Tigecycline: an update.

Tigecycline is a broad-spectrum antibiotic with activity against difficult-to-treat pathogens such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., Acinetobacter baumannii, and Gram-negative bacterial strains that produce extended-spectrum ß-lactamases. Minimal organ toxicity and lack of dosage adjustment in most patients are important considerations for tigecycline use. Tigecycline has been shown to be as effective and safe as standard antimicrobial therapy for treatment of adults with complicated intra-abdominal infections, complicated skin and skin structure infections, and community-acquired bacterial pneumonia. The clearest applications of tigecycline are for on-label indications. Whether tigecycline should be utilized as therapy for other infections including hospital-acquired infections with a high likelihood of multidrug-resistant pathogens is a complex issue that requires ongoing assessment. This article offers an updated overview of tigecycline clinical studies, current microbial resistance patterns, pharmacokinetic/pharmacodynamic investigations, and safety analyses.

A randomized trial of tigecycline versus ampicillin-sulbactam or amoxicillin-clavulanate for the treatment of complicated skin and skin structure infections.

BACKGROUND: Complicated skin and skin structure infections (cSSSIs) frequently result in hospitalization with significant morbidity and mortality. METHODS: In this phase 3b/4 parallel, randomized, open-label, comparative study, 531 subjects with cSSSI received tigecycline (100 mg initial dose, then 50 mg intravenously every 12 hrs) or ampicillin-sulbactam 1.5-3 g IV every 6 hrs or amoxicillin-clavulanate 1.2 g IV every 6-8 hrs. Vancomycin could be added at the discretion of the investigator to the comparator arm if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed or suspected within 72 hrs of enrollment. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test-of-cure (TOC) visit. Microbiologic response and safety were also assessed. The modified intent-to-treat (mITT) population comprised 531 subjects (tigecycline, n = 268; comparator, n = 263) and 405 were clinically evaluable (tigecycline, n = 209; comparator, n = 196). RESULTS: In the CE population, 162/209 (77.5%) tigecycline-treated subjects and 152/196 (77.6%) comparator-treated subjects were clinically cured (difference 0.0; 95% confidence interval [CI]: -8.7, 8.6). The eradication rates at the subject level for the microbiologically evaluable (ME) population were 79.2% in the tigecycline treatment group and 76.8% in the comparator treatment group (difference 2.4; 95% CI: -9.6, 14.4) at the TOC assessment. Nausea, vomiting, and diarrhea rates were higher in the tigecycline group. CONCLUSIONS: Tigecycline was generally safe and effective in the treatment of cSSSIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00368537.

Switch therapy in hospitalized patients with community-acquired pneumonia: tigecycline vs. levofloxacin.

BACKGROUND: Switch therapy is a management approach combining early discontinuation of intravenous (IV) antibiotics, switch to oral antibiotics, and early hospital discharge. This analysis compares switch therapy using tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia (CAP). METHODS: A prospective, randomized, double-blind, Phase 3 clinical trial; patients were randomized to IV tigecycline (100 mg, then 50 mg q12h) or IV levofloxacin (500 mg q24h). Objective criteria were used to define time to switch therapy; patients were switched to oral levofloxacin after ≥6 IV doses if criteria met. Switch therapy outcomes were assessed within the clinically evaluable (CE) population. RESULTS: In the CE population, 138 patients were treated with IV tigecycline and 156 were treated with IV levofloxacin. The proportion of the population that met switch therapy criteria was 67.4% (93/138) for tigecycline and 66.7% (104/156) for levofloxacin. The proportion that actually switched to oral therapy was 89.9% (124/138) for tigecycline and 87.8% (137/156) for levofloxacin. Median time to actual switch therapy was 5.0 days each for tigecycline and levofloxacin. Clinical cure rates for patients who switched were 96.8% for tigecycline and 95.6% for levofloxacin. Corresponding cure rates for those that met switch criteria were 95.7% for tigecycline and 92.3% for levofloxacin. CONCLUSIONS: Switch therapy outcomes in hospitalized patients with CAP receiving initial IV therapy with tigecycline are comparable to those of patients receiving initial IV therapy with levofloxacin. These data support the use of IV tigecycline in hospitalized patients with CAP when the switch therapy approach is considered. CLINICALTRIALS.GOV IDENTIFIER: NCT00081575.

Epidemiology, microbiology, and treatment considerations for bacterial pneumonia complicating influenza.

Post-influenza bacterial pneumonia is a major cause of morbidity and mortality associated with both seasonal and pandemic influenza virus illness. However, despite much interest in influenza and its complications in recent years, good clinical trial data to inform clinicians in their assessment of treatment options are scant. This paucity of evidence needs to be addressed urgently in order to improve guidance on the management of post-influenza bacterial pneumonia. The objectives of the current article are to evaluate the emergence of the 2009 H1N1 influenza pandemic and use this information as background for an in-depth review of the epidemiology of bacterial pneumonia complicating influenza, to review the bacterial pathogens most likely to be associated with post-influenza bacterial pneumonia, and to discuss treatment considerations in these patients. When determining optimal management approaches, both antiviral and antibacterial agents should be considered, and their selection should be based upon a clear understanding of how their mechanisms of action intervene in the pathogenesis of post-influenza acute bacterial pneumonia.

Safety and efficacy of intravenous tigecycline in subjects with secondary bacteremia: pooled results from 8 phase III clinical trials.

BACKGROUND: Tigecycline is effective in the treatment of complicated skin/skin-structure infection (cSSSI), complicated intraabdominal infection (cIAI), and community-acquired bacterial pneumonia (CAP), but its efficacy in subjects with secondary bacteremia is unknown. METHODS: Pooled data from subjects enrolled for treatment of cSSSI, cIAI, or CAP presenting with bacteremia from 7 double-blind and 1 open-label trial of tigecycline compared with vancomycin-aztreonam, imipenem-cilastatin, levofloxacin, vancomycin, or linezolid were analyzed. The primary efficacy end point was the clinical cure rate at the test-of-cure assessment. RESULTS: A total of 170 subjects were identified (91 tigecycline recipients and 79 recipients of the comparator agent). Clinical cure rates were 81.3% and 78.5% for tigecycline and the comparator, respectively (P = .702). Analysis by sex, age, creatinine clearance, infection site, Acute Physiology and Chronic Health Evaluation score, and Fine score demonstrated no significant between-group differences. Clinical cure rates for the most commonly represented pathogens (Staphylococcus aureus, Streptococcus pneumoniae, and gram-negative species) were also not significantly different between treatment groups. No decrease in the rate of cure was found in organisms with increasing tigecycline minimum inhibitory concentrations. Nine subjects treated with tigecycline and 1 subject treated with comparator were found to have persistent bacteremia. No clinically significant differences in safety parameters were identified. CONCLUSIONS: Tigecycline was generally safe and well tolerated in the treatment of secondary bacteremia associated with cSSSI, cIAI, and CAP; cure rates were similar to comparative standard therapies.

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.

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.

Use of ribotyping to retrospectively identify methicillin-resistant Staphylococcus aureus isolates from phase 3 clinical trials for tigecycline that are genotypically related to community-associated isolates.

A retrospective study was performed to identify methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained from patients enrolled in phase 3 clinical trials for tigecycline that were genotypically similar to known community-associated MRSA (CA-MRSA) strains. The clinical trials were double-blind comparator studies for complicated skin and skin structure infections or complicated intra-abdominal infections. We obtained 85% of the MRSA isolates from patients with complicated skin and skin structure infections. Using ribotyping, MRSA isolates were compared with well-characterized North American CA-MRSA strains and negative-control hospital-associated (HA) MRSA strains by cluster analysis; 91 of the 173 isolates clustered with two groups of known CA-MRSA strains, 60% of which shared an indistinguishable ribotype. These isolates were subsequently tested for the presence of SCCmec type IV and the Panton-Valentine leukocidin (PVL)-encoding genes as well as susceptibility to clindamycin, characteristics that are typically associated with CA-MRSA; 89 of the 91 isolates carried the type IV SCCmec element and 76 were also positive for the PVL-encoding genes; 73 of these isolates were susceptible to clindamycin. A similar analysis performed on 26 nonclustering isolates identified only four with these characteristics; 89 of the 91 clustering isolates were inhibited by tigecycline at MICs of < or = 0.5 microg/ml. On the basis of clustering information and preliminary genetic characterization, it appears that ribotyping is a useful tool in identifying potential CA-MRSA isolates and 76 MRSA isolates from patients enrolled in the tigecycline phase 3 trials have genetic markers typically associated with CA-MRSA.

A multicenter trial of the efficacy and safety of tigecycline versus imipenem/cilastatin in patients with complicated intra-abdominal infections [Study ID Numbers: 3074A1-301-WW; ClinicalTrials.gov Identifier: NCT00081744].

BACKGROUND: Complicated intra-abdominal infections (cIAI) remain challenging to treat because of their polymicrobial etiology including multi-drug resistant bacteria. The efficacy and safety of tigecycline, an expanded broad-spectrum glycylcycline antibiotic, was compared with imipenem/cilastatin (IMI/CIS) in patients with cIAI. METHODS: A prospective, double-blind, multinational trial was conducted in which patients with cIAI randomly received intravenous (IV) tigecycline (100 mg initial dose, then 50 mg every 12 hours [q12h]) or IV IMI/CIS (500/500 mg q6h or adjusted for renal dysfunction) for 5 to14 days. Clinical response at the test-of-cure (TOC) visit (14-35 days after therapy) for microbiologically evaluable (ME) and microbiological modified intent-to-treat (m-mITT) populations were the co-primary efficacy endpoint populations. RESULTS: A total of 825 patients received >or= 1 dose of study drug. The primary diagnoses for the ME group were complicated appendicitis (59%), and intestinal (8.8%) and gastric/duodenal perforations (4.6%). For the ME group, clinical cure rates at TOC were 80.6% (199/247) for tigecycline versus 82.4% (210/255) for IMI/CIS (95% CI -8.4, 5.1 for non-inferiority tigecycline versus IMI/CIS). Corresponding clinical cure rates within the m-mITT population were 73.5% (227/309) for tigecycline versus 78.2% (244/312) for IMI/CIS (95% CI -11.0, 2.5). Nausea (31.0% tigecycline, 24.8% IMI/CIS [P = 0.052]), vomiting (25.7% tigecycline, 19.4% IMI/CIS [P = 0.037]), and diarrhea (21.3% tigecycline, 18.9% IMI/CIS [P = 0.435]) were the most frequently reported adverse events. CONCLUSION: This study demonstrates that tigecycline is as efficacious as imipenem/cilastatin in the treatment of patients with cIAI.

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.

Compact quadruple therapy with the lamivudine/zidovudine combination tablet plus abacavir and efavirenz, followed by the lamivudine/zidovudine/abacavir triple nucleoside tablet plus efavirenz in treatment-naïve HIV-infected adults.

PURPOSE: To assess efficacy, safety, and adherence with compact quadruple therapy comprising one lamivudine 150-mg/zidovudine 300-mg tablet (COM) twice daily + one abacavir (ABC) 300-mg tablet twice daily + three efavirenz (EFV) 200-mg capsules at bedtime for 24 weeks, followed by one lamivudine 150-mg/zidovudine 300-mg/ABC 300-mg triple nucleoside tablet (TZV) twice daily + three EFV 200-mg capsules at bedtime for 24 weeks. METHOD: A pilot 48-week, prospective, open-label trial in which 38 antiretroviral-naïve HIV-infected adults (baseline median HIV-1 RNA 5.1 log(10) copies/mL, CD4+ cell count 285/microL) received the above treatment and were monitored regularly with respect to plasma HIV-1 RNA levels, CD4+ cell counts, T-cell receptor excision circles (TRECs), adherence, and adverse events. RESULTS: At Week 48, intent-to-treat, switch-included analysis showed plasma HIV-1 RNA levels <400 copies/mL in 100% (29/29) of patients and <50 copies/mL in 93% (27/29); 59% of patients who achieved <50 copies/mL had <3 copies/mL (16/27). Similar virologic suppression was observed in patients with baseline HIV-1 RNA above or below 100000 copies/mL. HIV-1 RNA and CD4+ cell counts changed from baseline by a median of -3.4 log(10) copies/mL and +172 cells/microL, respectively. One virologic failure occurred at Week 16. Median TRECs/100000 peripheral blood lymphocytes increased 6-fold between baseline and Week 48. Median adherence rates were consistently 100% by self-report and 94% by pill count. Grade 2-4 treatment-related adverse events included dreams (16%), nausea (13%), decreased white cells (8%), dizziness (8%), sleep disorders (8%), and malaise and fatigue (8%). A suspected ABC hypersensitivity reaction occurred in 8% (3/38) of patients. CONCLUSION: COM/ABC/EFV or TZV/EFV produced potent, durable virologic suppression and immunologic benefits, was associated with high adherence rates, and was generally well tolerated.

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.

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.

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.