Timothy Babinchak

A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole plus Placebo versus Fluconazole plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects

A randomized, blinded, multicenter trial was conducted to compare fluconazole (800 mg per day) plus placebo with fluconazole plus amphotericin B (AmB) deoxycholate (0.7 mg/kg per day, with the placebo/AmB component given only for the first 5-6 days) as therapy for candidemia due to species other than Candida krusei in adults without neutropenia. A total of 219 patients met criteria for a modified intent-to-treat analysis. The groups were similar except that those who were treated with fluconazole plus placebo had a higher mean (+/- standard error) Acute Physiology and Chronic Health Evaluation II score (16.8+/-0.6 vs. 15.0+/-0.7; P=.039). Success rates on study day 30 by Kaplan-Meier time-to-failure analysis were 57% for fluconazole plus placebo and 69% for fluconazole plus AmB (P=.08). Overall success rates were 56% (60 of 107 patients) and 69% (77 of 112 patients; P=.043), respectively; the bloodstream infection failed to clear in 17% and 6% of subjects, respectively (P=.02). In nonneutropenic subjects, the combination of fluconazole plus AmB was not antagonistic compared with fluconazole alone, and the combination trended toward improved success and more-rapid clearance from the bloodstream.

Inflammatory Reactions in HIV-1–Infected Persons after Initiation of Highly Active Antiretroviral Therapy

Highly active antiretroviral therapy (HAART)combination antiretroviral therapy that has potent in vivo effects on HIV-1 replicationhas led to significant decreases in AIDS-associated morbidity and mortality (1). Although patients receiving HAART have reduced plasma HIV-1 viral load and increased CD4+ T-lymphocyte counts, they still develop AIDS-defining events, particularly in the first 2 months of treatment (2, 3). A delay in restoration of immune function may account for the development of opportunistic infections. It is possible, however, that HAART may actually promote the clinical expression and development of such infections, as well as AIDS-related malignant conditions and other noninfectious diseases. Several authors have recently reported cases that may represent progression of previously quiescent disorders to symptomatic diseases after initiation of HAART. We searched MEDLINE for studies of such cases, which some authors have referred to as immune restoration disorders (4-8). Bibliographies of relevant studies were also reviewed. In this paper, we summarize clinical presentations (Table 1) and potential mechanisms of these conditions and describe therapeutic methods (Table 2). Table 1. Clinical Presentation of Specific Opportunistic Infections in HIV-1Infected Patients with and without Highly Active Antiretroviral Therapy Table 2. Successful Treatments Used for Opportunistic Infections in HIV-1Infected Patients after Highly Active Antiretroviral Therapy For the cases reported in this review, HAART refers to the initiation of a regimen that involves nucleoside reverse transcriptase inhibitors with one or more protease inhibitors or the addition of a protease inhibitor to a regimen of nucleoside reverse transcriptase inhibitors. Similarly, the usual response to HAART in the following cases involves marked reductions in plasma HIV-1 RNA levels and increases in CD4+ T-lymphocyte counts. It should be noted, however, that degrees of response to HAART varied. Mycobacterium avium Complex Several case reports have discussed the development of Mycobacterium avium complex and other nontuberculous mycobacterial infections in patients receiving HAART (6, 9-16). Many affected patients presented with focal or diffuse lymphadenitis within 2 months of initiating HAART. Mycobacteremia was rarely demonstrated, but the lymph nodes (some of which were suppurative) were usually culture positive for M. avium complex. In a retrospective chart review, Phillips and colleagues (17) found that patients who developed M. avium complex lymphadenitis within 12 weeks of starting HAART had higher CD4+ T-lymphocyte counts, were more likely to develop a localized draining sinus, and were less likely to have weight loss and disseminated M. avium complex disease than patients who had been receiving HAART for more than 12 weeks. Of interest, a case of recurrent leprosy, in the tuberculoid form secondary to increased antiM. leprae immunity, has been reported in an HIV-1infected person after initiation of HAART (18). Uncommon presentations of M. avium complex, such as granulomatous masses, osteomyelitis, bursitis, Addison disease, and skin nodules, were also seen after HAART (6, 11). Of note, similar focal M. avium complex disease was noted as early as 1988 in patients receiving zidovudine monotherapy (19, 20). In the above cases, antimycobacterial therapy, corticosteroids, or local surgical drainage alone was successful, usually in conjunction with HAART. Mycobacterium tuberculosis Inflammatory reactions in HIV-1infected patients receiving antituberculous therapy and HAART have been well documented (21-27). Affected patients had pansensitive pulmonary or extrapulmonary tuberculosis and developed inflammatory reactions several weeks after initiation of HAART despite initial response to antituberculous therapy. Examples of such reactions included fever, worsening pulmonary infiltrates, lymphadenopathy, and in some cases intracranial tuberculomas. Cultures of sputum and lymph nodes usually did not reveal acid-fast bacilli. All patients improved when anti-inflammatory agents were added to HAART. A case of regional lymphadenitis secondary to CalmetteGurin bacillus has also been reported in an HIV-1infected child after initiation of antiretroviral therapy (16). Narita and coworkers (24) noted that HIV-1infected patients treated with antituberculous therapy and HAART had a higher incidence of paradoxical reactions (new fever; worsening or emergence of lymphadenopathy, pulmonary infiltrates, or pleural effusion; or worsening of other tuberculous lesions) than HIV-1infected patients not treated with HAART. Patients in the former group developed paradoxical reactions a mean of 11 to 15 days after initiation of HAART and had a larger decrease in plasma HIV-1 viral load than those in the latter group. Cytomegalovirus Both ocular and extraocular cytomegalovirus infections have been reported after HAART. One of the earliest reports described five HIV-1infected patients with no history of ocular disease who received a first diagnosis of cytomegalovirus retinitis after CD4+ T-lymphocyte counts increased from less than 0.085 109 cells/L to more than 0.195 109 cells/L with HAART (28). Similarly, cytomegalovirus viremia, colitis, pancreatitis, and submandibular inflammation have also been reported after HAART in patients with no history of cytomegalovirus infection (29). Other authors have described the development of vitritis in patients treated with HAART who previously had active or inactive cytomegalovirus retinitis (30-35). Patients with a history of unilateral cytomegalovirus retinitis developed vitritis in the same eye after HAART. In one patient with vitritis, anterior chamber paracentesis showed no evidence of cytomegalovirus by polymerase chain reaction or antibody titer and no evidence of other infectious agents. Most cases improved without evidence of relapse, regardless of therapy (topical medications, periocular injection of steroids, or anticytomegalovirus agents). Karavellas and colleagues (36) conducted a cohort study of 30 patients with cytomegalovirus retinitis who responded to HAART. Nineteen patients (63%) developed immune recovery vitritis after a median of 43 weeks. All affected patients reported floaters, and 17 of 19 had decreased visual acuity. All patients had inactive cytomegalovirus retinitis in the affected eye when vitritis was diagnosed. In a retrospective review by Jabs and coworkers (37), this disorder was observed in only 6 of 33 patients, perhaps because of previous therapy with ganciclovir implants for cytomegalovirus retinitis. Hepatitis C Virus Several patients with previously quiescent hepatitis C virus (HCV) infection developed acute hepatitis, cirrhosis, or an HCV-associated disorder, such as cryoglobulinemia, within 1 to 9 months after initiation of HAART (5, 38-41). Hepatitis C virus was implicated because HCV IgG antibody developed or plasma HCV RNA level increased after introduction of HAART, although this was not observed in all cases. Some patients improved with interferon- therapy; however, in other patients, protease inhibitor therapy had to be discontinued. The response of plasma HCV RNA to HAART in patients co-infected with HIV-1 has been evaluated (40, 42-46). One study found that mean plasma HCV RNA level initially increased 6 weeks after addition of HAART and later decreased to below baseline, with minimal changes in serum aminotransferase levels (42). Other studies, however, noted a moderate increase in plasma HCV RNA level after HAART, and liver biopsy showed associated lobular necrosis and inflammation in some patients (40, 43, 46). Hepatitis B Virus Some studies have attributed acute hepatitis in the setting of HAART to hepatitis B virus (HBV) (47-51). Affected patients had previous HBV infection and developed clinical hepatitis 5 to 12 weeks after beginning HAART. Most of these patients demonstrated newly detectable plasma HBV RNA or increased levels of HBV RNA during acute hepatitis. In some cases, serologic tests for HBV also showed active HBV infection. Researchers discontinued HAART in one patient (51), but most other patients improved without changes in therapy. Cryptococcus and Histoplasma Species A case report of Histoplasma capsulatum infection and a retrospective review of cryptococcal infection occurring after HAART have been described. Bottaro and coworkers (52) described a 35-year-old South American HIV-1infected man with a CD4+ T-lymphocyte count of 0.005 109 cells/L who received a diagnosis of disseminated histoplasmosis on the basis of blood culture results. Successful treatment with amphotericin B was followed by itraconazole therapy. Three weeks after initiation of HAART, the patients inguinal lymph node became enlarged; excisional biopsy revealed a granulomatous reaction and H. capsulatum by culture. The CD4+ T-lymphocyte count had increased to 0.066 109 cells/L. Itraconazole therapy and HAART were continued, and the patients symptoms improved. A retrospective review of all HIV-1infected patients with culture-proven cryptococcal meningitis between 1996 and 1999 identified three patients who developed cryptococcal meningitis in temporal association with initiation of HAART (53). Two patients developed clinical meningitis within 1 to 6 weeks after introduction of HAART. Studies of cerebrospinal fluid were remarkable for leukocytosis (leukocyte count 14 109 cells/L) and the presence of Cryptococcus neoformans by culture. A third patient developed recrudescence of previously suppressed C. neoformans meningitis, also marked by cerebrospinal fluid leukocytosis (leukocyte count, 100 109 cells/L) and an elevated cerebrospinal fluid C. neoformans antigen titer within 10 days of beginning HAART. Therapy was not changed in this patient, and meningeal signs and symptoms resolved over 2 weeks. Herpes Zoster Several studies have reported development of herpes zoster after HAART (8, 54, 55).

The Efficacy and Safety of Tigecycline for the Treatment of Complicated Intra-Abdominal Infections: Analysis of Pooled Clinical Trial Data

This pooled analysis includes 2 phase 3, double-blind trials designed to evaluate the safety and efficacy of tigecycline, versus that of imipenem-cilastatin, in 1642 adults with complicated intra-abdominal infections. Patients were randomized to receive either tigecycline (initial dose of 100 mg, followed by 50 mg intravenously every 12 h) or imipenem-cilastatin (500/500 mg intravenously every 6 h) for 5-14 days. The primary end point was the clinical response at the test-of-cure visit (12-42 days after therapy) in the co-primary end point microbiologically evaluable and microbiological modified intent-to-treat populations. For the microbiologically evaluable group, clinical cure rates were 86.1% (441/512) for tigecycline, versus 86.2% (442/513) for imipenem-cilastatin (95% confidence interval for the difference, -4.5% to 4.4%; P < .0001 for noninferiority). Clinical cure rates in the microbiological modified intent-to-treat population were 80.2% (506/631) for tigecycline, versus 81.5% (514/631) for imipenem-cilastatin (95% confidence interval for the difference, -5.8% to 3.2%; P < .0001 for noninferiority). Nausea (24.4% tigecycline, 19.0% imipenem-cilastatin [P = .01]), vomiting (19.2% tigecycline, 14.3% imipenem-cilastatin [P = .008]), and diarrhea (13.8% tigecycline, 13.2% imipenem-cilastatin [P = .719]) were the most frequently reported adverse events. This pooled analysis demonstrates that tigecycline was efficacious and well tolerated in the treatment of patients with complicated intra-abdominal infections.

Intensification and Stimulation Therapy for Human Immunodeficiency Virus Type 1 Reservoirs in Infected Persons Receiving Virally Suppressive Highly Active Antiretroviral Therapy

Highly active antiretroviral therapy (HAART) has led to significant changes in mortality and morbidity in the human immunodeficiency virus type 1 (HIV-1) epidemic. Nevertheless, because of molecular mechanisms of viral persistence, HAART does not eradicate HIV-1. Didanosine and hydroxyurea were added to the antiretroviral regimens of 3 HIV-1-infected men who were receiving stable HAART and who had HIV-1 RNA levels <50 copies/mL at the initiation of the study protocol, as a novel intensification to attack cryptic viral replication; low-dose OKT3 was then administered, followed by a course of interleukin-2, to stimulate latent provirus. Replication-competent virus was undetectable after treatment, and plasma viral RNA was either undetectable or <5 copies/mL. In trial periods during which no antiretroviral therapy was administered, the patients developed plasma viral rebound. This translational approach combines novel intensification and stimulation therapy to deplete residual HIV-1 reservoirs. Additional experimental approaches must be developed if HIV-1 eradication is to become possible in patients receiving virally suppressive HAART.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Skin and Skin-Structure Infections

ABSTRACT Exposure-response analyses were performed for the microbiological and clinical efficacy of tigecycline in the treatment of complicated skin and skin-structure infections, where Staphylococcus aureus and streptococci are the predominant pathogens. A prospective method was developed to create homogeneous patient populations for PK-PD analyses. Evaluable patients from three clinical trials were pooled for analysis. Patients received a tigecycline 100-mg loading dose/50 mg every 12 h or a 50-mg loading dose/25 mg every 12 h. At the test-of-cure visit, microbiologic and clinical responses were evaluated. Patients were prospectively evaluated and classified into cohorts based on baseline pathogens: S. aureus only (cohort 1), monomicrobial S. aureus or streptococci (cohort 2), two gram-positive pathogens (cohort 3), polymicrobial (cohort 4), or other monomicrobial infections (cohort 5). A prospective procedure for combining cohorts was used to increase the sample size. Logistic regression evaluated steady-state 24-h area under the concentration-time curve (AUC24)/MIC ratio as a predictor of response, and classification and regression tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with pooled cohorts 2 and 3, the focus of these analyses, and included 35 patients with 40 S. aureus and/or streptococcal pathogens. CART analyses identified a significant AUC/MIC breakpoint of 17.9 (P = 0.0001 for microbiological response and P = 0.0376 for clinical response). The continuous AUC/MIC ratio was predictive of microbiological response based on sample size (P = 0.0563). Analysis of all pathogens combined decreased the ability to detect exposure-response relationships. The prospective approach of creating homogeneous populations based on S. aureus and streptococci pathogens was critical for identifying exposure-response relationships.

Exposure-Response Analyses of Tigecycline Efficacy in Patients with Complicated Intra-Abdominal Infections

ABSTRACT Exposure-response analyses were performed to test the microbiological and clinical efficacies of tigecycline in complicated intra-abdominal infections where Escherichia coli and Bacteroides fragilis are the predominant pathogens. Data from evaluable patients enrolled in three clinical trials were pooled. Patients received intravenous tigecycline (100-mg loading dose followed by 50 mg every 12 h or 50-mg loading dose followed by 25 mg every 12 h). At the test-of-cure visit, microbiological and clinical responses were evaluated. Patients were prospectively classified into cohorts based on infection with a baseline pathogen(s): E. coli only (cohort 1), other mono- or polymicrobial Enterobacteriaceae (cohort 2), at least one Enterobacteriaceae pathogen plus an anaerobe(s) (cohort 3), at least one Enterobacteriaceae pathogen plus a gram-positive pathogen(s) (cohort 4), and all other pathogens (cohort 5). The cohorts were prospectively combined to increase sample size. Logistic regression was used to evaluate ratio of steady-state 24-hour area under the concentration-time curve (AUC) to MIC as a response predictor, and classification-and-regression-tree (CART) analyses were utilized to determine AUC/MIC breakpoints. Analysis began with cohorts 1, 2, and 3 pooled, which included 71 patients, with 106 pathogens. The small sample size precluded evaluation of cohorts 1 (34 patients, 35 E. coli pathogens) and 2 (16 patients, 24 Enterobacteriaceae). CART analyses identified a significant AUC/MIC breakpoint of 6.96 for microbiological and clinical responses (P values of 0.0004 and 0.399, respectively). The continuous AUC/MIC ratio was also borderline predictive of microbiological response (P = 0.0568). Cohort 4 (21 patients, 50 pathogens) was evaluated separately; however, an exposure-response relationship was not detected; cohort 5 (31 patients, 60 pathogens) was not evaluated. The prospective approach of creating homogenous populations of pathogens was critical for identifying exposure-response relationships in complicated intra-abdominal infections.

Treatment of Mycobacterium avium complex immune reconstitution disease in HIV-1-infected individuals.

Immune reconstitution disease caused by Mycobacterium avium complex (MAC) infection presenting shortly after the introduction of highly active antiretroviral therapy (HAART) has been reported with increasing frequency in persons with HIV-1 infection during the past several years. Several therapeutic modalities have been utilized for this entity, but the optimal means of treating MAC immune reconstitution disease remains unclear. We now describe a patient who underwent some of these therapies. We then review the therapeutic outcomes from the numerous case reports of this disorder. Finally, we propose recommendations and a clinical algorithm regarding the optimal means of treatment of MAC immune reconstitution disease during HIV-1 infection.

Use of a clinically derived exposure-response relationship to evaluate potential tigecycline-Enterobacteriaceae susceptibility breakpoints

Potential tigecycline-Enterobacteriaceae susceptibility breakpoints were evaluated using 2 approaches, which differed in the nature of the probabilities assessed by MIC value. Using a previously derived tigecycline population pharmacokinetic model and Monte Carlo simulation, a probability density function of steady-state area under the concentration-time curve for 24 h (AUC(SS(0-24))) values for 9999 patients was generated. AUC(SS(0-24)) values were divided by clinically relevant fixed MIC values to derive AUC(SS(0-24))/MIC ratios, which were used to calculate the clinical response expectation by MIC value based upon a logistic regression model for efficacy (1st approach). For the 2nd approach, the probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment was calculated as the proportion of patients with AUC(SS(0-24))/MIC ratios greater than the threshold value of 6.96, the PK-PD target associated with optimal clinical response. Probabilities of clinical response and PK-PD target attainment were poorly correlated at MIC values >0.25 mg/L. For instance, the median probability of clinical success was 0.76, whereas the probability of PK-PD target attainment was 0.27 at an MIC value of 1 mg/L, suggesting that the probability of PK-PD target attainment metrics underestimates the clinical performance of tigecycline at higher MIC values.

Impact of Different Factors on the Probability of Clinical Response in Tigecycline-Treated Patients with Intra-Abdominal Infections

ABSTRACT Patients with intra-abdominal infections differ with regard to the type of infection and the severity of illness. However, the impact of these factors, together with differences in drug exposure, on clinical response is not well understood. Using phase 2 and 3 data for patients with complicated intra-abdominal infections, the relative importance of tigecycline exposure, host factors, and disease factors, alone or in combination, for the probability of clinical response was examined. Patients with complicated intra-abdominal infections who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for 5 to 14 days and who had adequate clinical, pharmacokinetic, and response data were evaluated. Multivariable logistic regression was used to identify factors associated with clinical response. A final multivariable logistic regression model demonstrated six factors based on 123 patients to be predictive of clinical success: a weight of <94 kg (P = 0.026), the absence of Pseudomonas aeruginosa in baseline cultures (P = 0.021), an APACHE II score of <13 (P = 0.029), non-Hispanic race (P = 0.005), complicated appendicitis or cholecystitis (P = 0.004), and a ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) of ≥3.1 (P = 0.003). The average model-predicted probability of clinical success when one unfavorable factor was present was 0.940. This probability was lower (0.855) when the AUC/MIC ratio was <3.1 and the remaining five factors were set to the favorable condition. The average model-predicted probability of clinical success in the presence of two unfavorable factors was 0.594. These findings demonstrated the impact of individual and multiple factors on clinical response in the context of drug exposure.

Exposure–response analyses of tigecycline tolerability in healthy subjects☆

Tigecycline exposure (area under the concentration-time curve [AUC((0-infinity))] and maximum serum concentration [C(max)]) and first occurrence of nausea and vomiting were evaluated in 136 healthy subjects after 12.5- to 300-mg single doses. Nausea was more frequent in females (46%, 10/22) compared with males (31%, 11/36) after 100-mg doses. Most nausea (vomiting) events occurred < or =4 h (<6 h) after tigecycline. For doses < or =100 mg, the median duration of nausea and vomiting was approximately 5 h. Based on logistic regression, increased exposure (AUC((0-infinity)) >C(max)) to tigecycline results in an increased rate of nausea (P < or = .0001; = .0022) and vomiting (P < or = .0001; = .0006). At the median AUC((0-infinity)) (C(max)) for the 50-mg dose group, the probability of nausea and vomiting was 0.26 (0.29) and 0.07 (0.11), respectively. Model-predicted rates of nausea and vomiting were comparable with those observed for the tetracycline class of antibiotics, with tolerable rates predicted after 50-mg doses of tigecycline.