Stephen E. Follansbee

Pulmonary Aspergillosis in the Acquired Immunodeficiency Syndrome

BACKGROUND AND METHODSnSymptomatic pulmonary aspergillosis has rarely been reported in patients with the acquired immunodeficiency syndrome (AIDS). We describe the predisposing factors, the clinical and radiologic features, and the therapeutic outcomes in 13 patients with pulmonary aspergillosis, all of whom had human immunodeficiency virus (HIV) infection and 12 of whom had AIDS.nnnRESULTSnPulmonary aspergillosis was detected a median of 25 months after the diagnosis of AIDS, usually following corticosteroid use, neutropenia, pneumonia due to other pathogens, marijuana smoking, or the use of broad-spectrum antibiotics. Two major patterns of disease were observed: invasive aspergillosis (in 10 patients) and obstructing bronchial aspergillosis (in 3). Cough and fever, the most common symptoms, tended to be insidious in onset in patients with invasive disease (median duration, 1.3 months before diagnosis). Breathlessness, cough, and chest pain predominated in the three patients with obstructing bronchial aspergillosis, who coughed up fungal casts. Radiologic patterns included upper-lobe cavitary disease (sometimes mistaken for tuberculosis), nodules, pleural-based lesions, and diffuse infiltrates, usually of the lower lobe. Transbronchial biopsies were usually negative, but positive cultures were obtained from bronchoalveolar-lavage fluid or percutaneous aspirates. Dissemination to other organs occurred in at least two patients, and direct invasion of extrapulmonary sites was seen in two others. The results of treatment with amphotericin B, itraconazole, or both were variable. Ten of the patients died a median of 3 months after the diagnosis (range, 0 to 12 months).nnnCONCLUSIONSnPulmonary aspergillosis is a possible late complication of AIDS; if diagnosed early, it may be treated successfully.

Acyclovir-Resistant Herpes Simplex Virus Infections in Patients with the Acquired Immunodeficiency Syndrome

RECURRENT herpes simplex virus (HSV) infections are frequent in patients with the acquired immunodeficiency syndrome (AIDS). Although they are usually self-limiting in the normal host, such infecti...

A Controlled Trial of Fluconazole or Amphotericin B to Prevent Relapse of Cryptococcal Meningitis in Patients with the Acquired Immunodeficiency Syndrome

BACKGROUNDnAfter primary treatment for cryptococcal meningitis, patients with the acquired immunodeficiency syndrome (AIDS) require some form of continued suppressive therapy to prevent relapse.nnnMETHODSnWe conducted a multicenter, randomized trial that compared fluconazole (200 mg per day given orally) with amphotericin B (1 mg per kilogram of body weight per week given intravenously) in patients with AIDS who had completed primary therapy for cryptococcal meningitis with amphotericin B (greater than or equal to 15 mg per kilogram). To be eligible, patients had to have at least two negative cultures of cerebrospinal fluid immediately before randomization. The primary end point was relapse of cryptococcal disease as confirmed by biopsy or culture.nnnRESULTSnOf 218 patients initially enrolled, 119 were assigned to fluconazole and 99 to amphotericin B. Twenty-three patients were found not to have met the entry criteria; six other patients assigned to amphotericin B did not receive it and were lost to follow-up. Of the remaining 189 patients, after a median follow-up of 286 days 14 of 78 receiving amphotericin B (18 percent) and 2 of 111 assigned to fluconazole (2 percent) had relapses of symptomatic cryptococcal disease (P less than 0.001 by Fishers exact test). There was a difference of 19 percent in the estimated probability of remaining relapse-free at one year between the fluconazole group (97 percent) and the amphotericin B group (78 percent) (95 percent confidence interval, 7 percent to 31 percent; P less than 0.001). Serious drug-related toxicity was more frequent in the amphotericin B group (P = 0.02), as were bacterial infections (P = 0.004) and bacteremia (P = 0.002).nnnCONCLUSIONSnFluconazole taken by mouth is superior to weekly intravenous therapy with amphotericin B to prevent relapse in patients with AIDS-associated cryptococcal meningitis after primary treatment with amphotericin B.

Oral Ganciclovir for the Prevention of Cytomegalovirus Disease in Persons with AIDS

BACKGROUNDnIn the advanced stages of the acquired immunodeficiency syndrome (AIDS), cytomegalovirus (CMV) disease, particularly vision-damaging retinitis due to CMV is common. We evaluated prophylactic treatment with orally administered ganciclovir as a way to prevent CMV disease.nnnMETHODSnWe conducted a prospective, randomized, double-blind, placebo-controlled study of CMV infected persons with AIDS with either CD4+ lymphocyte counts of < or = 50 per cubic millimeter or counts of < or = 100 per cubic millimeter in those with a history of an AIDS defining opportunistic infection. Patients were randomly assigned, in a 2:1 ratio, to receive either oral ganciclovir (1000 mg three times daily) or placebo.nnnRESULTSnThe study was stopped after a median 367 days of follow-up. In an intention-to-treat analysis, the twelve month cumulative rates of confirmed CMV disease were 26 percent in the placebo group (n = 239) and 14 percent in the ganciclovir group (n = 486), representing an overall reduction in risk of 49 percent in the ganciclovir group (P < 0.001). The incidence of CMV retinitis after 12 months was 24 percent in the placebo group and 12 percent in the ganciclovir group (P < 0.0001). The prevalence of CMV-positive urine cultures at base line was 42 percent; after two months it was 43 percent in the placebo group and 10 percent in the ganciclovir group (P < 0.0001). The one year mortality rate was 26 percent in the placebo group and 21 percent in the ganciclovir group (P = 0.14). Therapy with granulocyte colony stimulating factor was more frequent in the ganciclovir group (24 percent) than in the placebo group (9 percent).nnnCONCLUSIONSnIn persons with advanced AIDS, phophylactic oral ganciclovir significantly reduces the risk of CMV disease.

Oral Ganciclovir as Maintenance Treatment for Cytomegalovirus Retinitis in Patients with AIDS

BACKGROUNDnCytomegalovirus retinitis, a sight-threatening infection associated with the acquired immunodeficiency syndrome (AIDS), currently requires lifelong intravenous treatment. An effective oral treatment would be an important advance.nnnMETHODSnWe compared oral with intravenous ganciclovir in an open-label, randomized study in patients with AIDS and newly diagnosed, stable cytomegalovirus retinitis (the disease was stabilized by three weeks of treatment with intravenous ganciclovir). Sixty subjects were randomly assigned to maintenance therapy with intravenous ganciclovir at a dose of 5 mg per kilogram of body weight daily, and 63 to maintenance therapy with oral ganciclovir at a dose of 3000 mg daily. The subjects were followed for up to 20 weeks, with photography of the fundi conducted every other week. The photographs were evaluated at the completion of the study by an experienced grader who was unaware of the subjects treatment assignments.nnnRESULTSnEfficacy could be evaluated in 117 subjects; photographs were ungradable for 2 of the 117. On the basis of the masked assessment of photographs from 115 subjects, the mean time to the progression of retinitis was 62 days in those given intravenous ganciclovir and 57 days in those given oral ganciclovir (P = 0.63; relative risk [oral vs. intravenous], 1.08; 95 percent confidence interval for the difference in means, -22 to +12 days). On the basis of funduscopy by ophthalmologists who were aware of the subjects treatment assignments, the mean time to progression was 96 days in subjects given intravenous ganciclovir and 68 days in subjects given oral ganciclovir (P = 0.03; relative risk [oral vs. intravenous], 1.68; 95 percent confidence interval for the difference in means, -45 to -11 days). Survival, changes in visual acuity, the incidence of viral shedding, and the incidence of adverse gastrointestinal events were similar in the two groups. Neutropenia, anemia, intravenous-catheter-related adverse events, and sepsis were more common in the group given intravenous ganciclovir.nnnCONCLUSIONSnOral ganciclovir is safe and effective as maintenance therapy for cytomegalovirus retinitis and is more convenient for patients to take than intravenous ganciclovir.

Evolution of Mutations Conferring Multidrug Resistance during Prophylaxis and Therapy for Cytomegalovirus Disease

In a human immunodeficiency virus-infected subject, cytomegalovirus (CMV) isolated 9 months after the patient began oral ganciclovir prophylaxis was resistant to ganciclovir and cidofovir and contained mutations in both UL97 and Pol coding regions. At 1 year, retinitis developed, which progressed despite intravenous ganciclovir followed by foscarnet and then cidofovir. A subsequent buffy coat virus isolate was resistant to all three drugs and contained new mutations in UL97 and Pol. By individually transferring the observed mutations to laboratory strain AD169, it was shown that a mutation at codon 603 of UL97 conferred resistance to ganciclovir, a mutation at codon 412 of Pol conferred resistance to both ganciclovir and cidofovir, and a mutation at codon 802 of Pol conferred resistance to ganciclovir and foscarnet. This case illustrates the development of multidrug resistance during prolonged exposure to antiviral therapy for CMV and cross-resistance arising from point mutations in the CMV Pol gene.

An Outbreak of Pneumocystis carinii Pneumonia in Homosexual Men

Pneumocystis carinii pneumonia has rarely been reported in previously healthy persons over the age of 6 months. Five cases of P. carinii pneumonia in adult homosexual men, confirmed by biopsy results, are reported. All five patients were seropositive when tested for antibodies to cytomegalovirus and four had evidence of active concurrent cytomegalovirus infections. Kaposis sarcoma was shown in two of the patients and one had possible Pneumocystis infection of the central nervous system as well as P. carinii pneumonia. Three patients had second episodes of Pneumocystis pneumonia. Four of the five patients have died. Past or concurrent cytomegalovirus infection and homosexuality were the only common epidemiologic features in all five patients.

Zalcitabine Compared with Zidovudine in Patients with Advanced HIV-1 Infection Who Received Previous Zidovudine Therapy

Zidovudine (3-azido-3-deoxythymidine [AZT]) prolongs survival and decreases the frequency of and time to development of the acquired immunodeficiency syndrome (AIDS) [1-3]. Anemia and neutropenia are the most common serious toxicities associated with zidovudine therapy and may limit treatment in some patients with advanced disease [2-4]. In patients with advanced human immunodeficiency virus type 1 (HIV) infection, long-term treatment with zidovudine is associated with a progressive decline in CD4 lymphocyte counts, disease progression, increasing fatality, and emergence of virus isolates with reduced in vitro susceptibility to zidovudine [1, 5-7]. Therefore, alternative treatments for patients with progressive HIV disease are needed. Zalcitabine (dideoxycytidine [ddC]) is another deoxynucleoside analog that inhibits the in vitro replication of HIV [8] and improves certain measures of HIV infection, including the CD4 lymphocyte count and the p24 antigen level [9, 10]. In addition, zidovudine-resistant isolates are susceptible to zalcitabine in vitro [11]. The major toxicity associated with zalcitabine differs from that seen with zidovudine and includes a dose-limiting peripheral neuropathy [9, 10]. These observations prompted us to study the safety and efficacy of zalcitabine among patients with advanced HIV disease who had received previous zidovudine therapy for 48 weeks or more. Figure 1. Estimated distributions of the time to the first critical event, including AIDS-defining opportunistic infection, malignancy, or death. Methods Patients The study sample consisted of patients who had tolerated 48 weeks or more of zidovudine therapy (total daily dose 500 mg) and who had a first episode of Pneumocystis carinii pneumonia or advanced AIDS-related complex at the time of initiation of zidovudine therapy. All patients had to be receiving and tolerating zidovudine at the time of enrollment in the study. Advanced AIDS-related complex was defined by the presence of oral candidiasis, oral hairy leukoplakia, herpes varicella infection, unintentional weight loss exceeding 10% of body weight or 4.5 kg (10 lb), unexplained diarrhea (defined as two or more liquid stools per day persisting for 30 days or more) or unexplained fever (defined as a temperature greater than 38.5 C occurring for more than 14 consecutive days or for more than 15 days in a 30-day period), and a CD4-lymphocyte count of less than 200 cells/mm3. The criteria for eligibility also included a hemoglobin concentration of 95 g/L or more, a total granulocyte count of 0.750 109/L or more, a platelet count of 75 109/L or more, serum transaminase levels no higher than five times the upper limit of normal, a Karnofsky performance score of 60 or more, and seropositivity for HIV antibody as determined by any licensed enzyme-linked immunosorbent assay. At least 20% of the patients were also required to have a serum HIV p24 antigen level of 70 pg/mL or more. Patients were also excluded from the study for the following reasons: interruption of previous zidovudine therapy for more than 30 consecutive days or a total of 90 days, development of a serious toxicity during zidovudine therapy, previous zalcitabine therapy, the presence of visceral or symptomatic Kaposi sarcoma requiring therapy, the presence of peripheral neuropathy, or pregnancy. All patients received inhaled pentamidine isethionate, 300 mg every 4 weeks, for the prevention of P. carinii pneumonia. Maintenance therapy for other AIDS-related opportunistic infections was allowed. The use of other antiretroviral drugs, biologic-response modifiers, systemic corticosteroids, drugs that could cause peripheral neuropathy other than isoniazid, and experimental drugs was not allowed. The patients were recruited from four AIDS Clinical Trials Units, five university-affiliated medical centers, and private practice groups. The study was approved by institutional review boards at each center, and all patients gave written informed consent. Study Design and Treatment Regimen The study was an open-label, randomized trial. Patients were stratified according to a diagnosis of AIDS or advanced AIDS-related complex at the time of initiation of zidovudine therapy and according to the dose of zidovudine that they were receiving at study entry. The intended sample size was 160 patients per treatment arm, the number required to detect a 15% difference in survival outcome with a power of 80% and a two-sided significance level of 0.05. After the enrollment of only 115 patients, the study was closed to enrollment in July 1991 because of slow accrual. A blocked randomization procedure was used to assign patients in each center to zalcitabine or zidovudine. Zalcitabine (Hivid, Hoffmann-La Roche, Nutley, New Jersey) was given in two 0.375-mg tablets every 8 hours. Zidovudine (Retrovir, Burroughs Wellcome, Inc., Research Triangle Park, North Carolina) was initially given in two 100-mg capsules every 4 to 5 hours and then in one 100-mg capsule every 4 to 5 hours. Management of Toxicity If a serious toxicity occurred, therapy with the study medication was interrupted. After abnormal values returned to levels indicating a lower-grade toxicity or to pretreatment values, therapy with the study medication was restarted at half the dose. If severe anemia developed, red-cell transfusions or therapy with recombinant erythropoietin was administered. If patients had a toxicity that was persistent, recurred after reduction of study medication, or was life threatening, their study medication was permanently withdrawn. Zalcitabine therapy was permanently discontinued in patients who developed severe treatment-related peripheral neuropathy. Severe peripheral neuropathy was defined as moderate discomfort associated with the loss of a deep tendon reflex, the presence of paresthesias, or pain that either was refractory to non-narcotic analgesics, amitriptyline, or clonazepam or worsened during a 1-week period. Evaluation of Patients The pretreatment evaluation included a medical history, a physical examination, a signs-and-symptoms questionnaire, an evaluation for peripheral neuropathy, a Karnofsky performance score, and laboratory studies. Lymphocyte phenotyping was done by flow cytometry at the same laboratory at each center on peripheral blood mononuclear cells prepared on a Ficoll-Hypaque gradient or by the whole-blood lysis method with monoclonal reagents. The serum specimens collected for HIV p24 antigen determinations were frozen for batch testing with a commercial test kit (Abbott, North Chicago, Illinois). All patients were re-evaluated every 2 weeks for the first 12 weeks and every 4 weeks thereafter. Patients who discontinued therapy with the study medication were followed for survival only. Clinical measures of efficacy were survival and time to a first critical event, which was defined as any AIDS-related condition or death. Secondary measures of efficacy were increases in CD4 lymphocyte counts, reduction of serum p24 antigen levels, weight gain, and changes in Karnofsky performance scores. Statistical Analysis Differences in proportions were assessed using the Fisher exact test. Time-to-event distributions were estimated using the method of Kaplan and Meier and compared using the Cox proportional-hazards regression model. To assess changes in the CD4 lymphocyte count, the serum p24 antigen level, weight, and Karnofsky performance score, parametric analyses of covariance were used. Subgroup analyses were carried out, with patients stratified according to diagnosis (AIDS or AIDS-related complex) and pretreatment CD4 lymphocyte count ( 100 cells/mm3 or >100 cells/mm3). All analyses were based on an intent-to-treat approach, using clinical data available through 15 June 1991 and survival data collected through 31 December 1991. The hazard ratio expressed as relative risk and 95% two-sided CIs are given when appropriate. All P values were two sided. Results Patient Sample Between January 1990 and June 1991, 111 patients were enrolled in the study. Patients included 110 men and 1 woman (mean age, 36 years). Most patients were white and non-Hispanic. One hundred six patients were homosexual or bisexual, 7 had a history of intravenous drug use, 12 had a history of receipt of blood products, and 8 had heterosexual contact with a person at risk for HIV infection. Twenty-two patients had AIDS and 89 had AIDS-related complex at the time zidovudine therapy was first instituted. Fifty-nine patients were randomly assigned to receive zalcitabine and 52 to receive zidovudine. No significant differences were noted between the two treatment groups regarding pretreatment characteristics (Table 1). The median duration of study treatment was 279 days (range, 16 to 437 days) for the zalcitabine group and 174.5 days (range, 8 to 400 days) for the zidovudine group. The time to discontinuation of study medication was statistically shorter in the zidovudine group compared with the zalcitabine group (P = 0.001). Table 1. Patient Characteristics by Treatment Group* Of the 111 patients enrolled, 56 were withdrawn from the study medication, 20 completed the study, and 35 were still receiving study medication when the database was closed for analysis on 15 June 1991. The reasons for discontinuation of study medication included treatment with nonallowed medications (5 patients in the zidovudine group); death (2 patients in the zalcitabine group and 1 patient in the zidovudine group); toxicity (12 patients in the zalcitabine group and 5 in the zidovudine group); self-withdrawal (6 patients in the zalcitabine group and 18 in the zidovudine group); loss to follow-up (2 patients in the zalcitabine group and 3 in the zidovudine group); and administrative reasons (2 patients in the zidovudine group). Significantly more patients were withdrawn from the zidovudine group than from the zalcitabine group (34 patients compared with 22 patients; P = 0.004). For patients who complet

Foscarnet Therapy for Severe Acyclovir-Resistant Herpes Simplex Virus Type-2 Infections in Patients with the Acquired Immunodeficiency Syndrome (AIDS): An Uncontrolled Trial

STUDY OBJECTIVEnTo determine whether trisodium phosphonoformate (foscarnet) is efficacious in treating severe mucocutaneous disease due to acyclovir-resistant herpes simplex virus type-2 (HSV-2) infection in patients with the acquired immunodeficiency syndrome (AIDS).nnnDESIGNnOpen-labeled drug administration to patients with AIDS and severe ulcerative disease due to acyclovir-resistant HSV-2 infection.nnnSETTINGnMedical floors of acute care hospital.nnnPATIENTSnFour patients with AIDS who developed progressive ulcerative mucocutaneous lesions of the genitals, perineum, perianal region, or finger due to acyclovir-resistant, thymidine-kinase (TK)-negative strains of HSV-2.nnnINTERVENTIONnFoscarnet, 60 mg/kg body weight intravenously every 8 hours (with reduced dosage for renal impairment), for 12 to 50 days.nnnMEASUREMENT AND MAIN RESULTSnAll patients receiving foscarnet had dramatic improvement in their clinical findings with marked clearing of mucocutaneous lesions and eradication of HSV from mucosal surfaces.nnnCONCLUSIONnFoscarnet may be an effective treatment for severe mucocutaneous disease due to acyclovir-resistant, TK-negative strains of HSV-2.

Oral Atovaquone Compared with Intravenous Pentamidine for Pneumocystis carinii Pneumonia in Patients with AIDS

Pneumocystis carinii pneumonia was one of the first observed manifestations of the acquired immunodeficiency syndrome (AIDS) epidemic in the United States [1, 2]. It continues to be a source of morbidity and mortality for persons with human immunodeficiency virus (HIV) infection; it is estimated that more than 20 000 cases of P. carinii pneumonia develop annually [3]. The current standard of care is administration of trimethoprim-sulfamethoxazole or intravenous pentamidine for 21 days, with adjunctive steroid therapy for patients with moderate or severe P. carinii pneumonia [3, 4]. Although generally successful, these therapies are associated with many treatment-limiting adverse reactions. In comparative 21-day trials, discontinuation of therapy because of adverse drug effects ranges from 50% to 57% for trimethoprim-sulfamethoxazole and from 14% to 55% for pentamidine [5-7]. During shorter treatment courses with drug-level monitoring and dose adjustments, more patients are able to complete therapy, but adverse reactions occur in most patients [8]. Atovaquone (formerly 566C80) is one of the oral treatment alternatives for P. carinii pneumonia. It is a hydroxynaphthoquinone whose mode of action against P. carinii is unknown. However, in plasmodia it acts by inhibiting de novo pyrimidine synthesis through reduction of dihydroorotate dehydrogenase activity [9]. Atovaquone has activity against P. carinii in experimental pneumonia and in human pneumonia [10-13]. In human studies, it has a favorable adverse effect profile [11-13]; the ability of mammalian cells to bypass de novo pyrimidine synthesis may explain the relative paucity of adverse effects. Our multicenter randomized study compared oral atovaquone with intravenous pentamidine for treatment of P. carinii pneumonia in patients with AIDS. Results indicate that the efficacy of atovaquone and pentamidine for treatment of mild and moderate P. carinii pneumonia was similar, and there were fewer adverse events resulting in treatment discontinuation with atovaquone. Methods Experimental Design This study was an open, randomized trial to compare the efficacy and safety of oral atovaquone (Mepron, Burroughs Wellcome Co., Research Triangle Park, North Carolina) with that of intravenous pentamidine (Pentam 300, Fujisawa Pharmaceutical Co., Deerfield, Illinois) for the treatment of mild and moderate P. carinii pneumonia in adults with AIDS who were intolerant of trimethoprim or sulfa antimicrobial agents. Mild P. carinii pneumonia was defined by an alveolar-to-arterial oxygen difference of less than 4.7 kPa (35 mm Hg), and moderate pneumonia was defined by an alveolar-to-arterial oxygen difference of 4.7 to 6.0 kPa (35 to 45 mm Hg). Patients with an alveolar-to-arterial oxygen difference of greater than 6.0 kPa (45 mm Hg) were excluded because oral therapy is often inappropriate for severe pneumonia. Patients with a history of intolerance to trimethoprim or sulfa (that is, they had stopped a previous therapeutic or prophylactic regimen because of an intolerance to these medicines) would receive study medication as primary therapy for this episode of P. carinii pneumonia. The sample size (156 patients with confirmed P. carinii pneumonia) was based on the intention to establish whether the difference in efficacy between treatment groups was fewer than 15 percentage points. Because of a lower-than-expected therapy success rate, statistical power for the efficacy component would not have been attained even with full enrollment. Therefore, enrollment was discontinued prematurely. Final enrollment was adequate for comparisons of safety with adequate statistical precision. The protocol was amended in July 1991 to remove the requirement for intolerance to trimethoprim-sulfamethoxazole after results of a trial comparing atovaquone and trimethoprim-sulfamethoxazole were known. At termination of the study, approximately 75% of the patients receiving primary therapy were intolerant of trimethoprim or sulfa. Patients were to receive treatment with study medications for 21 days unless absence of a response or treatment-limiting toxicity was encountered. Patients were followed for 8 weeks after therapy was discontinued, and the status of their therapy was rated as one of the following: therapy success, therapy failure because of absence of response, therapy failure because of adverse events, or unevaluable. This study was unmasked, that is, both patients and investigators were aware of which treatment the patient was receiving. Double-masking of this study would have required intravenous placebos for patients randomly assigned to receive atovaquone, and this option was rejected to protect patients from the risk of intravenous placebos. Single-masking, in which the investigator would not know which treatment the patient was receiving, was also rejected as an option. The logistics of single-masking were problematic, and it was thought probable that investigators would be able to distinguish which patients were receiving daily intravenous infusions. The disadvantage of an unmasked (or open) study is that investigators previous perceptions may affect decisions to continue or discontinue study therapy for toxicities or absence of response. Although the protocol gave objective definitions of toxicities and criteria to determine response to therapy, the unmasked nature of the study may have resulted in some investigator classification bias. Definitions of End Points Survival was defined as being alive without ventilatory support 4 weeks after therapy was discontinued. Successful therapy was defined as sustained clinical improvement 4 weeks after therapy was discontinued, with no additional or alternate antipneumocystis treatment during that time. Prophylaxis for P. carinii pneumonia was allowed after completion of acute therapy. Patients who received treatment for less than 21 days but did not require additional therapy for P. carinii pneumonia were considered therapeutic successes if they had sustained improvement for 4 weeks after treatment was discontinued. Absence of response was defined by the following criteria: 1) mechanical ventilation required after the first 3 days of therapy; 2) any two of the following after 7 days: an increase in the alveolar-to-arterial oxygen difference of 2.7 kPa (20 mm Hg) or more over baseline, with an absolute value of more than 4.0 kPa (30 mm Hg); worsening chest radiographs; or worsening clinical symptoms not due to another identifiable cause; or 3) no improvement after 10 days of any two of the second set of conditions. However, use of alternate antipneumocystis therapy within 4 weeks of discontinuation of therapy always defined a patient as a therapy failure. Therapy failure because of treatment-limiting toxicity was defined as the discontinuation of therapy because of an adverse event and the requirement of additional treatment. Adverse events requiring discontinuation of therapy included the following: neutropenia (neutrophil count, 0.5 109/L); thrombocytopenia (platelet count, 25.0 109/L); hepatotoxicity (aspartate or alanine aminotransferase levels increased more than fivefold from baseline or >10 times the upper limit of normal; or bilirubin, >5 times the upper limit of normal); nephrotoxicity (creatinine level, >2.5 times the upper limit of normal; or calculated creatinine clearance, reduced >40% from baseline); anemia (hemoglobin concentration, <65.0 g/L despite transfusion); a prothrombin time of twice the upper limit of normal (or a prothrombin time >1.5 times the upper limit of normal and platelet counts of <40.0 109/L); pancreatic toxicity (amylase level >5 times the upper limit of normal); vomiting for more than 2 consecutive days despite antiemetic therapy; the Stevens-Johnson syndrome, urticaria with systemic symptoms, or significant exfoliative dermatitis. Unevaluable patients were those with documented P. carinii pneumonia who discontinued therapy for reasons other than treatment success, absence of response, or treatment-limiting toxicity (for example, noncompliance or lost to follow-up). Patients Eligible patients must have had HIV infection and clinical presentations consistent with P. carinii pneumonia. Histologic documentation of P. carinii pneumonia required within 7 days of study entry. Enrollment was limited to nonpregnant patients 13 years of age or older with an alveolar-to-arterial oxygen difference of 6.0 kPa ( 45 mm Hg) or less and a Pao 2 of 8.0 kPa ( 60 mm Hg) or greater while breathing room air; an absolute neutrophil count greater than 0.75 109/L; a platelet count of 80 109/L or greater; a hemoglobin concentration of 90 g/L or greater; a total bilirubin concentration of 43 mol/L or less; an alanine aminotransferase level of 5 times the upper limit of normal or less; and a willingness and ability to give written informed consent. Exclusion criteria included the following: known intolerance to parenteral pentamidine or previous failure of pentamidine for treatment of P. carinii pneumonia, previous treatment for the current episode or another episode of P. carinii pneumonia within 4 weeks of entry, an investigators opinion that the patient would require mechanical ventilator support in the near future, the presence of a concurrent pulmonary condition that would confound interpretation of drug effect, vomiting or malabsorption (including severe diarrhea), and known prolongation of the Q-T interval. Clinical and Laboratory Assessments Patients were monitored for therapeutic efficacy with chest radiographs, arterial blood gas measurements, and clinical symptom scores for dyspnea, chest pain or tightness, and cough (Table 1). Signs of drug toxicity were monitored through patient reports, clinical observation, electrocardiograms, and evaluation of laboratory results. Table 1. Clinical Symptom Scores Patients were evaluated at baseline; on days 2, 4, 7, 10, 14, 17, and 21 or the end of therapy; and 4 and 8 weeks after therapy