Biomedical subjects
Publications and source records attributed to C A Kauffman.
The azole antifungal drugs fluconazole and itraconazole have changed our approach to the treatment of serious fungal infections. Increased use of these drugs has generated information of value for clinical practice.
BACKGROUND: Invasive aspergillosis is the most common invasive mould infection and a major cause of mortality in immunocompromised patients. Response to amphotericin B, the only antifungal agent licensed in the United States for the treatment of aspergillosis, is suboptimal. METHODS: A multicenter open study with strict entry criteria for invasive aspergillosis evaluated oral itraconazole (600 mg/d for 4 days followed by 400 mg/d) in patients with various underlying conditions. Response was based on clinical and radiologic criteria plus microbiology, histopathology, and autopsy data. Responses were categorized as complete, partial, or stable. Failure was categorized as an itraconazole failure or overall failure. RESULTS: Our study population consisted of 76 evaluable patients. Therapy duration varied from 0.3 to 97 weeks (median 46). At the end of treatment, 30 (39%) patients had a complete or partial response, and 3 (4%) had a stable response, and in 20 patients (26%), the protocol therapy was discontinued early (at 0.6 to 54.3 weeks) because of a worsening clinical course or death due to aspergillosis (itraconazole failure). Twenty-three (30%) patients withdrew for other reasons including possible toxicity (7%) and death due to another cause but without resolution of aspergillosis (20%). Itraconazole failure rates varied widely according to site of disease and underlying disease group: 14% for pulmonary and tracheobronchial disease, 50% for sinus disease, 63% for central nervous system disease, and 44% for other sites; 7% in solid organ transplant, 29% in allogeneic bone marrow transplant patients, and 14% in those with prolonged granulocytopenia (median 19 days), 44% in AIDS patients, and 32% in other host groups. The relapse rates among those who completed therapy and those who discontinued early for possible toxicity were 12% and 40%, respectively; all were still immunosuppressed. CONCLUSION: Oral itraconazole is a useful alternative therapy for invasive aspergillosis with response rates apparently comparable to amphotericin B. Relapse in immunocompromised patients may be a problem. Controlled trials are necessary to fully assess the role of itraconazole in the treatment of invasive aspergillosis.
PURPOSE: To study the epidemiology of oral candidiasis and the effect of treatment of thrush in human immunodeficiency virus (HIV)-infected patients. PATIENTS AND METHODS: We conducted a prospective observational study of 92 patients over 1 year, including a nonblinded, randomized treatment trial of thrush with clotrimazole troches or oral fluconazole. Oral sites were cultured monthly and when thrush occurred. Candida albicans strains were typed by contour-clamped homogeneous electric field (CHEF) electrophoresis. Changes in strains were evaluated over time and in regard to their associations with particular sites, episodes of thrush, relapse after treatment, and colonization of sexual partners. Susceptibility to fluconazole was tested and CHEF analysis was done on these strains to determine the epidemiology of fluconazole resistance. RESULTS: Yeasts colonized 84% of patients. C albicans accounted for 81% of all isolates and was separated into 34 distinct strains. Most patients had persistent carriage of 1 or 2 dominant strains of C albicans. Three couples shared strains. Nineteen different C albicans strains caused 82 episodes of thrush in 45 patients. CD4 < 200/microL was associated with development of thrush. Clinical cure rates were similar with fluconazole (96%) and clotrimazole (91%), but mycologic cure was better with fluconazole (49%) than clotrimazole (27%). Following mycologic cure, colonization recurred with the same strain 74% of the time. Colonization with Torulopsis glabrata and Saccharomyces cerevisiae increased after treatment with either drug, but these organisms were never a sole cause of thrush. In a subset of 35 patients followed for over 3 months in whom fluconazole susceptibilities were performed, minimum inhibitory concentrations (MICs) to fluconazole increased only in those on fluconazole prophylaxis. Clinical failure of fluconazole was associated with an MIC > or = 64 micrograms/mL in 3 patients, and with an MIC of 8 micrograms/mL in 1 patient. In 2 of these 4 patients, the prior colonizing strain developed fluconazole resistance. In the other 2, new resistant strains were acquired. CONCLUSIONS: Many different strains of C albicans colonize and cause thrush in patients infected with HIV. Patients are usually persistently colonized with a single strain, and recurrences following treatment are usually due to the same strain. Transmission of strains may occur between couples. Fluconazole and clotrimazole are equally effective in treating thrush, but mycologic cure occurs more often with fluconazole. Fluconazole resistance in C albicans occurs most often in patients who have low CD4 counts and are taking fluconazole prophylactically for recurrent thrush. Fluconazole resistance may occur through acquisition of a new resistant strain or by development of resistance in a previously susceptible strain.
Fungal infections of prosthetic dialysis fistulae are rare. We report the first case of infection of a polytetrafluoroethylene dialysis access graft with the yeast Cryptococcus neoformans. Therapy with antifungal agents alone failed to cure the infection and significant improvement was observed only when all prosthetic material was surgically removed. This case emphasizes the potential for fungal infection of prosthetic dialysis fistulae and the importance of removal of intravascular foreign material in conjunction with antifungal therapy for treatment of fungal prosthetic graft infections.
OBJECTIVES: To assess the prevalence of high-level gentamicin-resistant enterococcus (HGRE) colonization, transmission patterns, and spectrum of illness among residents of a long-term care facility. DESIGN: Monthly surveillance for HGRE colonization of wounds, rectum, and perineum over a 1-year period. SETTING: A Veterans Affairs long-term care facility attached to an acute-care facility. PATIENTS: All 341 patients in the facility during the observation period. RESULTS: Over the 1-year period, 120 patients (35.2%) were colonized with HGRE at least once, with an overall monthly colonization rate of 20 +/- 1.5%. HGRE were isolated from rectum (12.8%), wounds (11.7%), and perineum (9.3%). Patients with the poorest functional status had the highest rate of colonization (P < 0.0005). HGRE-colonized patients were more likely to be colonized with methicillin-resistant Staphylococcus aureus (51% versus 25%; P < 0.0005). Seventy-four patients (21.7%) were colonized at admission or at the start of the study. Another 46 patients (13.5%) acquired HGRE during the study, including 36 who acquired HGRE while in the long-term care facility and 10 who were positive when transferred back from the acute-care hospital. Based on plasmid profiles, only two patients appeared to have isolates similar to those of current or previous roommates. Carriage of HGRE was transient in most cases. Only 20 patients were colonized for 4 or more months, and those patients usually carried different strains intermittently. Infections were infrequent, occurring in only 4.1% of total patients. CONCLUSIONS: In our long-term care facility, HGRE were endemic, and new acquisition of HGRE occurred frequently. However, only two patients had evidence of acquisition from a roommate, suggesting that cross-infection from a roommate was not a major route of spread of HGRE.
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Chronic meningitis is an uncommon manifestation of candidiasis. We present the case of an elderly woman who had symptoms such as headache, malaise, and fever for 8 months and was found to have Candida albicans meningitis, and we review 17 similar cases. An underlying illness or risk factor for candidiasis was present in only 13 (72%) of the 18 patients. Headache, fever, and nuchal rigidity were the predominant clinical findings. Analysis of CSF showed either mononuclear or neutrophilic pleocytosis, an elevated protein level, and a decreased level of glucose. Only 17% of CSF smears were positive, and only 44% of initial CSF cultures yielded Candida species. In four cases, Candida species grew only after special techniques were used; in three cases, CSF cultures remained negative. The overall mortality associated with candidal meningitis was 53%, but among 12 patients who were treated and followed, the rate was 33%. In addition to acute meningitis seen with disseminated infection, Candida species can cause chronic meningitis that mimics tuberculosis and the more common fungal meningitides, such as cryptococcosis.
We report the case of a 41-year-old man infected with human immunodeficiency virus who had two episodes of aseptic meningitis that occurred 2 weeks apart; the first was associated with ingestion of trimethoprim-sulfamethoxazole (TMP-SMZ) and the second was associated with ingestion of TMP alone. Onset of fever, headache, and flushing was abrupt, followed by somnolence, hearing loss, and aphasia. Analysis of the CSF showed pleocytosis and an elevated protein level. The findings resolved within 48 hours after withdrawal of the drug. We also review 18 previously reported cases of TMP-SMZ- or TMP-induced meningitis, 17 of which occurred in women. In all of these cases, a similar abrupt onset and resolution were noted. Six of the 18 patients had collagen-vascular diseases. All but two of these patients had multiple recurrent episodes of meningitis before the diagnosis was made. We conclude that the diagnosis of TMP-SMZ- or TMP-induced meningitis should be considered when a patient receiving these drugs has recurrent episodes of aseptic meningitis.
In the 1960s and 1970s, amphotericin B was the only effective therapy for serious systemic endemic fungal infections due to Histoplasma capsulatum, Blastomyces dermatitidis, and Sporothrix schenckii. In the 1980s, ketoconazole was introduced as therapy for endemic mycoses; after this antifungal agent was introduced, some of these infections could be treated orally in an outpatient setting rather than intravenously in an inpatient setting. The 1990s have become the triazole era. It is now standard practice to treat nonmeningeal, non-life-threatening histoplasmosis and blastomycosis orally on an outpatient basis; the drug of choice for this treatment is itraconazole. Itraconazole also has proved useful as treatment for histoplasmosis in patients infected with human immunodeficiency virus. Although itraconazole has not yet been approved for the treatment of sporotrichosis, in preliminary studies it has been shown to be effective therapy not only for cutaneous and lymphocutaneous sporotrichosis but also for disseminated infection with S. schenckii.
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OBJECTIVE: To assess colonization and infection with methicillin-resistant Staphylococcus aureus (MRSA), high-level gentamicin-resistant enterococci (R-ENT) and gentamicin and/or ceftriaxone-resistant Gram-negative bacilli (R-GNB) and the factors that are associated with colonization and infection with these organisms. DESIGN: Monthly surveillance for colonization and infection over a period of 2 years. In the second year, an intervention to decrease MRSA colonization by the use of mupirocin ointment was carried out. SETTING: Long-term care facility attached to an acute care Veterans Affairs Medical Center. PATIENTS: A total of 551 patients in the facility were followed for a period of 2 years. MEASUREMENTS: Colonization and infection rates with MRSA, R-ENT, and R-GNB. Analysis of risk factors associated with colonization and infection with these three groups of organisms. MAIN RESULTS: In the first year, colonization rates were highest for MRSA (22.7 +/- 1% patients colonized each month) and R-ENT (20.2 +/- 1%) and lower for R-GNB (12.6 +/- 1%). After introduction of decolonization of nares and wounds with mupirocin, the rate of MRSA colonization fell significantly to 11.5 +/- 1.8%, but rates remained unchanged for R-ENT and R-GNB. Risk factors for MRSA colonization included the presence of wounds and decubitus ulcers. For R-ENT, the presence of wounds, renal failure, intermittent urethral catheterization, low serum albumin, and poor functional level were significant. For R-GNB, intermittent urethral catheterization, chronic renal disease, inflammatory bowel disease, presence of wounds, and prior pneumonia were significantly associated with colonization. Overall, of infections caused by known organisms, 49.6% were due to MRSA, R-ENT, or R-GNB, and 50.4% were due to susceptible organisms. Infections were more commonly due to R-GNB (21.1% of all infections) than to R-ENT (8.3%) or MRSA (4.6%). The most common infections were urinary tract infections (42.9% of all infections) and skin and soft tissue infections (31.9% of all infections). Risk factors for MRSA infections were diabetes mellitus and peripheral vascular disease, for R-GNB infections were intermittent urethral catheterization and indwelling urethral catheters, and no one factor was associated with R-ENT infection. CONCLUSIONS: In our long-term care facility, colonization with resistant MRSA and R-ENT was more common than R-GNB, but infections were more often due to R-GNB than R-ENT and MRSA. Several host factors, which potentially could be modified in order to prevent infections, emerged as important in colonization and infection with these antibiotic-resistant organisms.
For 212 oropharyngeal isolates of Candida albicans, the fluconazole MICs for 50 and 90% of strains tested were 0.5 and 16 micrograms/ml, respectively, and those of itraconazole were 0.05 and 0.2 micrograms/ml, respectively. Of 16 isolates for which fluconazole MICs were > 64 micrograms/ml, itraconazole MICs for 14 were < or = 0.8 micrograms/ml and for 2 were > 6.4 micrograms/ml. Most fluconazole-resistant strains remained susceptible to itraconazole; whether itraconazole will prove effective for refractory thrush remains to be shown.
Absorption of ketoconazole is impaired in subjects with an increased gastric pH due to administration of antacids, H2-receptor antagonists, proton pump inhibitors, or the presence of hypochlorhydria. Sucralfate could provide an attractive alternative in patients receiving ketoconazole who require therapy for acid-peptic disorders. Twelve healthy human volunteers were administered a single 400-mg oral dose of ketoconazole in each of three randomized treatment phases. In phase A, ketoconazole was administered orally with 240 ml of water. In phase B, ketoconazole and sucralfate (1.0 g) were administered simultaneously with 240 ml of water. In phase C, ketoconazole was administered with 240 ml of water 2 h after administration of sucralfate (1.0 g) orally with 240 ml of water. A 680-mg oral dose of glutamic acid hydrochloride was administered 10 min prior to and with each dose of ketoconazole, sucralfate, or ketoconazole plus sucralfate. Simultaneous administration of ketoconazole and sucralfate led to a significant reduction in the area under the concentration-time curve and maximal concentration of ketoconazole in serum (78.12 +/- 12.20 versus 59.32 +/- 13.61 micrograms.h/ml and 12.34 +/- 3.07 versus 8.92 +/- 2.57 micrograms/ml, respectively; P < 0.05). When ketoconazole was administered 2 h after sucralfate, the observed ketoconazole area under the concentration-time curve was not significantly decreased compared with that of ketoconazole alone. The time to maximal concentrations in serum and the ketoconazole elimination rate constant were not significantly different in any of the three treatment phases. In patients receiving concurrent administration of ketoconazole and sucralfate, doses should be separated by at least 2 h.
Methicillin-resistant Staphylococcus aureus (MRSA) has become a major nosocomial pathogen in community hospitals, long-term-care facilities, and tertiary care hospitals. The basic mechanism of resistance is alteration in penicillin-binding proteins of the organism. Methods for isolation by culture and typing of the organism are reviewed. MRSA colonization precedes infection. A major reservoir is the anterior nares. MRSA is usually introduced into an institution by a colonized or infected patient or health care worker. The principal mode of transmission is via the transiently colonized hands of hospital personnel. Indications for antibiotic therapy for eradication of colonization and treatment of infection are reviewed. Infection control guidelines and discharge policy are presented in detail for acute-care hospitals, intensive care and burn units, outpatient settings, and long-term-care facilities. Recommendations for handling an outbreak, surveillance, and culturing of patients are presented based on the known epidemiology.
PURPOSE: To assess the impact of the use of mupirocin ointment on colonization, transmission, and infection with methicillin-resistant Staphylococcus aureus (MRSA) in a long-term-care facility. PATIENTS AND METHODS: All 321 residents of a Veterans Affairs long-term-care facility from June 1990 through June 1991 were studied for MRSA colonization and infection. MRSA-colonized patients received mupirocin ointment to nares in the first 7 months and to nares and wounds in the second 5 months. The effect of mupirocin use on MRSA colonization and infection was monitored. All S. aureus strains isolated were tested for the development of resistance to mupirocin. RESULTS: A total of 65 patients colonized with MRSA received mupirocin ointment. Mupirocin rapidly eliminated MRSA at the sites treated in most patients by the end of 1 week. Weekly maintenance mupirocin was not adequate to prevent recurrences--40% of patients had recurrence of MRSA. Overall, MRSA colonization in the facility, which was 22.7% +/- 1% prior to the use of mupirocin, did not change when mupirocin was used in nares only (22.2% +/- 2.1%), but did decrease to 11.5% +/- 1.8% when mupirocin was used in nares and wounds. Although colonization decreased, roommate-to-roommate transmission and MRSA infection rates, low to begin with, did not change when mupirocin was used. Mupirocin-resistant MRSA strains were isolated in 10.8% of patients. CONCLUSIONS: Mupirocin ointment is effective at decreasing colonization with MRSA. However, constant surveillance was required to identify patients colonized at admission or experiencing recurrence of MRSA during maintenance treatment. Long-term use of mupirocin selected for mupirocin-resistant MRSA strains. Mupirocin should be saved for use in outbreak situations, and not used over the long term in facilities with endemic MRSA colonization.
PURPOSE: To describe the clinical presentation and outcomes of treatment with itraconazole in patients with sporotrichosis. METHODS: A culture for Sporothrix schenckii or compatible histopathology was required for inclusion in the study. Patients with both cutaneous and systemic sporotrichosis were treated. Patients received from 100 to 600 mg of itraconazole daily for 3 to 18 months. Patients were classified as responders or nonresponders. Responders were further classified as remaining on treatment, relapsed, or free of disease. Nonresponders included patients who failed to respond or progressed during treatment with itraconazole. RESULTS: Twenty-seven patients (mean age: 53 years) were treated with 30 courses of itraconazole. Diabetes mellitus and alcoholism were present in eight and seven patients, respectively. Sites of involvement included lymphocutaneous alone in 9 patients, articular/osseous in 15 (multifocal in 3), and lung in 3. Prior therapy was unsuccessful in 11 patients. Among the 30 courses, there were 25 responders and 5 nonresponders. All 5 nonresponders received at least 200 mg daily of itraconazole for durations that ranged from 6 to 18 months. Of the 25 responders, 7 relapsed 1 to 7 months after treatment durations of 6 to 18 months. Of the 7 who relapsed, 2 are responding to a second course. One responder was lost to follow-up after 10 months of treatment with itraconazole. Of the remaining 17 responders, 3 remain on treatment, and 14 are free of disease over follow-up durations of 6 to 42 months (mean: 17.6 months). Itraconazole was well tolerated with few side effects noted. CONCLUSIONS: These results document the efficacy of itraconazole in the treatment of cutaneous and systemic sporotrichosis.
Fourteen mupirocin-resistant Staphylococcus aureus strains were isolated over 18 months; 12 exhibited low-level resistance, while two showed high-level resistance. Highly mupirocin-resistant strains contained a large plasmid which transferred mupirocin resistance to other S. aureus strains and to Staphylococcus epidermidis. This plasmid and pAM899-1, a self-transferable gentamicin resistance plasmid, have molecular and biologic similarities.
OBJECTIVE: To assess the efficacy and toxicity of orally administered itraconazole in the treatment of nonmeningeal, nonlife-threatening forms of blastomycosis and histoplasmosis. DESIGN: Prospective, nonrandomized, open trial. SETTING: Multicenter trial at 14 university referral centers. PATIENTS: Eighty-five patients with culture or histopathologic evidence of blastomycosis (48 patients) or histoplasmosis (37 patients). Patients receiving other systemic antifungal therapy were excluded. INTERVENTIONS: Itraconazole was administered orally at doses of 200 to 400 mg/d. Patients in whom treatment was considered a success were treated for a median duration of 6.2 months (blastomycosis) and 9.0 months (histoplasmosis). Disease activity was assessed at baseline; drug efficacy and toxicity were evaluated at monthly intervals during therapy, and efficacy was evaluated at regular follow-up visits after completion of therapy. The median duration of posttreatment evaluation for successfully treated patients was 11.9 months (blastomycosis) and 12.1 months (histoplasmosis). MEASUREMENTS AND MAIN RESULTS: Among the 48 patients with blastomycosis, success was documented in 43 (90%). The success rate for patients treated for more than 2 months was 95% (38 of 40). Among the 37 patients with histoplasmosis, success was documented in 30 (81%). The success rate for patients treated for more than 2 months was 86% (30 of 35). All patients with histoplasmosis in whom treatment failed had chronic cavitary pulmonary disease. Toxicity was minor; only 25 (29%) patients experienced any side effects, and itraconazole toxicity necessitated stopping therapy in only 1 patient. CONCLUSIONS: Itraconazole is a highly effective therapy for nonmeningeal, nonlife-threatening blastomycosis and histoplasmosis. The drug is associated with minimal toxicity.