In animal models, immunity to cryptococcal infection, as in many chronic fungal and bacterial infections, is associated with a granulomatous inflammatory response, intact cell-mediated immunity, and a Th1 pattern of cytokine release. To examine the correlates of human immunity to cryptococcal infection in vivo, we analyzed immune parameters at the site of infection over time and assessed the rate of clearance of infection by serial quantitative cerebrospinal fluid (CSF) fungal cultures in 62 patients in a trial of antifungal therapy for HIV-associated cryptococcal meningitis. CSF IL-6, IFN-γ, TNF-α, and IL-8 were significantly higher in survivors compared with nonsurvivors. There were negative correlations between log TNF-α, IFN-γ, and IL-6 levels and baseline cryptococcal CFU. Log IFN-γ, G-CSF, TNF-α, and IL-6 were correlated positively with the rate of fall in log CFU/ml CSF/day. In a linear regression model including antifungal treatment group, baseline CFU, and these cytokines, only treatment group and log IFN-γ remained independently associated with rate of clearance of infection. The results provide direct in vivo evidence for the importance of quantitative differences in IFN-γ secretion in human immune control of granulomatous infections, and increase the rationale for adjunctive IFN-γ in the treatment of refractory HIV-associated cryptococcosis.
In a randomized controlled trial of amphotericin B-based therapy for human immunodeficiency virus (HIV)-associated cryptococcal meningitis in Thailand, we also compared the mycological efficacy, toxicity, and pharmacokinetics of oral versus intravenous flucytosine at 100 mg/kg of body weight/day for the initial 2 weeks. Half of 32 patients assigned to the two arms containing flucytosine were randomized to oral and half to intravenous flucytosine. Early fungicidal activity was determined from serial quantitative cultures of cerebrospinal fluid (CSF), and toxicity was assessed by clinical and laboratory monitoring. Flucytosine and fluorouracil concentrations in plasma and CSF were measured by high-performance liquid chromatography. No significant bone marrow or hepatotoxicity was seen, there was no detectable difference in bone marrow toxicity between patients on intravenous and those on oral formulation, and no patients discontinued treatment. In patients receiving intravenous flucytosine, the median 24-h area under the concentration-time curve was significantly higher than in the oral group. Despite this difference, there was no difference in early fungicidal activity between patients on intravenous compared with patients on oral flucytosine. The results suggest that either formulation can be used safely at this dosage in a developing country setting, without drug concentration monitoring. The bioavailability of the oral formulation may be reduced in late-stage HIV-infected patients in Thailand. Concentrations of flucytosine with intravenous formulation at 100 mg/kg/day may be in excess of those required for maximal fungicidal activity.Flucytosine (5FC) in combination with amphotericin B (AMB) is standard therapy for cryptococcal meningitis in the United States and Europe. 5FC is taken up by fungal cells by cytosine permease and converted into fluorouracil (5FU) by fungal cytosine deaminase. Further metabolism of 5FU leads to the formation of 5-fluorouridine triphosphate, which is incorporated into fungal RNA, and 5-fluorodeoxyuridine monophosphate, an inhibitor of thymidylate synthetase. This results in inhibition of protein and DNA synthesis in the fungal cell (19).Side effects of 5FC include nausea, vomiting, diarrhea, bone marrow depression, and hepatotoxicity. The latter two are thought to be due to effects of 5FU. Human cells lack the enzyme cytosine deaminase and are unable to convert 5FC into 5FU. However, the human intestinal microflora has been shown to be capable of converting 5FC into 5FU in vitro (8, 10, 17), and 5FU, at concentrations known to be associated with bone marrow depression, has been measured in the plasma of patients treated with oral 5FC (6). If intestinal bacteria do play a role in conversion of 5FC to 5FU in patients, then oral administration of 5FC might be associated with increased 5FU concentrations and more side effects than intravenous (i.v.) administration of the drug. On the other hand, i.v. 5FC is more costly to administer in resource-poor settings and carries the added incon...
Melioidosis is an infectious disease with a propensity for relapse, despite prolonged antibiotic eradication therapy for 12 to 20 weeks. A pharmacokinetic (PK) simulation study was performed to determine the optimal dosing of cotrimoxazole ( Melioidosis, a serious human infectious disease caused by the gram-negative bacterium Burkholderia pseudomallei, is endemic in northern Australia and southeast Asia. The in-hospital mortality rate averages 20% in Australia and 40 to 50% in northeast Thailand. In survivors of acute disease, recurrence after apparent clinical response, despite appropriate antibiotic treatment, is reported at rates of between 13 and 23% (5, 9). Molecular typing has determined that the majority (75%) of recurrent disease is due to persistence and subsequent relapse of the original infecting strain, with 25% of cases being second infections (17). Current antibiotic recommendations are for an intensive intravenous phase (ceftazidime or a carbapenem) for 10 to 14 days followed by a prolonged eradication phase (trimethoprim-sulfamethoxazole [TMP-SMX], or cotrimoxazole, alone or in combination with doxycycline) (6).Dosing regimens for the eradication phase of treatment vary between countries. In Australia, a TMP-SMX dose of 320/ 1,600 mg (two double-strength tablets) every 12 h (q12h) is recommended. In Ubon Ratchathani, Thailand, a TMP-SMX dose of 160/800 mg (two single-strength tablets) q12h (with doxycycline) has been used previously. However, a new weightbased dosing protocol (for patients of Ͻ40 kg [body weight], 160/800 mg q12h; 40 to 60 kg, 240/1,200 mg q12h; and Ͼ60 kg, 320/1,600 mg q12h, plus doxycycline) is now used.TMP-SMX is a commonly used synergistic antibiotic combination that acts on successive enzymes in the bacterial folate synthesis pathway. The appropriate pharmacokinetic-pharmacodynamic (PK-PD) parameter has not been defined for TMP-SMX. Limited data from children with pneumococcal otitis media suggested that clinical efficacy correlates with the proportion of time when antibiotic concentrations exceed the MIC of the infecting organism (8).In this study, we performed time-kill studies to assess the likely PK-PD target and evaluated the TMP-SMX dosing regimens using a simulation model with Thai and Australian populations. MATERIALS AND METHODSTime-kill studies. We performed time-kill studies using three Thai clinical isolates (strains 4861a [MIC, 4 g/ml], 3126a [MIC, 1 g/ml], and 3131a [MIC, 0.25 g/ml]). These were identified as B. pseudomallei by the use of standard methods, and the MIC was determined by Etest. Time-kill studies were performed in duplicate in 30-ml bottles containing 10 ml of Mueller-Hinton broth (Oxoid, United Kingdom). A logarithmic-phase broth culture was diluted to give a starting inoculum of approximately 1 ϫ 10 6 CFU/ml. Bottles were then incubated in a rotary shaker at 37°C in air with various concentrations of TMP-SMX corresponding to the MIC, 4 times the MIC, 6 times the MIC, and 10 times the MIC. Antibiotic-free broth was included as a control. Viabili...
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