the lower respiratory tract (58%) and skin and soft tissue (18%). These changes evolved significantly later (mean of 5.1 and 4.3 days respectively) than did other foci which mainly presented at the onset of fever (p < 0.01). However the infectious aetiology was established in only 54 cases overall with fungi being responsible for 25 of 45 cases of lower respiratory tract infections with a known microbiological aetiology. The mortality associated with initial bacteraemia, focus at onset and unexplained fever was 11-14% while that associated with the development of a subsequent focus was 28% with lung infiltrates carrying the worst prognosis. Therefore rather than being seen as a final solution for possible infectious complications, empiric therapy provides an opportunity for daily review of the patient thereby increasing the likelihood of both explaining initial fever and diagnosing subsequent infection.

Amikacin plus piperacillin versus ceftazidime as initial therapy in granulocytopenic patients with presumed bacteremia.

69 febrile granulocytopenic episodes without an initial focus of infection were assessed for empiric treatment either with high-dose amikacin plus piperacillin or ceftazidime. 90% of patients in each group survived the granulocytopenic episode; 15 (44 +/- 17%) episodes treated with the combination and 23 (66 +/- 16%) given ceftazidime responded without any modification of initial therapy and half defervesced within 72 h. Persistent fever was the most frequent reason for altering treatment which was done empirically in 90% of cases, but two-thirds of patients required further treatment modification. An infectious focus mainly involving the lung developed during granulocytopenia in 21 patients (30%), of which 17 occurred during antimicrobial therapy. Only 1 infection was shown to be due to bacteria, while 7 were due to fungi. Amikacin levels were similar to those expected following a normal dose (mean peak of 34.7 and mean trough of 12.6 mg/l). Therapy with the combination resulted in a higher serum creatinine (p less than 0.001) and a lower potassium level (p less than 0.001) in comparison with monotherapy. Potassium supplementation was required in 45 +/- 17% of patients given the combination compared with only 4 +/- 7% of those treated with ceftazidime. While both regimens appeared to be equally effective as initial therapy, the need for modification was high in both patient groups. Monotherapy being both simpler to administer and less toxic seems therefore to be the logical choice although the period of empiric therapy must be fully exploited in order to improve diagnosis and therefore antimicrobial management.

Thirteen novel mutations in the factor VIII gene in the Nijmegen haemophilia A patient population.

The development of neutralising antibodies to factor VIII (FVIII) is a major complication of haemophilia A (HA) therapy. We aimed to construct an individual risk profile for the development of inhibitors in HA and started by screening for the causative mutation in our HA patient population. A total of 109 patients and 28 carriers were screened. The analysis revealed 38 different mutations in the FVIII gene, of which 13 have not been described on the Haemophilia A Mutation, Search, Test and Resource Site (HAMSTeRS). Twenty‐five mutations have been reported previously and all except two had a similar phenotype to what has been described. Three novel mutations were associated with severe HA: one non‐missense mutation, a small insertion in the A2 domain, and two missense mutations, a H256R mutation in the A1 domain and a L2025P substitution in the C1 domain. One novel mutation, Y156C, was associated with moderate HA. Nine novel mutations caused mild HA. The P130R, D167E and V278M mutations are located in the A1 domain. R439C, Y511H, A544G and Q645H in the A2 domain, L1758F in the A3 domain and a S2157R mutation in the C1 domain. In conclusion, the genotypic profile of our HA population was not different from others described and is suitable to study inhibitor formation.

Options and limitations of teicoplanin in febrile granulocytopenic patients.

Summary During the years 1985–89 three studies on the efficacy and safety of teicoplanin in the treatment of febrile granulocytopenic patients suffering from haematological malignancies were assessed. In the first prospective study, teicoplanin at a dose of 400 mg/d was added to the initial empiric therapy of 65 febrile granulocytopenic episodes. When teicoplanin was given because of proven or presumed Gram‐positive infection, 67% of cases were treated successfully. Patients with skin and soft‐tissue infections achieved a 78% response rate. The second study on 120 patients was designed as a prospective randomized trial to compare the efficacy and toxicity of ceftazidime with and without teicoplanin. Response was achieved in 25/51 (49%) cases from the ceftazidime and in 33/52 cases (63%) from the combination groups. Seven of 18 (39%) cases with initial bacteraemia in the monotherapy group compared with 10/20 (50%) cases in the combination group responded to the empiric regimen. A retrospective analysis was carried out on the efficacy of teicoplanin in 125 cases of proven Gram‐positive Hickman line‐associated bacteraemia. Teicoplanin proved to be effective in eradicating 80% of the Staphylococcus epidermidis. 72% of the Staph. aureus, 90% of the ‘viridans’ streptococci and 67% of the enterococci. Removal of the catheter was required in 13% of cases in order to control the infection, and only one patient died of a catheter‐related septicaemia caused by Staph. aureus. The total success rate leaving the catheter in situ was 78%, and 92% if cases with catheter removal were included. Serum levels of teicoplanin were predictable giving a peak and trough concentration on the fourth day of 30.4 ± 5.0 mg/l and 9.8 ± 1.7 mg/l. Hearing loss of 20 dB at 8000 Hz was noted in one case and transient liver or kidney disturbances attributable to the drug were observed in 4% of cases.