Ignatius W. Fong

Chlamydia Pneumoniae, Cytomegalovirus, and Herpes Simplex Virus in Atherosclerosis of the Carotid Artery

BACKGROUND Chlamydia pneumoniae and the herpes viruses cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) have been associated with human atherosclerosis in seroepidemiological and separate histopathological studies. We investigated the concurrent presence of these microorganisms in patients undergoing carotid endarterectomy. METHODS AND RESULTS Endarterectomy specimens from 76 patients with carotid artery stenosis were stained for C. pneumoniae, CMV, and HSV-1 particles with specific IgG monoclonal antibodies by the avidin-biotin-peroxidase method. IgG antibodies to CMV and C. pneumoniae were also measured in the serum. These were correlated with plaque morphology and the presence of the microorganisms in the atherosclerotic plaques. C. pneumoniae was detected in 54 (71%) (95% confidence interval [CI], 59.5% to 80.9%), CMV was detected in 27 (35.5%) (CI, 24.9% to 47.3%), and HSV-1 was detected in 8 (10.5%) (CI, 4.7% to 19.7%) versus none of 20 (0%) control normal carotid artery and aortic tissue (autopsy) specimens (CI, 0% to 16.8%) (P<.001 for CMV and C. pneumoniae). At least one microorganism was detected in 59 of the specimens (77.6%) (CI, 66.6% to 86.4%), with a single microorganism present only in 35 (46%), two microorganisms present in 18 (23.7%) (CI, 14.7% to 34.8%), and all three present in 6 (7.9%) (CI, 3.0% to 16.4%). Atherosclerotic plaques with thrombosis were more likely to have C. pneumoniae (80.4%) or CMV (57.8%) than were plaques without thrombosis (56.7% and 16.7%, respectively; P=.04 and .007). There was no correlation between the presence of CMV and C. pneumoniae in the atherosclerotic vessels and serum antibody titers. CONCLUSIONS C. pneumoniae and CMV are commonly detected in atherosclerotic plaques of the carotid arteries, but their presence cannot be predicted by measuring serum antibodies. The presence of these microorganisms may predispose to a greater risk of thrombosis in the plaques, but further studies are needed to confirm this observation.

Multicenter randomized trial of fluconazole versus amphotericin B for treatment of candidemia in non-neutropenic patients

A randomized trial was conducted to compare the efficacy and safety of fluconazole versus that of amphotericin B in the treatment of candidemia in non-neutropenic adults. Enrollment was stratified by disease severity (APACHE II score). Patients were randomized (1∶:1) to receive amphotericin B 0.6 mg/kg/day (cumulative dose 8 mg/kg) or fluconazole 800 mg intravenous loading dose, then 400 mg daily for four weeks (intravenous for at least 10 days). Patients were monitored for six months. A total of 106 patients were enrolled. A protocol amendment implemented midway through the trial required patients to be removed from the study and treated with amphotericin B if species identification indicated candidemia due toCandida glabrata orCandida krusei. Baseline characteristics were similar for the two groups; 103 patients (fluconazole, 50; amphotericin B, 53) met the major enrollment criteria. The intention-to-treat analysis indicated successful therapy in 50% of fluconazole recipients compared to 58% of the amphotericin B group (p=0.39; one-sided 95% Cl, −8 to 24%). The efficacy analysis included 84 patients (fluconazole, 42; amphotericin B, 42); successful outcomes were observed in 57% and 62% of cases in the fluconazole and amphotericin B groups, respectively (p=0.66: one-sided 95% Cl, −12 to 22%). The mortality at day 14 for the fluconazole group was 26% and for the amphotericin B group 21% (p=0.52; chi-square test) and remained similar throughout the course of follow-up. Drug-related adverse events were more frequent with amphotericin B than with fluconazole and prompted switching of therapy for two (4%) and zero cases, respectively. Fluconazole and amphotericin B were associated with similar clinical response rates and survival in the treatment of candidemia among non-neutropenic patients; however, drug-related adverse events were more frequent with amphotericin B.

Effects of an acidic beverage (Coca-Cola) on absorption of ketoconazole.

Absorption of ketoconazole is impaired in patients with achlorhydria. The purpose of this study was to determine the effectiveness of a palatable acidic beverage (Coca-Cola Classic, pH 2.5) in improving the absorption of ketoconazole in the presence of drug-induced achlorhydria. A prospective, randomized, three-way crossover design with a 1-week wash-out period between each treatment was employed. Nine healthy nonsmoking, nonobese volunteers between 22 and 41 years old were studied. Each subject was randomized to receive three treatments: (A) ketoconazole 200-mg tablet with water (control), (B) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with water, and (C) omeprazole (60 mg) followed by ketoconazole (200 mg) taken with 240 ml of Coca-Cola Classic. The pH values of gastric aspirates were checked after omeprazole was administered to confirm attainment of a pH of > 6. Multiple serum samples were obtained for measurements of ketoconazole concentrations by high-pressure liquid chromatography. The mean area under the ketoconazole concentration-time curve from zero to infinity for the control treatment (17.9 +/- 13.1 mg.h/liter) was significantly greater than that for treatment B (3.5 +/- 5.1 mg.h/liter; 16.6% +/- 15.0% of control). The mean peak concentration was highest for the control treatment (4.1 +/- 1.9 micrograms/ml), for which the mean peak concentration showed a significant increase over that for treatment B. The absorption of ketoconazole was reduced in the presence of omeprazole-induced achlorhydria. However, drug absorption was significantly increased, to approximately 65% of the mean for the control treatment, when the drug was taken with an acidic beverage, such as Coca-Cola.

Aerosol Pentamidine for Secondary Prophylaxis of AIDS-related Pneumocystis carinii Pneumonia: A Randomized, Placebo-Controlled Study

OBJECTIVE To assess the safety and efficacy of aerosol pentamidine for secondary prophylaxis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome (AIDS). PARTICIPANTS Patients recovering from a first confirmed episode of AIDS-related P. carinii pneumonia who had no evidence of either another active AIDS-defining opportunistic infection or another pulmonary abnormality were considered eligible for the study but were included only if they had received no immunomodulators or antiretroviral agents other than zidovudine within 30 days of entry. One hundred sixty-two patients were randomized and started on the study drug. INTERVENTION Patients were randomly assigned to receive aerosol pentamidine, 60 mg per dose, or placebo, delivered using a hand-held, patient-triggered, ultrasonic nebulizer. The induction phase of treatment consisted of 5 doses over 14 days, followed by a maintenance phase beginning on day 21 and consisting of one dose every 2 weeks. RESULTS Thirty-two cases of P. carinii pneumonia were diagnosed before the termination of the trial; 27 cases occurred among 78 patients receiving placebo and 5 occurred among 84 patients receiving aerosol pentamidine. Estimates of the cumulative relapse rate of P. carinii pneumonia by 24 weeks were 50% and 9% for the placebo and pentamidine groups, respectively (P less than 0.001). Adverse reactions attributed to the study drug occurred in 15 of 78 patients receiving placebo and in 28 of 84 patients receiving pentamidine (P = 0.04). These were all mild or moderate in severity and did not preclude continued administration of the study drug. CONCLUSION Intermittent therapy with aerosol pentamidine is highly effective and well tolerated as secondary prophylaxis for AIDS-related P. carinii pneumonia.

Ciprofloxacin concentrations in bone and muscle after oral dosing.

Ciprofloxacin, a quinoline derivative with marked gram-negative and staphylococcal activity, may be a valuable orally administered agent for use against soft-tissue and bone infections. The concentrations of this antibiotic in serum, bone, and muscle samples were determined in patients undergoing orthopedic surgery. A total of 18 patients undergoing hip or knee replacement surgery or osteotomy were randomized to receive single oral doses of ciprofloxacin (500 mg, 750 mg, or 1 g); 10 patients with osteomyelitis were given single doses of 500 or 750 mg. Mean levels in bone of more than 1 microgram/g were achieved with the 750-mg ciprofloxacin doses in patients with osteomyelitis (1.4 +/- 1 microgram/g) or with the 1-g doses in patients without infections (1.6 +/- 0.6 microgram/g). The levels in muscle were significantly higher with each increasing dose level. Orally administered ciprofloxacin (750 mg given every 12 h) should provide adequate concentrations in bones and soft tissues to treat most osteomyelitis and soft-tissue infections.

Relative Inactivation by Staphylococcus aureus of Eight Cephalosporin Antibiotics

These studies extend the recent observation that cefazolin is inactivated to a greater extent than cephaloridine by some strains of penicillinase-producing Staphylococcus aureus, whereas cephalothin undergoes little if any inactivation. In Mueller-Hinton broth (inoculum, 3 × 106) 100 recently isolated strains had minimal inhibitory concentrations (MICs) ≤ 2 μg/ml for cephalothin and cephaloridine, whereas in Trypticase soy broth (TSB) 50% had MICs > 2 μg/ml and 10% (designated “resistant” strains) were >8 μg/ml for cephaloridine but remained ≤2 μg/ml for cephalothin. A large inoculum (3 × 107) of strains with high MICs in TSB almost completely inactivated 50 μg of cefazolin per ml in 6 h, with progressively less inactivation, in the following order, of cephaloridine, cephalexin, cephradine, cephapirin, and cefamandole; cefoxitin and cephalothin underwent little if any inactivation. The greater inactivation in TSB than in Mueller-Hinton broth appeared to be due to a greater production of β-lactamases by each colony-forming unit, since the inoculum size in the two broths was not significantly different. In contrast, “susceptible” strains (MICs ≤ 2 μg/ml in both broths) inactivated cephaloridine more than cefazolin, and equal amounts of powdered bacterial extracts confirmed the fact that qualitatively different β-lactamases were produced by the susceptible and resistant strains. Disk diffusion tests were unreliable in separating the two groups of staphylococci. The clinical significance of inactivation by strains with high MICs is not known but, unless susceptibility can be clearly established, cephalothin appears preferable for severe staphylococcal infections, since it undergoes little if any inactivation by any strains of staphylococci.

Disseminated fungal infection in a renal transplant recipient involving Macrophomina phaseolina and Scytalidium dimidiatum: case report and review of taxonomic changes among medically important members of the Botryosphaeriaceae

We report the first case of human infection with the fungal plant pathogen Macrophomina phaseolina in a Sri Lankan-born Canadian man following a renal transplant in India. The patient subsequently succumbed to invasive infection with Scytalidium dimidiatum. Molecular sequence analysis confirmed the identification of both fungi and revealed that they are related species within the ascomycete family Botryosphaeriaceae. We review the rationale for the recent reclassification of S. dimidiatum as Neoscytalidium dimidiatum and of Nattrassia mangiferae (formerly considered a synanamorph of S. dimidiatum) as Neofusicoccum mangiferae. This and other recent cases illustrate the potential for plant pathogenic fungi to cause invasive human diseases which are refractory to antifungal therapy.

Clinical Pharmacology of Cefamandole as Compared with Cephalothin

We compared the pharmacology of cefamandole and cephalothin in six healthy adult male volunteers. After a 1-g, 20-min intravenous (i.v.) infusion, the average peak blood level of cefamandole was 87.6 versus 64.1 μg/ml for cephalothin. An i.v. infusion of 500 mg/h for 2 h (after a loading dose of 750 mg) gave an average steady-state blood level of 28.5 μg/ml for cefamandole and 18.2 μg/ml for cephalothin. Mean peak serum levels after 1 g intramuscularly were similar for the two antibiotics (about 21 μg/ml), but with cefamandole they persisted longer, and the area under the blood level curve was about 25% greater. The average t½ as determined from both i.v. studies was 34 min for cefamandole versus 30 min for cephalothin. The mean serum clearance for cephalothin, due to its partial conversion to a metabolite, was much greater than for cefamandole (425 versus 272 ml/min per 1.73 m2), but the renal clearances were similar for the two antibiotics (268 versus 257 ml/min per 1.73 m2). Other values for cefamandole and cephalothin were: 24-h urinary excretion, 80 and 66%; serum protein binding, 74 and 70%; and apparent volume of distribution, 12.8 and 18.5 liters/1.73 m2, respectively. Thus, the pharmacology of the two antibiotics was similar. Blood levels were somewhat higher with cefamandole i.v., but the results suggest that dosage regimens should be the same for the two antibiotics.

Value of Long-Term Administration of Acyclovir and Similar Agents for Protecting Against AIDS-Related Lymphoma: Case-Control and Historical Cohort Studies

Acyclovir or similar agents with activity against Epstein-Barr virus (EBV) theoretically may prevent non-Hodgkins lymphoma (NHL) in AIDS. A case-control study of 29 patients with AIDS-related NHL and 58 matched control subjects assessed the frequency with which daily acyclovir (>/=800 mg/d) or similar agents were used for > or =1 year. In a historical cohort of 304 patients with AIDS for > or =2 years, the prevalence of NHL was assessed among 3 groups of patients: those who received long-term treatment with high-dose acyclovir (or similar agents) or low-dose or intermittent acyclovir; those treated with ganciclovir/foscarnet for <1 year; and those who had not previously been treated with acyclovir, ganciclovir, or foscarnet. In the case-control study, 22 patients (72.4%) with NHL never received acyclovir or similar drugs versus 19 control subjects (32.8%; P=. 002); 2 patients (6.9%) with NHL received acyclovir (> or =800 mg/d) for > or =1 year versus 27 (46.6%) of control subjects (P=.0001). In the cohort study, 6 (6.8%) of 88 patients who received acyclovir (> or =800 mg/d) for > or =1 year developed NHL versus 15 (15.5%) of 97 patients who received intermittent or lower-dose acyclovir and 30 (25.2%) of 119 patients who never received these agents (P=.002). Long-term administration (>1 year) of high-dose acyclovir or similar agents with anti-EBV activity may prevent NHL in patients with AIDS. A prospective, randomized study is warranted to confirm these results.

Infection of arterio-venous fistulas created for chronic haemodialysis

One of the complications of chronic haemodialysis is infection at the venous access site. A retrospective chart review (1985-1990) was done on patients requiring venoaccess for haemodialysis. 197 patients had 254 arterio-venous (A-V) fistulas created. 40 patients had 71 prosthetic implants and 157 patients had 183 autogenous fistulas created. 16 (22%) prosthetic grafts were infected versus 8 (4.3%) autogenous fistulas (p < 0.0001). Bacteraemia was present in 9/16 (56%) infected prosthetic grafts and 4/8 (50%) infected autogenous fistulas. Seven (43.8%) of the prosthetic grafts required removal; 6 (37.5%) were cured with drainage, irrigation and antibiotics, and 3 (18.8%) with antibiotics alone. One (12.5%) of the autogenous fistulas was removed, 4 (50%) required revision and 3 (37.5%) were treated with antibiotics alone. Whenever possible, A-V fistulas should be created in the arms with an autogenous graft as infections are less and easier to treat.