Tawanda Gumbo

Pharmacokinetics-Pharmacodynamics of Antimicrobial Therapy: It's Not Just for Mice Anymore

Since the advent of the modern era of antimicrobial chemotherapy in the 1930s, animal infection models have allowed for the in vivo evaluation of antimicrobial agents for the treatment of experimentally induced infection. Today, animal pharmacokinetic-pharmacodynamic (PK-PD) infection models serve as a cornerstone of the preclinical assessment process for antibacterial agents and dose and dosing interval selection, as decision support for setting in vitro susceptibility breakpoints, and, finally, for the evaluation of the meaning of in vitro resistance. Over the past 15 years, considerable PK-PD data have been derived from infected patients for many classes of antimicrobial agents. These data provide the opportunity to confirm knowledge gained from animal PK-PD infection models.

Concentration-Dependent Mycobacterium tuberculosis Killing and Prevention of Resistance by Rifampin

ABSTRACT Rifampin is a cornerstone of modern antituberculosis therapy. However, rifampins half-life of 3 h is believed to limit its utility for intermittent therapy, so new congeners with long half-lives are being developed. Using an in vitro pharmacokinetic-pharmacodynamic model of tuberculosis, we examined the relationships between rifampin exposure, microbial killing of log-phase-growth Mycobacterium tuberculosis, and suppression of resistance. Rifampins microbial killing was linked to the area under the concentration-time curve-to-MIC ratio. The suppression of resistance was associated with the free peak concentration (Cmax)-to-MIC ratio and not the duration that the rifampin concentration was above MIC. Rifampin prevented resistance to itself at a free Cmax/MIC ratio of ≥175. The postantibiotic effect duration was ≥5.2 days and was most closely related to the Cmax/MIC ratio (r2 = 0.96). To explain rifampins concentration-dependent effect, we examined the kinetics of rifampin entry into M. tuberculosis. Rifampin achieved concentration-dependent intracellular steady-state concentrations within 15 min. Our results suggest that doses of rifampin higher than those currently employed would optimize the effect of rifampin, if patients could tolerate them. Another major implication is that in the design of new rifampin congeners for intermittent therapy, the important properties may include (i) the efficient entry of the rifamycin into M. tuberculosis, (ii) the achievement of a free Cmax/MIC of >175 that can be tolerated by patients, and (iii) a long postantibiotic effect duration.

Pharmacokinetics-Pharmacodynamics of Pyrazinamide in a Novel In Vitro Model of Tuberculosis for Sterilizing Effect: a Paradigm for Faster Assessment of New Antituberculosis Drugs

ABSTRACT There are currently renewed efforts to develop drugs that could shorten the duration of antituberculosis therapy. This is best achieved by optimizing the sterilizing effect. However, the current pathway for the development of new molecules with the potential to have a sterilizing effect is inefficient. We designed an in vitro pharmacokinetic-pharmacodynamic model in which Mycobacterium tuberculosis replicating slowly at pH 5.8 was exposed to pyrazinamide by use of the concentration-time profiles encountered in patients. The sterilizing effect rates and the time to the emergence of drug resistance were examined. Daily pyrazinamide dosing for 28 days accurately achieved (i) the pyrazinamide pharmacokinetic parameters, (ii) the lack of early bactericidal activity, (iii) a sterilizing effect rate of 0.10 log10 CFU/ml per day starting on day 6 of therapy, and (iv) a time to the emergence of resistance of the from 2 to 3 weeks of monotherapy encountered in patients with tuberculosis. Next, dose-scheduling studies were performed. The sterilizing effect was linked to the pyrazinamide ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC (r2 = 0.80 to 0.90), with 90% of the maximal effect being achieved by an AUC0-24/MIC of 209.08. Resistance suppression was associated with the percentage of time that the concentration persisted above the MIC (r2 = 0.73 to 0.91). Monte Carlo simulations of 10,000 patients demonstrated that the currently recommended pyrazinamide doses (15 to 30 mg/kg of body weight/day) achieved the AUC0-24/MIC of 209.08 in the epithelial lining fluid of only 15.1 to 53.3% of patients. Doses of >60 mg/kg per day performed better. Our vitro model for the sterilizing effect, together with Monte Carlo simulations, can be used for the faster identification of the clinical doses that are needed to achieve a sterilizing effect and that can then be studied in clinical trials.

Isoniazid Bactericidal Activity and Resistance Emergence: Integrating Pharmacodynamics and Pharmacogenomics To Predict Efficacy in Different Ethnic Populations

ABSTRACT Isoniazid, administered as part of combination antituberculosis therapy, is responsible for most of the early bactericidal activity (EBA) of the regimen. However, the emergence of Mycobacterium tuberculosis resistance to isoniazid is a major problem. We examined the relationship between isoniazid exposure and M. tuberculosis microbial kill, as well as the emergence of resistance, in our in vitro pharmacodynamic model of tuberculosis. Since single-nucleotide polymorphisms of the N-acetyltransferase-2 gene lead to two different clearances of isoniazid from serum in patients, we simulated the isoniazid concentration-time profiles encountered in both slow and fast acetylators. Both microbial kill and the emergence of resistance during monotherapy were associated with the ratio of the area under the isoniazid concentration-time curve from 0 to 24 h (AUC0-24) to the isoniazid MIC. The time in mutant selection window hypothesis was rejected. Next, we utilized the in vitro relationship between the isoniazid AUC0-24/MIC ratio and microbial kill, the distributions of isoniazid clearance in populations with different percentages of slow and fast acetylators, and the distribution of isoniazid MICs for isonazid-susceptible M. tuberculosis clinical isolates in Monte Carlo simulations to calculate the EBA expected for ∼10,000 patients treated with 300 mg of isoniazid. For those patient populations in which the proportion of fast acetylators and the isoniazid MICs were high, the average EBA of the standard dose was ∼0.3 log10 CFU/ml/day and was thus suboptimal. Our approach, which utilizes preclinical pharmacodynamics and the genetically determined multimodal distributions of serum clearances, is a preclinical tool that may be able to predict the EBAs of various doses of new antituberculosis drugs.

Once-Weekly Micafungin Therapy Is as Effective as Daily Therapy for Disseminated Candidiasis in Mice with Persistent Neutropenia

ABSTRACT The effect of micafungin dose scheduling on the treatment of candidemia is unknown. Neutropenic mice with disseminated Candida glabrata infection were treated with single intraperitoneal micafungin doses of 0 to 100 mg/kg of body weight and sacrificed 7 days later. The maximal decline in kidney fungal burden was 5.8 log10 CFU/g. A 1-week pharmacokinetic-pharmacodynamic study revealed a micafungin serum half-life of 6.13 h. In mice treated with ≥50 mg/kg, there was maximal fungal decline without regrowth during the 1-week dosing interval. Next, doses associated with 34% (34% effective dose [ED34]) and 50% (ED50) of maximal kill were administered at one of three dose schedules: a single dose at t = 0, two equal doses at t = 0 and t = 3.5 days, and 7 equal doses daily. Some mice received a single dose of 100 mg/kg. Fungal burden was examined on days 1, 5, and 7. In mice treated with the ED34, microbial kill with the daily therapy initially lagged behind the intermittent doses but exceeded it by day 7. In mice treated with the ED50, daily and intermittent doses had equivalent day 7 effects. In mice treated with 100 mg/kg, there was no regrowth. The relative likelihoods that the area under the concentration-time curve/MIC ratio was linked to microbial kill versus peak concentration/MIC ratio or time above the MIC was 10.3 and 10,161.2, respectively. In all the experiments, no paradoxical increase in fungal burden was observed with high micafungin doses. However, only a single Candida isolate was tested. Regimens that simulated micafungin concentration-time profiles in patients treated with a single micafungin dose of 1,400 mg once a week demonstrated maximal fungal decline. Once-weekly micafungin therapy is as efficacious as daily therapy in a murine model of disseminated candidiasis.

Candida glabrata fungemia. Clinical features of 139 patients

Candida species are now the fourth leading cause of nosocomial bloodstream infection in hospitalized patients, and non-Candida albicans species now surpass Candida albicans. The clinical features of the most common non-Candida albicans species, Candida (Torulopsis) glabrata, have not been well studied. We retrospectively reviewed the clinical features of 139 patients with C. glabrata blood-stream infection over a period of 7 years. The mean age of patients was 62 years, and the most common admitting diagnoses were malignancy (28%) and coronary artery disease (18%). The most common identified portals of entry were abdominal (22%) and intravascular catheters (16%). At the time of fungemia, 63% of patients had fever, 45% had change in mental status, and 30% were in septic shock. Three of 50 patients examined by an ophthalmologist had chorioretinitis. The overall hospital mortality was 49%. Factors associated with increased mortality in a regression model were prior abdominal surgery (odds ratio [OR] = 2.8; 95% confidence interval [CI] = 1.2-6.3, p = 0.01), and an elevated creatinine (OR = 2.2; 95% CI = 1.0-4.7, p = 0.05). When early deaths (< or = 72 hours) were censored, amphotericin B treatment and total dose were associated with reduced mortality (OR = 0.2; 95% CI = 0.1-0.4, p < 0.001). Nosocomial C. glabrata fungemia is not just a disease of debilitated and neutropenic patients, but affects a wide variety of patients and is associated with a high mortality.

New Susceptibility Breakpoints for First-Line Antituberculosis Drugs Based on Antimicrobial Pharmacokinetic/Pharmacodynamic Science and Population Pharmacokinetic Variability

ABSTRACT Arguably, one of the most common and consequential laboratory tests performed in the world is Mycobacterium tuberculosis susceptibility testing. M. tuberculosis resistance is defined by growth of ≥1% of a bacillary inoculum on the critical concentration of an antibiotic. The critical concentration was chosen based on inhibition of ≥95% of wild-type isolates. The critical concentration of isoniazid is either 0.2 or 1.0 mg/liter, that of rifampin is 1.0 mg/liter, that of pyrazinamide is 100 mg/liter, that of ethambutol is 5.0 mg/liter, and that of fluoroquinolones is 1.0 mg/liter. However, the relevance of these concentrations to microbiologic and clinical outcomes is unclear. Critical concentrations were identified using the ability to achieve the antibiotic area under the concentration-time curve/MIC ratio associated with ≥90% of maximal kill (EC90) of M. tuberculosis in ≥90% of patients. Population pharmacokinetic parameters and their variability encountered in tuberculosis patients were utilized in Monte Carlo simulations to determine the probability that particular daily doses of the drugs would achieve or exceed the EC90 in the epithelial lining fluid of 10,000 tuberculosis patients. Failure to achieve EC90 in ≥90% of patients at a particular MIC was defined as drug resistance. The critical concentrations of moxifloxacin and ethambutol remained unchanged, but a critical concentration of 50 mg/liter was identified for pyrazinamide, 0.0312 mg/liter and 0.125 mg/liter were defined for low- and high-level isoniazid resistance, respectively, and 0.0625 mg/liter was defined for rifampin. Thus, current critical concentrations of first-line antituberculosis drugs are overoptimistic and should be set lower. With the proposed breakpoints, the rates of multidrug-resistant tuberculosis could become 4-fold higher than currently assumed.

Microsporidia infection in transplant patients.

BACKGROUNDnMicrosporidia are the most common cause of chronic diarrhea in patients infected with human immunodeficiency virus. Patients who have undergone organ transplantation may also be infected. The precise immune defect and the clinical picture in transplant patients have not been studied.nnnMETHODSnWe report a case of microsporidia infection in a heart transplant patient and review three other cases reported in the literature.nnnRESULTSnInfection in three solid organ transplant patients occurred when the patients were receiving immunosuppressive therapy for rejection 1.5-3 years after transplantation. Patients had chronic diarrhea, vomiting, dyspepsia, and weight loss for 1 month to 3 years.nnnCONCLUSIONSnMicrosporidia may be the cause of chronic unexplained diarrhea and gastrointestinal disturbances in transplant patients. Defects in cell-mediated immunity probably play a role in maintaining the chronicity of this infection. Specific screening requests should be made to the microbiology laboratory when microsporidia infection is suspected.

Anidulafungin pharmacokinetics and microbial response in neutropenic mice with disseminated candidiasis.

ABSTRACT Candidemia is often fatal, especially in patients with persistent neutropenia. New therapies are needed. We performed 24-h pharmacodynamic studies to compare the efficacies of anidulafungin, fluconazole, and amphotericin B in neutropenic mice with disseminated candidiasis caused by one of three strains of Candida glabrata. Anidulafungin produced a maximal fungal kill (Emax) of 1.4 to 1.9 log10 CFU/g in kidneys and was not influenced by resistance to either fluconazole or amphotericin B. Fluconazole produced an Emax of 1.3 log10 CFU/g in mice infected with fluconazole-susceptible C. glabrata, but the Emax was 0 for mice infected with a C. glabrata strain that had a fluconazole MIC of ≥32 mg/liter. Amphotericin B achieved an Emax of 4.2 log10 CFU/g in mice infected with amphotericin B-susceptible C. glabrata, but the Emax was 0 for mice infected with a C. glabrata strain with an amphotericin B MIC of 2 mg/liter. In all instances, anidulafungins maximal microbial kill was superior to that of fluconazole. Next, we performed a 96-h anidulafungin pharmacokinetic-pharmacodynamic study. Anidulafungin exhibited delayed peak concentrations in kidneys compared to those in serum, after which the concentrations declined, with a serum terminal half-life of 21.6 (±4.6) h. This was accompanied by a persistent 96-h decrease in the kidney fungal burden after treatment with a single anidulafungin dose of ≥8 mg/kg of body weight. This pharmacokinetic-pharmacodynamic picture of anidulafungin persistence in tissues and the resultant persistent fungal decline should be exploited to improve the efficacy of anidulafungin therapy for candidemia.

Aspergillus valve endocarditis in patients without prior cardiac surgery.

Aspergillus native valve endocarditis in patients who have not had cardiac surgery is uncommon. We report 3 cases and review 58 other adult patients reported in the English-language literature. Sixty-seven percent of the patients had underlying immunosuppression. The clinical features were fever (74%), embolic episodes (69%), a new or changing heart murmur (41%), and sudden visual loss (13%). Patients with mural endocarditis were more often immunosuppressed, especially due to solid organ transplants, but had lower frequency of heart murmurs and embolic episodes. Echocardiography revealed a vegetation in 78% of all the cases in which it was performed. Examination and culture of biopsy material often helped to establish a diagnosis of Aspergillus infection. Twenty-five patients had an antemortem diagnosis. These patients received a mean cumulative amphotericin B dose of 27 mg/kg. Twenty percent (3/15) of patients who received combined surgical and medical therapy survived, compared to none of those who received medical therapy alone (p = 0.08). Patients who survived were not immunosuppressed. We conclude that native valve aspergillus infective endocarditis is uniformly fatal without surgical intervention and antifungal therapy.