Protein-losing enteropathy during highly active antiretroviral therapy in a patient with AIDS-related disseminated Mycobacterial avium complex infection.

Protein-losing enteropathy (PLE) is defined as a condition in which excess protein loss into the gastrointestinal lumen, due to various causes, is severe enough to produce hypoproteinemia and hypoalbuminemia. We report a 28-year-old Japanese woman with PLE. She had been diagnosed with AIDS and disseminated Mycobacterium avium complex (MAC) infection at age 26. Although highly active antiretroviral and antimycobacterial treatments helped her overcome this critical situation, 2 years after initiation of the treatments, she was readmitted to our hospital because of hypoalbuminemia and edema of the lower extremities, and she was diagnosed, by the use of double-balloon enteroscopy, with PLE due to intestinal lymphangiectasia (IL). The etiology was thought to be obstruction of the mesenteric and retroperitoneal lymphatic drainage systems by MAC lymphadenitis. Even with intensive antimycobacterial treatment, octreotide treatment as a long-acting somatostatin analogue, and a low-fat diet enriched with medium-chain triglyceride, IL was not cured during the follow-up period. In patients with AIDS, complete clinical remission of MAC (especially disseminated MAC) infection is very difficult.

Acute pancreatitis in a patient treated with micafungin.

CASE SUMMARY: A 73-year-old man (height, 158.2 cm; weight, 49.8 kg) presented with upper abdominal tenderness after 3 weeks of treatment with 150 mg/d of micafungin (3 mg/kg . d) (Mycamine, Astellas Pharma US Inc., Deerfield, Illinois) intravenously for pulmonary aspergillosis accompanied by [DOSAGE ERROR CORRECTED] pulmonary Mycobacterium avium complex (MAC) infection. Pulmonary aspergillosis was noninvasively diagnosed by a fungus lump in a cavity in the right upper lung field with a high value of 1,3-beta-D-glucan and a positive result for aspergillosis antigen. The patient had a medical history of gastrectomy due to gastric cancer and idiopathic thrombocytopenic purpura (ITP). He had been prescribed 800 mg/d of clarithromycin, 400 mg/dL of rifampicin, and 750 mg/d of ethambutol hydrochloride for pulmonary MAC infection for 2 years and 5 mg/d of prednisolone for ITP for 7 years. No traditional or homeopathic medicine had been received/administered. Laboratory tests at the onset of abdominal pain revealed a white blood cell count of 4300/microL with 51% neutrophils. There was no eosinophilia. Platelet count was 15,100/muL, with normal coagulation. Immunoglobulin G and immunoglobulin M were 1720 and 154 mg/dL, respectively. The patient had no history of allergy, biliary tract disease, hyperlipidemia, or hypercalcemia. He did not report alcohol use. The laboratory findings, magnetic resonance imaging, and upper abdominal tenderness were consistent with acute pancreatitis. After cessation of all drugs, his symptoms improved with bowel rest and parenteral nutrition. His laboratory measurements normalized thereafter. All drugs, except micafungin, were readministered for pulmonary MAC infection and ITP, and itraconazole was administered for pulmonary aspergillosis after the recovery from pancreatitis. During 16 months of follow-up, the pancreatitis did not recur. DISCUSSION: We performed a literature search of all available English-language articles published on MEDLINE between January 1966 and January 2007 using the key terms micafungin (text and indexed terms) and pancreatitis (text and indexed terms). Based on the search of MEDLINE, there have been no reports of acute pancreatitis associated with micafungin. The Naranjo adverse drug reaction (ADR) probability scale was used to assess the probability of micafungin-associated acute pancreatitis. A score of 6 was obtained, indicating a probable ADR from micafungin treatment. CONCLUSION: We report a case of acute pancreatitis probably associated with micafungin use in an elderly patient.

Successful treatment of refractory disseminated Mycobacterium avium complex infection with the addition of linezolid and mefloquine.

Execpt in patients with AIDS, disseminated MAC infection has been rare. We describe a patient with chronic lymphatic leukemia who developed disseminated cutaneous MAC lesions refractory to conventional antimycrobial therapy. The lesions responded to the addition of compounds that were recently discovered to have anti-MAC activity (linezolid, moxifloxacin) as well as GM-CSF.

Macrolides, azalides, and streptogrammins.

AIDS: The Third International Conference on the Macrolides, Azalides, and Streptogramins was held in Lisbon, Portugal. Conferees were given news on the latest advances in the development of innovative antibiotics belonging to these increasingly important groups of drugs, and learned of their expanding clinical indications. The following areas were emphasized at the conference: multiresistant gram-positive bacteremias in patients with serious underlying infections, azithromycin's effectiveness against acute community-acquired pneumonia, results of clarithromycin plus ethambutol in HIV-infected patients with MAC bacteremia, duodenal ulcers associated with Helicobacter pylori infections, and use of roxithromycin against AIDS-related cryptosporidium diarrhea.^ieng

Treatment of Mycobacterium avium complex infection: do the results of in vitro susceptibility tests predict therapeutic outcome in humans?

The ability of various in vitro methods of antibiotic susceptibility testing to predict therapeutic outcome in patients infected with Mycobacterium avium complex (MAC) was evaluated. Pretreatment bloodstream MAC isolates from 38 patients with AIDS, previously treated in a randomized fashion with either ethambutol, rifampin, or clofazimine, were tested by three conventional methods using broth or agar, as well as by cocultivation with macrophages. The results obtained with each method were compared with the quantitatively determined bacteriologic response to the administration of the single agent in humans. None of the conventional in vitro susceptibility methods was predictive of therapeutic outcome, while the results of cocultivation with macrophages were of moderate predictive value. The positive predictive value of a response in humans based on a response in macrophages (defined by > or = to 1.0 log reduction in baseline colony counts after 5 days of treatment) was 74%. The negative predictive value was 82%.

Clarithromycin prophylaxis against disseminated Mycobacterium avium complex in patients with AIDS.

AIDS: The author presents results of a study concerning clarithromycin prophylaxis against disseminated Mycobacterium avium complex (MAC) in 57 adult patients with AIDS. Forty patients received 500 mg of clarithromycin two times a day by mouth as prophylaxis against disseminated MAC; seventeen patients received no medication. Results show that none of the forty patients developed MAC, while eight of the seventeen patients in the control group did. Data suggest that clarithromycin is successful as a prophylaxis against disseminated MAC in patients with advanced AIDS, and that the 500 mg dosage is well tolerated and not associated with serious side effects.^ieng

The individual microbiologic effect of three antimycobacterial agents, clofazimine, ethambutol, and rifampin, on Mycobacterium avium complex bacteremia in patients with AIDS.

The individual antibacterial activities of clofazimine, ethambutol, and rifampin in the treatment of Mycobacterium avium complex bacteremia in patients with AIDS were determined. Sixty human immunodeficiency virus 1-infected patients who had at least one blood culture positive for M. avium complex were randomized to receive either clofazimine (200 mg), ethambutol (15 mg/kg), or rifampin (600 mg) once daily for 4 weeks. Only ethambutol resulted in a statistically significant reduction in the level of mycobacteremia. The median change in individual baseline colony counts was -0.60 log10 cfu/mL after 4 weeks of ethambutol (P = .046). In contrast, median changes in individual baseline colony counts were -0.2 log10 cfu/mL and +0.2 log10 cfu/mL for clofazimine and rifampin, respectively (both, P > .4). Ethambutol had greater antibacterial activity, as determined by changes in the level of mycobacteremia, than either rifampin or clofazimine, supporting its continued use in combination with other agents in the treatment of M. avium infection.

Control of the body burden of M. avium complex is associated with improved quality of life and prolonged survival of patients with AIDS: a prospective trial with rifabutin combined with isoniazid, clofazimine, ethambutol.

The objectives of this study were to assess whether culture conversion affects quality of life (QoL), survival and Mycobacterium avium complex (MAC)-associated morbidity in patients with AIDS. Data from an open, multicenter, noncomparative trial were analyzed to test the benefit of suppressing mycobacteria: measures of QoL, clinical outcomes and quality-adjusted survival are compared on occasion of culture-negative and positive assessments. The study was conducted at AIDS clinics in France, coordinated by the GETIM, with the participation of 51 AIDS patients with culture-proven Non-Tuberculous Mycobacteria (NTM) disease. Patients underwent a quadruple drug-regimen. The following parameters were investigated: (i) Culture conversion to a negative finding (= suppression) or on > 2 occasions, including each patient's last valid observation (= conversion); (ii) survival after treatment start; (iii) QoL by using the ECOG score, re-coded 0 to 4 for worst to best performance status; (iv) quality-adjusted survival. On treatment, > 1 negative culture was recorded for 69% of the evaluable patients, corresponding to 111 person-months of observation. Positive culture findings accounted for 42 person-months only. Patients' performance status (mean 1.8 at entry) worsened or improved according to whether culture was positive or negative (means 1.2 and 2.2; total scores 109 and 217 person-months, respectively). Similarly, MAC-attributable morbidity was significantly reduced when culture was negative. Mean survival was 195 days longer in treatment success patients. These analyses suggest that, in patients with NTM disease occurring as a late complication of AIDS, treatment was effective in improving clinical status and survival, and in suppressing bacterial growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Low serum levels of oral antimycobacterial agents in patients with disseminated Mycobacterium avium complex disease.

Twenty-seven human immunodeficiency virus-infected patients with disseminated Mycobacterium avium complex disease who were treated with oral antimycobacterial agents (clofazimine, ciprofloxacin, ethambutol, and rifampin) were studied to evaluate the usefulness of monitoring serum drug concentrations and testing in vitro susceptibility of M. avium complex (MAC) isolates. Twenty patients tolerated treatment with three or four antimycobacterial agents for at least 8 weeks; mycobacteremia was eradicated in 7 (35%). The in vitro susceptibilities of MAC isolates to antimycobacterial agents were similar for these 7 and for the 13 who did not respond to antimycobacterial treatment. Serum drug levels were below the expected range in 6 of the 7 whose mycobacteremia was cleared and in 9 of the 13 nonresponders (P = .41). These low serum concentrations of antimycobacterial drugs may be due to impaired drug absorption in patients with AIDS and disseminated MAC disease.

Clarithromycin. A review of its pharmacological properties and therapeutic use in Mycobacterium avium-intracellulare complex infection in patients with acquired immune deficiency syndrome.

Results from noncomparative and placebo-controlled studies demonstrate the efficacy of clarithromycin in the treatment of disseminated Mycobacterium avium-intracellulare complex (MAC) infection in patients with acquired immune deficiency syndrome (AIDS). Whether given alone or in combination with other antimycobacterial treatments, doses of 500 to 2000mg (typically 1000mg) administered twice daily are effective in controlling bacteraemia in these patients. Clarithromycin has also been shown to improve clinical symptoms of infection and may improve quality of life in AIDS patients with MAC infection. Clarithromycin is generally well tolerated when used in the doses typically required for the treatment of MAC infection (1000 or 2000 mg/day). Gastrointestinal disturbances are the most commonly occurring adverse events and occur most frequently at dosages of 4000 mg/day. Thus, clarithromycin, as monotherapy or in combination with other antimycobacterial agents, is well tolerated and effectively eradicates MAC from the blood in the short term in patients with AIDS: however, short term monotherapy may lead to bacterial resistance, underscoring the importance of long term treatment with a combination of antimycobacterial agents. While the optimal combination regimen to prevent the development of resistance to antimycobacterial agents. While the optimal combination regimen to prevent the development of resistance to antimycobacterial agents by MAC remains to be determined, clarithromycin will almost certainly be a valuable agent in any such combination.

Controversies in the management of Mycobacterium avium complex infection in AIDS patients.

OBJECTIVE: To update readers on the clinical management of infections secondary to Mycobacterium avium complex (MAC) in patients with AIDS. A general description of the organism, culture and susceptibility testing, and clinical manifestations of the disease is provided. Several aspects of the treatment of the disease, including an historical perspective, current approaches, and future research opportunities, are described. DATA SOURCES: Current medical literature, including abstracts presented at international meetings, is reviewed. References were identified through MEDLINE, Current Contents, and published meeting abstracts. STUDY SELECTION: Data regarding the epidemiology, clinical manifestations, culture and susceptibility testing, and treatment of MAC are cited. Specific attention is given to the management of patients with MAC infection. DATA EXTRACTION: Information contributing to the discussion of the topics selected by the author is reviewed. Data supporting and disputing specific conclusions are presented. DATA SYNTHESIS: Disseminated MAC infection is diagnosed antemortem in approximately 30 percent of patients with AIDS; postmortem rates of isolation exceed 50 percent. The incidence of MAC may increase as attempts at isolating the organism become more aggressive. The traditional approach to the isolation, susceptibility testing, and treatment of MAC has been derived from the management of Mycobacterium tuberculosis, with disappointing results. Newer radiometric in vitro methods of susceptibility testing appear to show more promise. Current mouse models of MAC are not true AIDS models; new CD4-deficient mouse models are being developed. Clinical mycobacteriologic and pharmacokinetic laboratory support have been underused, with treatment generally proceeding empirically. New agents that may contribute to the management of disseminated MAC infection include the macrolide derivatives clarithromycin and azithromycin. Research also continues with new rifamycins (including rifabutin) and fluoroquinolones (ciprofloxacin, sparfloxacin). Preliminary results suggest a central role for macrolides in the treatment of disseminated MAC; effective companion drugs are needed to prevent the rapid emergence of macrolide-resistant MAC. CONCLUSIONS: Treatment results for disseminated MAC infection remain poor. Therapy may be improved by selecting drugs on the basis of susceptibility data for each isolate, rather than by using empiric regimens based on susceptibility trends. Significant antimycobacterial drug malabsorption has been documented, and may contribute to poor outcomes. More-potent agents are needed to improve the clinical outcome in AIDS patients with MAC.

Randomized, placebo-controlled trial of rifampin, ethambutol, and ciprofloxacin for AIDS patients with disseminated Mycobacterium avium complex infection.

Patients with AIDS and disseminated Mycobacterium avium complex (MAC) infection received rifampin (600 mg) plus ethambutol (25 mg/kg) plus ciprofloxacin (750 mg) or matching placebos daily for 8 weeks. Patients were monitored every 2 weeks clinically and by quantitating MAC colony-forming units (cfu) per milliliter of blood. Analysis of baseline characteristics revealed no significant differences between groups. After 8 weeks, MAC cfu had decreased by > or = 1 log/mL in 4 of 9 treated patients versus 0 of 10 placebo recipients while increasing by > or = 1 log/mL in 1 and 7, respectively (P = .006). While the average combined clinical response score declined in both groups, it tended to decrease less in treated patients (P = .36). On the other hand, dose-limiting toxicity (primarily nausea and adverse drug interactions) occurred in 9 of 12 treatment versus 1 of 12 placebo patients (P = .005). Combined rifampin [corrected]-ethambutol-ciprofloxacin therapy for disseminated MAC infection had significant microbiologic efficacy with some evidence of clinical efficacy but was associated with drug intolerance.

Clarithromycin-ciprofloxacin-amikacin for therapy of Mycobacterium avium-Mycobacterium intracellulare bacteremia in patients with AIDS.

A combination of clarithromycin, ciprofloxacin, and amikacin for the treatment of Mycobacterium avium-Mycobacterium intracellulare bacteremia was evaluated in 12 AIDS patients. Mycobacteremia cleared in all patients by 2 to 8 weeks of treatment, and symptoms resolved. Four patients died; all had negative blood cultures until death, and disseminated M. avium-M. intracellulare complex infection was not considered the primary cause of death.

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice.

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDS-associated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracellulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracellulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDS-associated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in present study.

Survival of patients with acquired immune deficiency syndrome and disseminated Mycobacterium avium complex infection with and without antimycobacterial chemotherapy.

The contribution of disseminated Mycobacterium avium complex (DMAC) infection to the morbidity and mortality of patients with acquired immune deficiency syndrome (AIDS) is unclear. Previous studies that suggested the decreased survival of patients with AIDS and DMAC had incomplete information on patient immunologic status and follow-up. We studied patients with AIDS and DMAC and compared their survival with that of AIDS patients without DMAC but with other comparable risk factors for survival. Case and control subjects were similar in terms of CD4 cell count, prior AIDS status, history of antiretroviral therapy, history of Pneumocystis carinii prophylaxis, and year of diagnosis. A group of 39 patients with untreated DMAC had significantly shorter survival, mean of 5.6 +/- 1.1 months (median 4 months), than 39 matched patients with AIDS but without DMAC, mean 10.8 +/- 1.3 months (median 11 months, p less than 0.0001). The survival of 16 additional patients with DMAC who received antimycobacterial therapy, mean of 9.5 +/- 1.4 months (median 8 months), was not significantly shorter than that of an additional 16 matched control subjects, mean 11.7 +/- 1.9 months (median 11 months, p = 0.58). Patients with treated DMAC survived significantly longer than those with untreated DMAC (p less than 0.01). We conclude that untreated DMAC significantly shortens survival. Moreover, these results indicate that patients with DMAC who receive antimycobacterial therapy do not experience the shortened survival seen in untreated DMAC.

Successful treatment of acquired immunodeficiency syndrome-related Mycobacterium avium complex disease with a multiple drug regimen including amikacin.

Disease due to Mycobacterium avium complex (MAC) in patients with the acquired immunodeficiency syndrome (AIDS) typically occurs late in the course of AIDS and is usually disseminated with evidence of multiorgan involvement. Most patients are persistently bacteremic. Previously published studies have noted a poor response to antimycobacterial chemotherapy. We describe successful treatment of MAC disease in an AIDS patient with a multiple drug regimen, including amikacin, clofazimine, rifampin, ethambutol, and ciprofloxacin. This patient, whose presentation and MAC disease course distinctly differ from most published experience, remains clinically and microbiologically MAC-disease free 25 months after initiation of therapy. We describe four additional AIDS patients with MAC disease who had a favorable clinical and microbiological response to this regimen without developing serious adverse effects after periods ranging from 4 to 12 months. We suggest a prospective, controlled clinical trial using this regimen for treatment of MAC disease in patients with AIDS may be warranted.

Treatment of disseminated Mycobacterium avium complex infection in AIDS with amikacin, ethambutol, rifampin, and ciprofloxacin. California Collaborative Treatment Group.

OBJECTIVE: To determine the efficacy of combination drug therapy for disseminated Mycobacterium avium complex infection in patients with the acquired immunodeficiency syndrome (AIDS). DESIGN: Prospective, nonrandomized, before-after comparison. SETTING: Outpatient clinics at three university medical centers. PATIENTS: Seventeen patients with at least two consecutive blood cultures positive for M. avium complex who had not been previously treated with antituberculous medications. Fifteen of the seventeen patients completed at least 4 weeks of treatment. INTERVENTION: Patients received daily intravenous amikacin (7.5 mg/kg body weight) for the first 4 weeks plus the following oral medications for at least 12 weeks: ciprofloxacin, 750 mg twice daily; ethambutol, 1000 mg daily; and rifampin, 600 mg daily. MEASUREMENTS AND MAIN RESULTS: The baseline geometric mean colony count from blood cultures decreased from 537/mL to 14/mL (P less than 0.001) after 4 weeks of therapy. The microbiologic suppression was sustained while on treatment and was associated with a decrease in systemic symptoms related to M. avium complex infection. Premature withdrawal from treatment (less than 12 weeks) occurred in 7 of 17 patients. The commonest reasons for early withdrawal were gastrointestinal intolerance and hepatic toxicity. CONCLUSIONS: Mycobacterial load and systemic symptoms in patients with AIDS and disseminated M. avium complex infection can be effectively reduced by a regimen containing amikacin, ethambutol, rifampin, and ciprofloxacin.

Non-cryptosporidial diarrhoea in human immunodeficiency virus (HIV) infected patients.

Thirty of 81 consecutive HIV antibody positive patients referred with non-cryptosporidial diarrhoea had no potential infectious cause; most had AIDS related complex rather than the full blown syndrome. Opportunistic infections with cytomegalovirus (CMV), mycobacterium avium-intracellulare (MAI), and herpes simplex virus (HSV), which allowed a diagnosis of AIDS to be made, were found in 19 patients and were the presenting features of AIDS in five. Other potential pathogenic species included entamoeba, giardia, campylobacter, and salmonella (without septicaemia). Cytomegalovirus infection was often accompanied by abdominal pain. Severe weight loss (greater than 10 kg) at presentation was found in patients with CMV infection and MAI. Bloody diarrhoea was confined to the group with HSV procitis. Malignant causes of diarrhoea were rare. Two patients developed a squamous carcinoma of the anorectal margin and one a non-Hodgkin's lymphoma. In only two of 12 patients who had Kaposi's sarcoma was this considered as a cause of diarrhoea. Rigid sigmoidoscopy showed macroscopic abnormalities in over a third (32) of the 81 patients with non-cryptosporidial diarrhoea. Most commonly this was severe inflammation (17) or discrete ulceration (four) [three of whom had CMV colitis]. Kaposi's sarcoma was identified in 11 patients. Non-specific inflammation was seen histologically in 40 of the 60 patients with no sigmoidoscopic inflammatory changes. Barium enema only revealed an abnormality in a minority of the patients and a colonoscopy only revealed information additional to rigid sigmoidoscopy in two patients--one with CMV ulcers in the transverse colon and the other with evidence of Kaposi's sarcoma not seen in the rectum. Ten patients had a rectal biopsy examined by electron microscopy as no infective cause of diarrhoea was uncovered. In four of these microtubular structures which are commonly seen in viral infections were found and two had prelymphomatous changes and in one of these frank lymphoma has developed. We recommend multiple stool analysis, sigmoidoscopy and rectal biopsy as the initial investigations in these patients reserving tests of malabsorption, colonoscopy, and barium enema for the small number of more difficult cases.