Edward M. Bernard

Treatment of Infections in Patients with the Acquired Immunodeficiency Syndrome

The microorganisms that regularly infect patients with the acquired immunodeficiency syndrome (AIDS) have become well recognized. Most take advantage of defects in T-lymphocyte function, but others, such as Streptococcus pneumoniae and Haemophilus influenzae, take advantage of B-cell defects. Still others, such as Staphylococcus aureus and Shigella species, occur or persist for reasons that are unclear. Infections with organisms associated with hospitalization and medical procedures are also seen and should be anticipated. Among the infections taking advantage of T-cell defects, Pneumocystis carinii pneumonia is the most commonly diagnosed, but cytomegalovirus infection may be equally common. Disseminated Mycobacterium avium-intracellulare infection has been found in one half of our patients at postmortem examination. The retrovirus responsible for AIDS commonly infects the central nervous system, as does Toxoplasma gondii. Although candida infections are common, dissemination is uncommon. Many of the infections respond to appropriate therapy but tend to recur when treatment is stopped. Often treatment courses must be prolonged even beyond those used in other immunocompromised hosts.

Aerosolized pentamidine: effect on diagnosis and presentation of Pneumocystis carinii pneumonia.

STUDY OBJECTIVE To determine the effect of previous aerosolized pentamidine therapy on diagnosis and presentation of Pneumocystis carinii pneumonia. DESIGN A retrospective study. SETTING A tertiary care hospital. PATIENTS Fifty-two consecutive patients with P. carinii pneumonia and underlying infection with the human immunodeficiency virus (HIV) who had bronchoscopy. Twenty-one patients who were on aerosolized pentamidine therapy served as the study group. Thirty-one patients who had not received the drug served as the control group. MEASUREMENTS AND MAIN RESULTS The yield of bronchoalveolar lavage for P. carinii pneumonia was 62% for the study group and 100% for the control group (P less than 0.05). This lower yield was significant for the subset of patients having their first episode of P. carinii pneumonia. The yield of transbronchial biopsy was similar for both groups of patients (81% compared with 84%). The yield of bronchoscopy was not influenced by use of zidovudine. Review of lavage specimen slides suggested that there may be fewer organisms present in patients receiving aerosolized pentamidine. An atypical roentgenographic presentation of upper lobe predominant infiltrates was seen in 38% of the study patients and 7% of the control patients. In addition, pneumothoraces and cystic changes were also frequently seen in the study patients. Gallium scans, when done, were also atypical in the study group. Markers of the severity of disease, however, were similar in both groups. CONCLUSION The yield of bronchoalveolar lavage for P. carinii pneumonia in HIV-infected patients is lower in patients receiving aerosolized pentamidine. Unusual roentgenographic presentations and atypical gallium scans are also found in this setting.

Continuous high-grade mycobacterium avium-intracellulare bacteremia in patients with the acquired immune deficiency syndrome

Serial quantitative blood cultures were performed before and during treatment in four patients with the acquired immune deficiency syndrome (AIDS) and Mycobacterium avium-intracellulare bacteremia. Initial colony counts were 350 to 28,000 cfu/ml, the counts declined substantially with treatment in two patients, and they declined modestly with treatment but rose when it was stopped in the other two. In one patient who was studied in detail, most of the circulating organisms were within the leukocytes, colony counts in blood subjected to lytic agents were 1.9- to 5.2-fold higher than in unlysed blood, and there were 10(5) to 10(6) times more organisms per gram in several tissue specimens obtained at autopsy than per milliliter of blood. It is concluded that continuous high-grade bacteremia is common in patients with AIDS and severe M. avium-intracellulare infections and that serial quantitative blood cultures provide a potential means for studying treatment in these patients.

Pneumothorax in AIDS

Objective: To determine risk factors for the development of pneumothorax in patients with the acquired immunodeficiency syndrome (AIDS). Design: Prospective cohort study. Setting: Tertiary care cen...

Aerosol amphotericin B is effective for prophylaxis and therapy in a rat model of pulmonary aspergillosis.

Invasive pulmonary aspergillosis is a major life-threatening complication among transplant recipients and patients receiving cancer chemotherapy. In a rat model of progressive pulmonary aspergillosis that is characterized by hyphal bronchopneumonia, aerosol amphotericin B (aero-AmB; 1.6 mg/kg given 2 days before infection) significantly delayed mortality in rats compared with animals in a control group. The first death in the aero-AmB-treated group occurred on day 11, by which time seven of the eight control animals had died. The same dose of aero-AmB given as treatment (1.6 mg/kg given 24 h after infection and then daily for 6 days) was also effective. In this trial, eight of the ten animals treated with aero-AmB survived for 7 days, whereas only one of ten control animals survived. Colony counts in lung homogenates obtained 24 h after infection showed an 80-fold reduction in the number of viable spores in animals that had received 6.4-mg/kg doses of aero-AmB 2 days prior to infection. At 48 h after administering a single 1.6- or 3.2-mg/kg dose of aero-AmB, mean lung concentrations were 2.79 and 5.22 micrograms/g of tissue, respectively. We conclude, therefore, that aero-AmB kills inhaled spores and delays the progression of pulmonary aspergillosis by inhibiting mycelial proliferation.

Systemic infection with Trichosporon cutaneum in a patient with acute leukemia: Report of a case

A case of disseminated infection with Trichosporon cutaneum, a fungus that causes white piedra, is described. The patient, a 58‐year‐old barber with acute leukemia, had fever, myalgias and skin lesions. He was receiving cytotoxic drug therapy and prednisone, was severely neutropenic and was being treated with broad spectrum antibiotics. Blood cultures and a biopsy of the skin lesion grew T. cutaneum. He died despite amphotericin B therapy. At autopsy, widespread infection with T. cutaneum was present. T. cutaneum is another fungus capable of causing widespread systemic disease in the immunocompromised host.

Activities of antimicrobial agents against clinical isolates of Mycobacterium haemophilum.

Mycobacterium haemophilum, first described in 1978, can cause severe infections of skin, respiratory tract, bone, and other organs of immunocompromised patients. There is no standardized antimicrobial susceptibility test, and for the 27 reported cases, a variety of test methods have been used. This paper reports the in vitro test results for 17 isolates of M. haemophilum recovered from 12 patients in the New York City area. MICs of 16 antimicrobial agents were determined in microtiter trays containing Middlebrook 7H9 broth plus 60 microM hemin, inoculated with 10(6) CFU of the organism per ml and incubated at 30 degrees C for 10 days. Ethambutol, ethionamide, tetracycline, cefoxitin, and trimethoprim-sulfamethoxazole were inactive against initial isolates from the 12 patients. Isoniazid was weakly active with a MIC for 50% of strains tested (MIC50) of 8 micrograms/ml and a MIC90 of > 32 micrograms/ml. Three quinolones, ciprofloxacin, ofloxacin, and sparfloxacin, were moderately active with MIC50s of 2 to 4 micrograms/ml and MIC90s of 4 to 8 micrograms/ml. Amikacin and clofazamine were active with MIC90s of 4 and 2 micrograms/ml, respectively. Clarithromycin was the most active macrolide with a MIC90 of < or = 0.25 microgram/ml. The MIC90 of azithromycin was 8 micrograms/ml, and the MIC90 of erythromycin was 4 micrograms/ml. The rifamycins were active with a MIC90 of 1 microgram/ml for rifampin and one of < or = 0.03 micrograms/ml for rifabutin. For a second isolate from the skin of one patient and a isolate from an autopsy culture of the spleen of a second patient, MICs of rifampin and rifabutin were > 16 microgram/ml, whereas initial isolates were inactivated by low concentrations of the rifamycins. Both patients had been treated for several months with several antimicrobial agents, including a rifamycin.

MIC and fungicidal activity of terbinafine against clinical isolates of Aspergillus spp.

Terbinafine and amphotericin B MICs for 90% of strains tested were 1.6 and 0.4 micrograms/ml against Aspergillus fumigatus (16 strains), 0.8 and 3.2 micrograms/ml against Aspergillus flavus (10 strains), and 0.4 and 1.6 micrograms/ml against Aspergillus niger (10 strains), respectively. For all species tested, the minimal inhibitory and fungicidal concentrations for 90% of strains of both drugs were identical and the inoculum size did not have a major effect on the results.

Pharmacokinetics of aerosol amphotericin B in rats

The distributions of amphotericin B (AmB) in tissue were compared after intraperitoneal or aerosol administration. Rats were sacrificed 24 h after receiving single or repeated daily doses; AmB concentrations in tissues were determined by high-performance liquid chromatography. After intraperitoneal doses of 4 mg/kg of body weight per day for 7 days, mean concentrations of AmB were 122.7, 55.2, and 4.31 micrograms/g in the spleen, liver, and lung, respectively. After aerosol doses (aero-AmB) of 1.6 mg/kg per day, the mean concentrations of AmB in the lung were 2.79 micrograms/g after a single dose and 9.88 micrograms/g after four doses, while the drug was undetectable (less than 0.1 micrograms/g) in serum, spleen, liver, kidney, and brain. The half-life of elimination of AmB from the lungs was 4.8 days according to serial sacrifices done after a single dose of 3.2 mg of aero-AmB per kg. Treatment with 60 mg of aero-AmB per kg was well tolerated and produced no histopathologic changes in the lungs. The aerosol route was much more efficient than the systemic route in delivering AmB to the lungs, and it limited the accumulation of AmB in other organs. Because AmB is eliminated slowly, infrequent dosing schedules can be used. These pharmacokinetic characteristics and its proven effectiveness in an animal model make aero-AmB a highly promising new method for the prevention of pulmonary aspergillosis. Aero-AmB should also be considered for use as an adjunct to intravenous AmB for treatment of fungal pneumonias.

Combination therapy in a model of pulmonary aspergillosis

Summary. The current treatment for pulmonary aspergillosis, amphotericin B, is toxic and not always effective. This study was done to evaluate combinations of amphotericin B with other agents in an animal model of pulmonary aspergillosis. Sprague‐Dawley rats were treated with cortisone acetate, infected intratracheally with 106 spores of Aspergillus fumigatus, and followed daily for survival. Mortality among controls started on day 2, and it was 80% by day seven, whereas therapy with amphotericin B resulted in survival of all animals. When given alone, ketoconazole, 5‐fluorocytosine and rifampin did not improve survival. The combination of ketoconazole with amphotericin B resulted in complete antagonism. When animals received a combination of aerosol amphotericin B prophylaxis two days prior to infection followed by treatments with SCH39304 or itraconazole seven days after infection, survival rates were superior as compared to animals that had received aerosol prophylaxis only. The combinations of either 5‐fluorocytosine or rifampin with amphotericin B were not better than amphotericin B alone. While combinations with 5‐fluorocytosine or rifampin appear not to offer any advantage over therapy with amphotericin B alone, additional studies to further evaluate the role of azoles in combination therapy are needed.