The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lymphocyte function in AIDS patients.

Foscarnet was administered by continuous intravenous infusion in 15 patients with the acquired immunodeficiency syndrome (AIDS) in an open, uncontrolled study. Mean steady state serum concentrations of foscarnet was 261 mumol/l. Treatment was given for 6-21 days, median 14 days, being interrupted prematurely due to renal function impairment in seven patients, and due to other reasons in three patients. Foscarnet therapy was accompanied by improvement of some, probably cytomegalovirus (CMV) related, symptoms but did not otherwise affect the clinical condition of the patients. The occurrence of positive CMV cultures decreased significantly during therapy. Human immunodeficiency virus (HIV) detection by culture was positive in 70-80% of cultures and was unaffected by foscarnet treatment. Eight patients had detectable, free HIV antigen in serum before therapy, and in five of these HIV antigen disappeared during therapy, but reappeared 4-23 weeks after therapy. No patient lost HIV antigen, except during foscarnet therapy. No patient became HIV antigen positive during foscarnet therapy. Immunological parameters did not change during or after foscarnet therapy. Renal function impairment was seen in 9 patients (95% confidence limits, 32-84%), apparently due to reversible tubular damage. At follow-up, serum creatine was normal in all surviving patients. Concomitant medication may have contributed to the renal side-effects. Severe renal function impairment, i.e. serum creatinine above 0.25 mumol/l, was only seen in patients who at the start of foscarnet therapy were chronically affected by their disease. Thus, foscarnet reduces HIV antigen production in AIDS patients. Renal function impairment limits foscarnet use in AIDS patients, but in individuals with less severe manifestations of HIV infection, this side effect may be less frequent.

Sensitivity of cytomegalovirus to intravenous foscarnet treatment.

Intravenous foscarnet was given on an emergency basis to 30 immunosuppressed patients with cytomegalovirus (CMV) disease, of whom 28 were organ transplant recipients. Thirteen patients responded to foscarnet by cessation of CMV secretion. The in vitro sensitivity to foscarnet of the CMV isolates from non-responders before, during and after foscarnet treatment was similar to that of viral isolates from responders before or during foscarnet treatment and also to CMV isolates from non-treated patients, with mean in vitro IC50 values of 239-294 microM of foscarnet. Thus, there was no evidence of increased resistance of the CMV isolates obtained after foscarnet treatment. A higher total foscarnet dose appeared to favor response.

Antibiotic resistance in staphylococci from a hospital environment.

The antibiotic resistance of Staphylococcus aureus and coagulase-negative staphylococci has been followed over 4 years (1977-1980). 90% of the strains produced beta-lactamase. Coagulase-negative staphylococci were more resistant than S. aureus, although beta-lactamase production occurred more rarely. Strains from the sputum of children with cystic fibrosis (CF) were more multiresistant than isolates from other sources. The strains from hospitalized patients (HP) were more resistant than isolates from out-patients. A higher frequency of beta-lactamase production occurred among strains from CF and HP patients compared to out-patients. This occurred in samples from pus and wounds in 66% of the strains derived from non-hospitalized patients compared with 93% from surgical patients.

Topical treatment of recurrent genital herpes infections with foscarnet.

In a double-blind study 86 patients with a total of 129 episodes of recurrent genital herpes were treated topically with 0.3% foscarnet or placebo cream. All patients considered, healing time was significantly shortened in the foscarnet group as compared to the placebo group (p less than 0.01). Subgrouped by sex, the healing time among men treated with foscarnet was significantly shortened as compared to those treated with placebo (p less than 0.002), whereas no statistical significant difference was observed among women. Foscarnet treated men with subpreputial lesions had a shorter period of ulcers (1.7 days) than placebo (3.4 days) treated men (p less than 0.02). Overall, foscarnet treatment reduced the period of redness, swelling, blisters and ulcers. Foscarnet was well tolerated, only in 1/57 patients treated was a moderate local adverse reaction recorded.

Treatment of chronic replicative hepatitis B virus infection with short-term continuous infusion of foscarnet.

Three patients with chronic replicative hepatitis B virus infection were treated for 7 days with a continuous intravenous infusion of foscarnet (trisodium phosphonoformate) after an initial bolus dose of 20 mg/kg body weight. Although the dose was calculated from a nomogram, approximately only half the intended plasma concentration (500 microM/l = 150 micrograms/l) was achieved. The levels of s-ALAT, HBV-DNA and DNA-polymerase changed only marginally during the treatment and 24-week follow-up period. All three patients remained HBsAg and HBeAg positive during treatment and follow-up. There were no severe side-effects. We conclude that foscarnet treatment with the dose regimen given in this study had no or only a minor antiviral effect in patients with chronic replicative HBV infection. It remains to be explored if higher doses, longer treatment periods or the use of foscarnet in combination regimen are more effective.

Treatment of AIDS-associated gastrointestinal cytomegalovirus infection with foscarnet and ganciclovir: a randomized comparison.

Patients with symptomatic gastrointestinal disease due to cytomegalovirus (CMV) were randomized to receive open-label ganciclovir (22) or foscarnet (26). Patients were stratified by disease site and concurrent gut infection. Response was assessed by a visual analogue score of symptoms, endoscopic appearances, histologic inflammation, and numbers of CMV inclusions. In each treatment group, 73% had a complete or good clinical response; 83% of foscarnet-treated and 85% of ganciclovir-treated patients showed response by endoscopy, and inclusion bodies disappeared from follow-up biopsies in 73% of these. Most patients (35) developed further evidence of CMV disease during follow-up. The time to progression was not significantly different between recipients (16 weeks) and nonrecipients (13 weeks) of maintenance therapy, although patients were not randomized to receive maintenance or not. Survival in both treatment groups was < 40 weeks and was unaffected by maintenance treatment. Both ganciclovir and foscarnet are effective first-line treatments for gastrointestinal (GI) CMV infection. Maintenance therapy does not prevent progression of disease.

Pharmacokinetics, safety and preliminary clinical experiences using foscarnet in the treatment of cytomegalovirus infections in bone marrow and renal transplant recipients.

Fifty seven episodes of severe cytomegalovirus (CMV) infection were treated with iv foscarnet in 13 bone marrow and 33 renal graft recipients. The ranges of the daily dose, duration, average steady state level and total dose were 23-268 mg/kg, 2-46 days, 42-400 mg/l and 2-399 g, respectively. Adverse effects, such as decreased haemoglobin, decreased renal function and increased serum calcium, were observed in a few patients only. Increased liver enzymes, hallucinations and tremor were seen in one uraemic patient and coincided with foscarnet plasma concentrations above 400 mg/l. Among 25 patients evaluated for clinical efficacy, 12 died. Improvements, such as eradication of CMV (8/14 assessable patients), resolution of fever (11/22), and improved laboratory values (13/23) were noted in 17/24 (70%). Controlled trials are warranted on the basis of this study.

Serum thymidine kinase in transplant patients: its relation to cytomegalovirus activity, renal transplant rejection and its use for monitoring of antiviral therapy.

Twenty patients, cadaveric renal transplant recipients, were retrospectively analysed for serum levels of deoxythymidine kinase. Special reference was made to the thymidine kinase level in relation to rejection, and viral infection. Seven of the patients experienced clinically suspected cytomegalovirus infection. All these patients had elevated levels of serum thymidine kinase during the period of clinical disease. Usually the thymidine kinase level parallelled the severity of the disease. All patients with irreversible rejection had increased levels of serum thymidine kinase, but normally not as high, as seen in patients with severe cytomegalovirus infection. There was also some correlation between clinically suspected rejection, that lead to rejection treatment, and moderate increase in thymidine kinase. However, not all rejection episodes were accompanied by a thymidine kinase increase. Serum thymidine kinase was analysed and compared in patients with self-healing cytomegalovirus disease, and those treated with phosphonoformate. A rapid decline in thymidine kinase level was found in connection with successful antiviral therapy, when compared to the decline in untreated patients. Some bone marrow transplanted patients were also included in this analysis.

Foscarnet in the treatment of cytomegalovirus retinitis in acquired immune deficiency syndrome.

Cytomegalovirus (CMV) retinitis is the major cause of visual loss in acquired immune deficiency syndrome (AIDS). Thirty-one patients with active CMV retinitis were treated with the new antiviral drug, Foscarnet (trisodium phosphonoformate). After a 3-week course of induction therapy, the retinitis improved in 29 of 31 patients (93.5%). Complete resolution of the retinitis was seen in 19 cases (61.3%). Ten patients had partial resolution (32.2%) and two (6.5%) failed to respond. After induction therapy, six patients were put on a low-dose maintenance regimen. All patients without maintenance therapy relapsed within 3 weeks after discontinuation of Foscarnet. The rate of relapse on maintenance therapy was 50% (3/6) within the first 5 weeks. The three other patients of Foscarnet maintenance did not relapse after a follow-up period of 12 weeks. In contrast to ganciclovir, Foscarnet did not induce neutropenia but it produced kidney toxicity that led to reversible renal insufficiency in three cases. Thus, Foscarnet appears to be a useful alternative to ganciclovir, particularly when combined with bone marrow toxic drugs, such as zidovudine (azidothymidine).

Intravenous foscarnet for the treatment of severe cytomegalovirus infection in allograft recipients.

Foscarnet, trisodium phosphonoformate, was administered intravenously to 6 immunosuppressed patients with life-threatening cytomegalovirus infection. Three of the patients were recipients of a kidney and 3 of a bone-marrow transplant. Favourable clinical responses were seen in 5 of the patients, 2 of whom were still in good health 5 and 8 months after the infection had cleared up. No toxic effect of the drug was detected. The results seem to justify further trials, in which foscarnet should be introduced at an earlier stage of the disease.