Sharon Safrin

The Clinical Course of Patients with Idiopathic Pulmonary Fibrosis

Context The natural history of idiopathic pulmonary fibrosis (IPF) is unclear. Contribution A total of 168 participants with mild to moderate IPF assigned to placebo in a randomized trial were followed at 12-week intervals for about 76 weeks. For 32 of 36 patients who died, IPF was a related or main cause of death. Although physiologic variables such as FVC changed little, acute clinical deterioration preceded death in half of the patients who died of IPF. Implications Clinicians may need to rethink referral timing for lung transplantation because many patients with IPF may experience precipitous clinical declines rather than gradual progression of disease. The Editors Idiopathic pulmonary fibrosis (IPF), the most frequent of the idiopathic interstitial pneumonias, is associated with the worst prognosis (1, 2). However, data on the natural history of IPF are sparse. To clearly describe the pace of progression and the cause of death in a well-characterized cohort with mild to moderate IPF, we analyzed data from the placebo group of a randomized, double-blind, controlled clinical trial evaluating therapy with interferon-1b in patients with IPF (3). These data provide important insight into the natural history of IPF and events preceding death in patients with IPF. The data suggest that a gradual, progressive decline does not occur in many patients, thereby supporting the need for early referral for lung transplantation. Methods Overview Using data from a recently completed clinical trial (3), we performed a series of exploratory analyses of physiologic variables, dyspnea measures, hospitalizations, and characteristics of mortality in patients randomly assigned to receive placebo. The prespecified primary end point analysis for the phase III study was to occur after the 306th randomly assigned patient was scheduled to complete 48 weeks of therapy. Patients were enrolled over an approximately 1-year period. Thus, follow-up times for the patients varied, and the numbers of patients available for visits beyond 48 weeks diminished over time. In the published report of the primary analysis of the trial, the median length of observation was 58 weeks (3). In the current report, we summarize data from randomization through the completion of blinded study therapy (the observation period); the median for this period was 76 weeks. Study Participants Study participants were all patients randomly assigned to the placebo group (n= 168) in the trial (3). Criteria for enrollment included a diagnosis of IPF according to American Thoracic Society criteria (4), an FVC of 50% to 90%, diffusing capacity of carbon monoxide (DLco) of 25% or greater, definite or probable IPF on high-resolution computed tomography according to prespecified criteria, and worsening of disease during the preceding year despite a total corticosteroid dose of 1800 mg or greater within the preceding 2 years (3). Patients were permitted to continue taking prednisone (15 mg/d) if the dosage remained stable. Data Collection Data were collected at 12-week intervals and recorded on standardized case report forms by trained research associates at each institution. Information derived from interview and examination of the patient included demographic and clinical data, physiologic assessments, measures of dyspnea, vital status, number of all-cause hospitalizations, and number of hospitalizations for which the primary reason was specified as respiratory. Physiologic measures included FVC, plethysmography, Dlco, and arterial blood gas at room-air ambient temperatures. The transition dyspnea score is derived from an instrument in which the patient assesses the extent of dyspnea in reference to his or her baseline at study entry (5). The transitions or changes in the patients dyspnea in 3 categories (function impairment, magnitude of task needed to evoke dyspnea, and magnitude of effort needed to evoke dyspnea) are rated in 7 grades from 3 (major deterioration) to 0 (unchanged) to 3 (major improvement); the final score ranged from 9 to 9. The lower the total score, the more severe the dyspnea. The validated University of California, San Diego, Shortness of Breath Questionnaire (6) has 24 items: Patients are asked to rate severity of shortness of breath using a 6-point scale (0 = not at all; 5 = maximal severity) during 21 different activities of daily living associated with varying levels of exertion; they are also asked to rate how their daily lives are limited by shortness of breath, fear of harm from overexertion, and fear of shortness of breath. Scores range from 0 to 120, with increasing score indicating worsening quality of life. The physician responsible for any patient who died during the study period completed a retrospective supplemental questionnaire. The investigator-physician, who had full access to all measurements obtained as a part of the study, specified the primary cause of death, whether the cause was respiratory, and whether death was related to IPF. Investigator-physicians were to cite IPF as the primary cause of death only in the absence of a known alternative cause and only if the event was witnessed. For deaths considered to be IPF-related, 1 of 4 categories was assigned on the basis of the interval from the onset of new or worsening symptoms or signs until death: abrupt (occurring within minutes to hours), acute (4 weeks), subacute (progressing over weeks or months), or unknown. In the current report, we combine the abrupt- and acute-onset events within a single category. Statistical Analysis Physiologic variables and measures of dyspnea were compared between baseline and week 72. The frequency of hospitalizations (all-cause and respiratory-related), number of hospital days in patients hospitalized, and mortality were assessed over the entire observation period. Mean values are followed by SDs. The relationships between baseline percentage predicted FVC and the incidence and length of hospitalization were examined by using the Fisher exact test or independent-sample t-test, as appropriate. Missing values were not imputed. The reasons for missing values are as follows: 1) To optimize data integrity, data obtained at visits outside a window of 7 days were not included in the analysis, 2) because trial enrollment was staggered, fewer patients were available for analysis at the latter time points, and 3) the value for a particular variable for a particular patient may be missing, even though all other values for that time point and patient are available. On the basis of the nature of the variations leading to the differences in available data over time, no apparent evidence indicated that the variations are not random. Data analyses were conducted by using SAS software, version 8.02 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source InterMune, Inc., funded this study. Authors from InterMune (Drs. Safrin, Starko, and Bradford) participated in the design and analysis of the study, as did the other authors. All authors had full access to the data. The funding source had no role in the decision to publish the results. Results Patients We analyzed 168 patients (mean age, 64 years, SD 9). Most patients were male (66%), white (86%), and nonsmokers (that is, never-smokers or ex-smokers) (91%). Mean time since the diagnosis of IPF was 378 days, SD, 295. The diagnosis of IPF was confirmed by surgical lung biopsy in 58% of patients; in 83%, findings on high-resolution computed tomography met prespecified criteria for definite IPF. At study entry, 31% of patients used supplemental oxygen and 82% were receiving systemic corticosteroids. During the observation period, 2 patients (1.2%) used azathioprine and 1 patient (0.6%) used cyclophosphamide. Physiologic Variables and Measures of Dyspnea For patients who survived to week 72, the mean percentage predicted FVC decreased from 64.5%, SD 11.1%, to 61.0%, SD 14.1%; the mean percentage predicted DLco decreased from 37.8%, SD 11.1%, to 37.0%, SD 19.9%; and the mean alveolararterial gradient increased from 23.2 mm Hg, SD 10.9, to 26.9 mm Hg, SD 13.0. The mean transition dyspnea index score was 1.29, SD 3.6, at week 72, indicating worsening dyspnea, whereas the mean University of California, San Diego, Shortness of Breath Questionnaire score changed minimally (from 45.1, SD 23.4, to 46.8, SD 25.1) (Figure 1). For patients who died during the trial, we observed a general trend toward increases in alveolararterial gradient and dyspnea and toward decreases in FVC and DLco (Figure 2). The spaghetti plots (Figure 2) highlight the finding that although dyspnea or alveolararterial gradient often increased sharply before a patients death, significant intrapatient variability occurs over time. Figure 1. Measures of physiology and dyspnea from study entry through week 72 for patients who survived throughout trial. Figure 2. Measures of physiology and dyspnea for each of the 36 patients who died during the trial; each line represents a single patient. Hospitalizations Fifty-seven (34%) patients had a total of 95 all-cause hospitalizations during the observation period. Among those hospitalized, the mean total number of hospital days was 14.3, SD 13.5. Thirty-eight (23%) patients had 57 hospitalizations for a respiratory disorder, with a mean total number of hospital days of 15.0, SD 14.6. The most commonly reported reason for respiratory hospitalization (33%) was presumed infection. When stratified by the baseline median percentage predicted FVC, patients with more severely impaired lung function (62%) were more likely to be hospitalized for any reason than patients with baseline percentage predicted FVC greater than 62%35 (42%) versus 22 (26%) patients (P= 0.05) and 58 versus 37 hospitalizations overall. Respiratory hospitalizations were similarly more frequent in the subset of patients with baseline FVC of 62% or less: 25 (30%) versus 13 (15%) patients (P= 0.04). In hospitalized patients, the total number

A Controlled Trial Comparing Foscarnet with Vidarabine for Acyclovir-Resistant Mucocutaneous Herpes Simplex in the Acquired Immunodeficiency Syndrome

BACKGROUND AND METHODS Most strains of herpes simplex virus that are resistant to acyclovir are susceptible in vitro to both foscarnet and vidarabine. We conducted a randomized trial to compare foscarnet with vidarabine in 14 patients with the acquired immunodeficiency syndrome (AIDS) and mucocutaneous herpetic lesions that had been unresponsive to intravenous therapy with acyclovir for a minimum of 10 days. The patients were randomly assigned to receive either foscarnet (40 mg per kilogram of body weight intravenously every 8 hours) or vidarabine (15 mg per kilogram per day intravenously) for 10 to 42 days. In the isolates of herpes simplex virus we documented in vitro resistance to acyclovir and susceptibility to foscarnet and vidarabine. RESULTS The lesions in all eight patients assigned to foscarnet healed completely after 10 to 24 days of therapy. In contrast, vidarabine was discontinued because of failure in all six patients assigned to receive it. The time to complete healing (P = 0.01), time to 50 percent reductions in the size of the lesions (P = 0.01) and the pain score (P = 0.004), and time to the end of viral shedding (P = 0.006) were all significantly shorter in the patients assigned to foscarnet. Three patients had new neurologic abnormalities while receiving vidarabine. No patient discontinued foscarnet because of toxicity. Although initial recurrences of herpes simplex infection after the index lesion had healed tended to be susceptible to acyclovir, acyclovir-resistant infection eventually recurred in every healed patient, a median of 42.5 days (range, 14 to 191) after foscarnet was discontinued. CONCLUSIONS For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.

A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients.

We report a randomized, double-blind, multicenter trial in which amphotericin B colloidal dispersion (ABCD [Amphotec]; 6 mg/kg/day) was compared with amphotericin B (AmB; 1.0-1.5 mg/kg/day) for the treatment of invasive aspergillosis in 174 patients. For evaluable patients in the ABCD and AmB treatment groups, respective rates of therapeutic response (52% vs. 51%; P=1.0), mortality (36% vs. 45%; P=.4), and death due to fungal infection (32% vs. 26%; P=.7) were similar. Renal toxicity was lower (25% vs. 49%; P=.002) and the median time to onset of nephrotoxicity was longer (301 vs. 22 days; P<.001) in patients treated with ABCD. Rates of drug-related toxicity in patients receiving ABCD and AmB, respectively, were 53% versus 30% (chills), 27% versus 16% (fever), 1% versus 4% (hypoxia) and 22% versus 24% (toxicity requiring study drug discontinuation). ABCD appears to have equivalent efficacy and superior renal safety, compared with AmB, in the treatment of invasive aspergillosis. However, infusion-related chills and fever occurred more frequently in patients receiving ABCD than in those receiving AmB.

Comparison of Atovaquone (566C80) with Trimethoprim-Sulfamethoxazole to Treat Pneumocystis carinii Pneumonia in Patients with AIDS

BACKGROUND Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

Foscarnet Therapy in Five Patients with AIDS and Acyclovir-resistant Varicella-Zoster Virus Infection

OBJECTIVE To determine whether foscarnet has potential efficacy in the treatment of acyclovir-resistant mucocutaneous varicella-zoster infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN Open-label study. SETTING Three university medical centers. PATIENTS Five patients with AIDS who were infected with thymidine-kinase-deficient or -altered strains of varicella-zoster virus. INTERVENTION Foscarnet, 40 mg/kg body weight every 8 hours in 1-hour infusions for 10 or more days. MAIN RESULTS Four patients had healing in response to foscarnet therapy, and each of four tested patients became culture negative for virus during foscarnet therapy. Results of fluorescent antigen testing remained positive during therapy in two patients; one of these patients had concomitant clinical failure but the other patient healed fully. One patient had complete healing despite the emergence of resistance to foscarnet in serial specimens obtained during foscarnet therapy. CONCLUSION Foscarnet is a potentially effective and tolerable antiviral agent for patients with acyclovir-resistant, varicella-zoster virus infection; however, the optimal dosage and duration of therapy require further study, as does the relation between clinical findings and in-vitro susceptibility results.

A Randomized, Double-Blind, Placebo-Controlled Trial of Cidofovir Gel for the Treatment of Acyclovir-Unresponsive Mucocutaneous Herpes Simplex Virus Infection in Patients with AIDS

The safety and efficacy of cidofovir gel for treatment of acyclovir-unresponsive herpes simplex virus infections in AIDS patients was evaluated in a randomized, double-blind, multicenter trial. Cidofovir (0.3% or 1%) or placebo gel was applied once daily for 5 days. Ten of 20 cidofovir-treated and none of 10 placebo-treated patients had complete healing or >50% decreased area (P = .008); 30% of cidofovir-treated patients versus 0 placebo recipients had complete healing (P = .031). Viral shedding ceased in 13 (87%) of 15 cidofovir-treated and 0 of 9 placebo-treated patients (P = .00004). For cidofovir-treated patients, median time to complete or good response was 21 days, and median time to negative viral culture was 2 days (P = .025, P = .0001, respectively). Median lesion area decreases were 58% for cidofovir-treated versus 0 for placebo-treated patients (P = .005), and mean pain score changes were -1.84 versus -0.34 (P = .042). Application site reactions occurred in 25% of cidofovir-treated and 20% of placebo-treated patients; none was dose-limiting. Cidofovir therapy provided significant benefits in lesion healing, virologic effect, and pain reduction.

Clinical uses of cidofovir

Cidofovir is a cytidine nucleotide analogue recently licensed as an intravenous treatment for CMV retinitis in AIDS patients. Three controlled clinical trials have demonstrated efficacy of cidofovir for this indication, and have generated data useful as a guideline to prevent potential toxicity. Although de novo emergence of resistance to cidofovir has not been observed clinically in patients receiving cidofovir, cross‐resistance to cidofovir in ganciclovir‐resistant clinical DNA polymerase mutants has been identified. Cross‐resistance of cidofovir and foscarnet has not been identified to date. A broad spectrum agent with in vitro activity against human herpesviruses, adenovirus, HPV, polyomaviruses and human poxviruses, cidofovir is under clinical investigation for a variety of potential applications. Examples include intravenous administration of cidofovir for treatment of progressive multifocal leukoencephalopathy and Kaposis sarcoma, intraocular injection for treatment of CMV retinitis, intralesional injection for treatment of respiratory papillomatosis, topical application for treatment of molluscum contagiosum, anogenital condyloma acuminata, and recurrent genital herpes, and ophthalmic instillation for treatment of viral keratoconjunctivitis.

Comparison of Three Regimens for Treatment of Mild to Moderate Pneumocystis carinii Pneumonia in Patients with AIDS A Double-Blind, Randomized Trial of Oral Trimethoprim-Sulfamethoxazole, Dapsone-Trimethoprim, and Clindamycin-Primaquine

*For additional members of the ACTG 108 study group, see the Appendix. In 1994, 15 440 cases of Pneumocystis carinii pneumonia occurring in the United States were reported to the Centers for Disease Control and Prevention [1]. Thus, despite the advent of prophylactic agents to prevent this infection, the need for effective and nontoxic therapeutic regimens remains. Increased physician and patient awareness, along with improved methods of diagnosis, have made earlier institution of ambulatory therapy with oral medications a feasible alternative to hospitalization for inpatient treatment in many instances. Previous studies [2-8] suggest that the efficacy of trimethoprim-sulfamethoxazole, available since 1968, is equivalent or superior to that of all alternative therapies for P. carinii pneumonia. However, rates of treatment-limiting toxicity ranging from 20% to 57% in patients with the acquired immunodeficiency syndrome (AIDS) who receive this regimen [2, 3, 5, 7, 8] have necessitated a continued search for better-tolerated regimens. In one study [9], the combination of dapsone and trimethoprim was successfully used to treat 15 patients with a first episode of P. carinii pneumonia. In a subsequent randomized trial [5], this combination was compared with trimethoprim-sulfamethoxazole in 60 patients with arterial oxygen pressures of 60 mm Hg or greater. In this latter study, the efficacy of dapsone-trimethoprim was similar to that of trimethoprim-sulfamethoxazole (93% compared with 90%), but dapsone-trimethoprim was associated with a lower frequency of major toxicities (30% compared with 57%). The combination of clindamycin with primaquine has shown excellent activity against P. carinii in in vitro studies and in an experimental rat model [10]. Successful use of this regimen in the treatment of P. carinii pneumonia, generally with intravenous administration of clindamycin for all or part of therapy, has been described since 1989 [11-15]. In one study of 60 patients with an alveolar-arterial oxygen difference (PAO2-PaO2) of 40 mm Hg or less [15], the administration of intravenous or oral clindamycin and oral primaquine was associated with therapeutic success in 92% of patients and with doselimiting toxicity in 15% of patients. A randomized trial [16] compared intravenous clindamycin and oral primaquine with intravenous or oral trimethoprim-sulfamethoxazole in 49 patients with a first episode of P. carinii pneumonia and an arterial oxygen pressure of 50 mm Hg or greater; 90% of patients in each group were classified as having successful therapy, and dose-limiting toxicity occurred in 18% and 20% of patients, respectively. Thus, although dapsone-trimethoprim and clindamycin-primaquine have gained widespread use in the treatment of P. carinii pneumonia, their relative efficacies have not yet been validated in a large controlled trial, and their toxicity profiles have not been directly compared. To guide the clinician in selecting the optimal oral therapy for patients with AIDS and mild to moderate P. carinii pneumonia, we compared the toxicities and efficacies of trimethoprim-sulfamethoxazole, dapsone-trimethoprim, and clindamycin-primaquine in a randomized, doubleblind multicenter trial. Methods Beginning in May 1991, patients were enrolled at 24 centers participating in the AIDS Clinical Trials Group (ACTG) of the National Institutes of Allergy and Infectious Diseases (NIAID). Each sites institutional review board approved the study (ACTG trial 108), and all participants gave informed consent before the study drug was administered. Patients Eligible patients had human immunodeficiency virus (HIV) infection, were older than 13 years of age, weighed 35 to 100 kg, and had symptoms or signs of P. carinii pneumonia, such as cough, shortness of breath, or an abnormal chest radiograph. Enrollment was limited to patients whose room air PAO2-PaO2 was 45 mm Hg or greater. Morphologic confirmation of the diagnosis by visualization of P. carinii in induced sputum, bronchoscopic lavage, or transbronchial biopsy specimens was required within 10 days of study entry. Treatment of P. carinii pneumonia lasting no more than 24 hours was permitted before randomization. Exclusion criteria were concurrent pulmonary pathologic conditions that could obscure the evaluation of response to therapy; the third trimester of pregnancy; receipt of systemic corticosteroids within 7 days of study entry; deficiency of glucose-6-phosphate-dehydrogenase (G6PD) or nicotinamide adenine dinucleotide methemoglobin reductase; hemoglobin M abnormality; previous enrollment in the study; inability to receive oral therapy; and serum creatinine level greater than 152.5 mol/L, hemoglobin level less than 80 g/L, absolute neutrophil count less than 0.75 109/L, platelet count less than 50 109/L, or alanine aminotransferase levels greater than 7.5 times the upper limit of normal. Randomization and Dosing Patients were assigned to treatment on the basis of a permuted block randomization. Randomization was stratified by treatment center and by the use of antipneumocystis prophylaxis within 30 days and was accomplished by computerized linkage to a central data management center. Active study drug and placebo assignments were implemented by each sites pharmacist, who labeled the bottles in a blinded manner. The Burroughs Wellcome Company (Research Triangle Park, North Carolina), the Jacobus Pharmaceutical Company (Princeton, New Jersey), the Upjohn Company (Kalamazoo, Michigan), and Sterling-Winthrop Pharmaceuticals (New York, New York) provided the study drug. The dosages of the study drugs were as follows: dapsone, 100 mg daily; clindamycin, 600 mg three times daily; and primaquine base, 30 mg daily. The dosages of trimethoprim and sulfamethoxazole were based on patient weight: Patients weighing 51 to 80 kg received two double-strength trimethoprim-sulfamethoxazole tablets (320:1600 mg) three times daily or trimethoprim (300 mg) three times daily with dapsone once daily. Patients weighing 36 to 50 kg received 240:1200 mg of trimethoprim-sulfamethoxazole (1.5 double-strength tablets) three times daily or 200 mg of trimethoprim three times daily with dapsone once daily. Patients weighing 81 to 99 kg received 400:2000 mg of trimethoprim-sulfamethoxazole (2.5 double-strength tablets) three times daily or 400 mg of trimethoprim three times daily with dapsone once daily. To maintain a doubleblind status, all patients received one active regimen and one placebo regimen. Patients with a PAO2-PaO2 of 35 to 45 mm Hg received adjunctive prednisone, 40 mg twice daily for 5 days, then 40 mg daily for 5 days, then 20 mg daily until antipneumocystis therapy was discontinued [17]. Patients with a history of intolerance to trimethoprim-sulfamethoxazole were enrolled beginning in September 1992 and were randomly assigned to one of the other treatment arms. Therapy was administered for 21 1 days. For patients with dose-limiting toxicity, the protocol specified either double-blind crossover to an alternative regimen (according to a second randomized list) or the substitution of intravenous pentamidine (3 to 4 mg/kg of body weight daily). Antipneumocystis therapy could be terminated if the patient had received therapy for at least 14 days and if clinical signs and symptoms had remitted. Patients meeting criteria for therapeutic failure (see below) were to receive intravenous pentamidine to complete therapy. We did not permit concurrent therapy with zidovudine, ganciclovir, colony-stimulating factors, rifampin, rifabutin, folinic acid, investigational agents other than triazole antifungal agents, and other medications potentially effective against P. carinii (such as pyrimethamine and sulfadiazine). Clinical and Laboratory Assessments At baseline, physical examination, venipuncture (for complete blood count with differential; reticulocyte count; and determination of creatinine, aminotransferase, and lactic acid dehydrogenase levels), measurement of room air arterial blood gas, and chest radiography were done. Physical examination and venipuncture were repeated on days 0, 3, 7, 10, 14, and 21 of therapy; arterial blood gas determination was repeated on days 7 and 21; and chest radiography was repeated on day 7. Serum methemoglobin levels were measured on days 3, 7, and 10 of therapy. Physical examination, venipuncture, and chest radiograph were repeated 2 weeks after therapy was completed. Survival status and recurrence of P. carinii pneumonia were determined 60 days after completion of therapy. Secondary antipneumocystis prophylaxis was advised for all patients who completed the study, and each patients primary physician chose the medication. We used a battery of instruments to assess the effect of treatment on patient-reported health status. Physical function was measured using the Duke Activity Status Index [18], a 12-item index weighted on the basis of known metabolic costs of each activity. Energy, pain, and general health perceptions were measured using scales from the Medical Outcomes Study [19], supplemented by four additional general health items [20]. Disability was measured by the number of days spent in bed or the decrease in the number of usual activities the patient could perform [21]. Severity of pulmonary (cough, dyspnea, and chest tightness) and other symptoms (fever, pain, nausea, rash, and dizziness) was assessed using a questionnaire that required approximately 5 minutes to complete and was available in English and Spanish [22]. Definitions of End Points Therapeutic failure at day 7 was defined by one of the following: 1) increase in PAO2-PaO2 of greater than 20 mm Hg over baseline without remission of baseline signs and symptoms; 2) change in antipneumocystis therapy for reasons other than toxicity; 3) intubation; and 4) death. Therapeutic failure at day 21 was defined by any of the above variables or by therapeutic failure at day 7. We used neither persistence of fe

Management of acyclovir-resistant herpes simplex and varicella-zoster virus infections.

Persons with AIDS who have CD4+ counts < or = 100 and transplant patients, especially bone marrow allograft recipients, may experience clinically significant infections with acyclovir-resistant herpes simplex virus (HSV) or varicella-zoster virus (VZV). Patients who have received prior repeated acyclovir treatment appear to be at the highest risk of harboring acyclovir-resistant strains. Algorithms for the management of these infections were developed at a recent roundtable symposium. The consensus of the panelists was that treatment with foscarnet should be initiated within 7-10 days in patients suspected to have acyclovir-resistant HSV or VZV infections. Foscarnet therapy should be continued for at least 10 days or until lesions are completely healed.

Pyelonephritis in adult women: inpatient versus outpatient therapy

PURPOSE The traditional treatment of acute pyelonephritis has been hospitalization and parenteral administration of antibiotics. No previous study, however, has attempted to differentiate between those patients with pyelonephritis who might be safely managed as outpatients and those in whom hospitalization is required. We therefore decided to determine whether women with pyelonephritis can be effectively and safely managed outside the hospital. PATIENTS AND METHODS The medical records of 94 female outpatients and 100 hospitalized women treated for acute pyelonephritis at San Francisco General Hospital were reviewed. Utilizing baseline clinical and laboratory data, we compared outcome in the two groups, and computed the cost-benefit of managing pyelonephritis on an outpatient basis. RESULTS We observed a similarity in the frequency of successful outcomes (approximately 90 percent in each group) and absence of serious adverse outcome in any outpatient. Results of urine culture were comparable in inpatients and outpatients, with Escherichia coli identified as the most common urinary pathogen in both groups. The frequency of resistance to ampicillin of E. coli and other urinary pathogens was nearly 30 percent. A cost analysis demonstrated a 7.5-fold difference between the inpatient and outpatient groups. CONCLUSION Our findings suggest that treatment of pyelonephritis with oral antibiotics poses a safe and effective method of therapy in immunocompetent women without underlying illness. The use of ampicillin as a single agent for the treatment of pyelonephritis, however, is inadvisable. Our study also demonstrates the potential savings in managing selected patients with pyelonephritis as outpatients.