Burden of pneumococcal community-acquired pneumonia in adults across Europe: A literature review.

BACKGROUND: The burden of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (pneumococcus) among adults in Europe is poorly defined. METHODS: Structured searches of PubMed were conducted to identify the incidence of pneumococcal CAP among adults across Europe. RESULTS: The overall incidence rates for CAP was 68-7000 per 100,000 and the incidence in hospitalised CAP cases of all causes was 16-3581 per 100,000. In general the incidence of CAP increased consistently with age. Available data indicated higher burdens of pneumococcal CAP caused in groups with more comorbidities. Most cases of pneumococcal CAP (30%-78%) were caused by serotypes covered by PCV13 vaccine; the incidence of PCV13-related pneumonia decreased after the introduction of childhood vaccination. CONCLUSIONS: We observed a high burden adult pneumococcal CAP in Europe despite use of the 23-valent pneumococcal polysaccharide vaccine, particularly in elderly patients with comorbidities. CAP surveillance presented wide variations across Europe. Pneumococcal CAP has to be monitored very carefully due to the possible effect of current vaccination strategies.

Community-acquired pneumonia in adults: Highlighting missed opportunities for vaccination.

Pneumococcal pneumonia remains a clear unmet medical need for adults worldwide. Despite advances in vaccine technology, vaccination coverage remains low, putting many people at risk of significant morbidity and mortality. The herd effect seen with paediatric vaccination is not enough to protect all older and vulnerable people in the community, and more needs to be done to increase the uptake of pneumococcal vaccination in adults. Several key groups are at increased risk of contracting pneumococcal pneumonia, and eligible patients are being missed in clinical practice. At present, community-acquired pneumonia costs over €10 billion annually in Europe alone. Pneumococcal conjugate vaccination could translate into preventing 200,000 cases of community-acquired pneumonia every year in Europe alone. This group calls on governments and decision makers to implement consistent age-based vaccination strategies, and for healthcare professionals in daily clinical practice to identify eligible patients who would benefit from vaccination strategies.

A Retrospective Study of the Clinical Burden of Hospitalized All-Cause and Pneumococcal Pneumonia in Canada.

Background. Routine vaccination against Streptococcus pneumoniae is recommended in Canada for infants, the elderly, and individuals with chronic comorbidity. National incidence and burden of all-cause and pneumococcal pneumonia in Canada (excluding Quebec) were assessed. Methods. Incidence, length of stay, and case-fatality rates of hospitalized all-cause and pneumococcal pneumonia were determined for 2004-2010 using ICD-10 discharge data from the Canadian Institutes for Health Information Discharge Abstract Database. Population-at-risk data were obtained from the Statistics Canada census. Temporal changes in pneumococcal and all-cause pneumonia rates in adults ≥65 years were analyzed by logistic regression. Results. Hospitalization for all-cause pneumonia was highest in children <5 years and in adults >70 years and declined significantly from 1766/100,000 to 1537/100,000 per year in individuals aged ≥65 years (P < 0.001). Overall hospitalization for pneumococcal pneumonia also declined from 6.40/100,000 to 5.08/100,000 per year. Case-fatality rates were stable (11.6% to 12.3%). Elderly individuals had longer length of stay and higher case-fatality rates than younger groups. Conclusions. All-cause and pneumococcal pneumonia hospitalization rates declined between 2004 and 2010 in Canada (excluding Quebec). Direct and indirect effects from pediatric pneumococcal immunization may partly explain some of this decline. Nevertheless, the burden of disease from pneumonia remains high.

Which individuals are at increased risk of pneumococcal disease and why? Impact of COPD, asthma, smoking, diabetes, and/or chronic heart disease on community-acquired pneumonia and invasive pneumococcal disease.

Pneumococcal disease (including community-acquired pneumonia and invasive pneumococcal disease) poses a burden to the community all year round, especially in those with chronic underlying conditions. Individuals with COPD, asthma or who smoke, and those with chronic heart disease or diabetes mellitus have been shown to be at increased risk of pneumococcal disease compared with those without these risk factors. These conditions, and smoking, can also adversely affect patient outcomes, including short-term and long-term mortality rates, following pneumonia. Community-acquired pneumonia, and in particular pneumococcal pneumonia, is associated with a significant economic burden, especially in those who are hospitalised, and also has an impact on a patient's quality of life. Therefore, physicians should target individuals with COPD, asthma, heart disease or diabetes mellitus, and those who smoke, for pneumococcal vaccination at the earliest opportunity at any time of the year.

PCVs in individuals at increased risk of pneumococcal disease: a literature review.

The use of pneumococcal conjugate vaccine (PCV) in childhood pneumococcal immunization programs successfully reduced the incidence of pneumococcal disease in children. Nonetheless, there remains a high burden of pneumococcal disease in adults, especially the elderly, and children/adults with chronic medical conditions. Two pneumococcal vaccines are currently available for adults at risk of pneumococcal disease: the 23-valent pneumococcal polysaccharide vaccine (PPV23) and the more recently licensed PCV13. As it is not possible to determine vaccine efficacy in all populations at risk of pneumococcal disease, immunogenicity studies, measuring pneumococcal-specific antibody concentrations and/or the opsonophagocytic activity of serum can provide valuable comparative data for PPV and PCV immunization. This article provides consolidated data on the immunogenicity of PCVs (largely PCV7, and a few studies with PCV9 or PCV13) based on a review of immunogenicity/safety studies in populations (mainly pediatric) at increased risk of pneumococcal disease.

Phase 3 study comparing tigecycline and ertapenem in patients with diabetic foot infections with and without osteomyelitis.

A phase 3, randomized, double-blind trial was conducted in subjects with diabetic foot infections without osteomyelitis (primary study) or with osteomyelitis (substudy) to determine the efficacy and safety of parenteral (intravenous [iv]) tigecycline (150 mg once-daily) versus 1 g once-daily iv ertapenem ± vancomycin. Among 944 subjects in the primary study who received ≥1 dose of study drug, >85% had type 2 diabetes; ~90% had Perfusion, Extent, Depth/tissue loss, Infection, and Sensation infection grade 2 or 3; and ~20% reported prior antibiotic failure. For the clinically evaluable population at test-of-cure, 77.5% of tigecycline- and 82.5% of ertapenem ± vancomycin-treated subjects were cured. Corresponding rates for the clinical modified intent-to-treat population were 71.4% and 77.9%, respectively. Clinical cure rates in the substudy were low (<36%) for a subset of tigecycline-treated subjects with osteomyelitis. Nausea and vomiting occurred significantly more often after tigecycline treatment (P = 0.003 and P < 0.001, respectively), resulting in significantly higher discontinuation rates in the primary study (nausea P = 0.007, vomiting P < 0.001). In the primary study, tigecycline did not meet criteria for noninferiority compared with ertapenem ± vancomycin in the treatment of subjects with diabetic foot infections.

A retrospective study of hospitalized pneumonia in two Polish counties (2006-2008).

INTRODUCTION: In Poland, multi-cause pneumonia is not well characterized, and there is limited pneumococcal vaccination in the youngest and oldest age groups. The goal of this study was to assess hospitalized pneumonia across all age groups in two Polish counties. MATERIAL AND METHODS: Using electronic administrative databases, cases were identified as county residents hospitalized at Chrzanów and Inowroclaw County Hospitals from 2006-2008, assigned a diagnosis of pneumonia. Calculations by admission year, sex, and age category were: hospitalization rates per 1000 persons; in-hospital mortality rates per 100 persons; and median length of stay (LOS). RESULTS: There were 1444 and 2956 hospitalizations for new episodes of pneumonia with rates of 3.76 (95% confidence interval [CI] 3.57-3.96) and 5.99 (95% CI 5.77-6.21) per 1000 persons in Chrzanów and Inowroclaw counties, respectively. In combined data, the highest hospitalization rate was among patients aged 0-4 years (30.77; 95% CI 29.06-32.55) followed by those aged ≥ 75 years (25.39; 95% CI 24.01-26.83). In-hospital mortality rates increased with age at both sites. The median LOS was 8 days. CONCLUSIONS: Pneumonia hospitalizations were substantial, especially for the youngest and oldest age groups. Future public health interventions aimed at these age groups might improve disease outlook.

Tigecycline versus levofloxacin in hospitalized patients with community-acquired pneumonia: an analysis of risk factors.

INTRODUCTION: This study was conducted to evaluate the efficacy of tigecycline (TGC) versus levofloxacin (LEV) in hospitalized patients with community-acquired pneumonia (CAP) using pooled data and to perform exploratory analyses of risk factors associated with poor outcome. MATERIALS AND METHODOLOGY: Pooled analyses of 2 phase 3 studies in patients randomized to intravenous (IV) TGC (100 mg, then 50 mg q12h) or IV LEV (500 mg q24h or q12h). Clinical responses at test of cure visit for the clinically evaluable (CE) and clinical modified intention to treat populations were assessed for patients with risk factors including aged ≥65 years, prior antibiotic failure, bacteremia, multilobar disease, chronic obstructive pulmonary disease, alcohol abuse, altered mental status, hypoxemia, renal insufficiency, diabetes mellitus, white blood cell count >30 x 10(9)/L or <4 x 10(9)/L, CURB-65 score ≥2, Fine score category of III to V and at least 2 clinical instability criteria on physical examination. RESULTS: In the CE population of 574 patients, overall cure rates were similar: TGC (253/282, 89.7%); LEV (252/292, 86.3%). For all but one risk factor, cure rates for TGC were similar to or higher than those for LEV. For individual risk factors, the greatest difference between treatment groups was observed in patients with diabetes mellitus (difference of 22.9 for TGC versus LEV; 95% confidence interval, 4.8 - 39.9). CONCLUSIONS: TGC achieved cure rates similar to those of LEV in hospitalized patients with CAP. For patients with risk factors, TGC provided generally favorable clinical outcomes.

Randomized phase 2 trial to evaluate the clinical efficacy of two high-dosage tigecycline regimens versus imipenem-cilastatin for treatment of hospital-acquired pneumonia.

In a previous phase 3 study, the cure rates that occurred in patients with hospital-acquired pneumonia treated with tigecycline at the approved dose were lower than those seen with patients treated with imipenem and cilastatin (imipenem/cilastatin). We hypothesized that a higher dose of tigecycline is necessary in patients with hospital-acquired pneumonia. This phase 2 study compared the safety and efficacy of two higher doses of tigecycline with imipenem/cilastatin in subjects with hospital-acquired pneumonia. Subjects with hospital-acquired pneumonia were randomized to receive one of two doses of tigecycline (150 mg followed by 75 mg every 12 h or 200 mg followed by 100 mg every 12 h) or 1 g of imipenem/cilastatin every 8 h. Empirical adjunctive therapy was administered for initial coverage of methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa infection, depending on the randomization regimen. Clinical response, defined as cure, failure of treatment, or indeterminate outcome, was assessed 10 to 21 days after the last day of therapy. In the clinically evaluable population, clinical cure with tigecycline 100 mg (17/20, 85.0%) was numerically higher than with tigecycline 75 mg (16/23, 69.6%) and imipenem/cilastatin (18/24, 75.0%). No new safety signals with the high-dose tigecycline were identified. A numerically higher clinical response was observed with the 100-mg dose of tigecycline. This supports our hypothesis that a higher area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC/MIC ratio) may be necessary to achieve clinical cure in patients with hospital-acquired pneumonia. Further studies are necessary. (The ClinicalTrials.gov identifier for this clinical trial is NCT00707239.).

Pharmacokinetics and safety profile of tigecycline in children aged 8 to 11 years with selected serious infections: a multicenter, open-label, ascending-dose study.

BACKGROUND: Tigecycline, a broad-spectrum antibiotic used for treating serious bacterial infections in adults, may be suitable for pediatric use once an appropriate dosage is determined. OBJECTIVE: The aim of this study was to assess the pharmacokinetic (PK) properties, safety profile, and descriptive efficacy of tigecycline. METHODS: In this Phase II, multicenter, open-label clinical trial, children aged 8 to 11 years with community-acquired pneumonia (CAP), complicated intra-abdominal infection (cIAI), or complicated skin and skin structure infections (cSSSI) were administered tigecycline 0.75, 1, or 1.25 mg/kg. RESULTS: A total of 58 patients received ≥ 1 dose of tigecycline (31 boys; 44 white; mean age, 10 years; mean weight, 35 kg); 47 had data from samples available for PK analysis. The mean (SD) PK values were: C(max), 1899 (2954) ng/mL; T(max), 0.56 (0.18) hour; between-dose AUC, 2833 (1557) ng · h/mL; weight-normalized clearance, 0.503 (0.293) L/h/kg; and Vd(ss), 4.88 (4.84) L/kg. Overall clinical cure rates at test-of-cure were 94% (16/17), 76% (16/21), and 75% (15/20) in the 0.75-, 1-, and 1.25-mg/kg cohorts, respectively. The rates of protocol violations were higher in the 1- and 1.25-mg/kg groups, resulting in higher proportions of indeterminate clinical cure assessments relative to the 0.75-mg/kg cohort (19% and 15% vs 0%). The most frequent adverse event was nausea, which occurred in 50% of patients overall (29/58) and the prevalence of which was significantly higher in the 1.25-mg/kg group versus the 0.75-mg/kg group (65% vs 18%; P = 0.007). Pharmacodynamic simulations using MIC data from an ongoing microbiological surveillance trial predicted that a dosage of 1.2 mg/kg q12h would lead to therapeutic target attainment levels of up to 82% for the target AUC(0-24)/MIC ratios. CONCLUSION: A tigecycline dosage of ∼1.2 mg/kg q12h may represent the most appropriate dosage for subsequent evaluation in Phase III clinical trials in children aged 8 to 11 years with selected serious bacterial infections. ClinicalTrials.gov identifier: NCT00488345.

Pharmacokinetics-pharmacodynamics of tigecycline in patients with community-acquired pneumonia.

Exposure-response analyses for efficacy and safety were performed for tigecycline-treated patients suffering from community-acquired pneumonia. Data were collected from two randomized, controlled clinical trials in which patients were administered a 100-mg loading dose followed by 50 mg of tigecycline every 12 h. A categorical endpoint, success or failure, 7 to 23 days after the end of therapy (test of cure) and a continuous endpoint, time to fever resolution, were evaluated for exposure-response analyses for efficacy. Nausea/vomiting, diarrhea, headache, and changes in blood urea nitrogen concentration (BUN) and total bilirubin were evaluated for exposure-response analyses for safety. For efficacy, ratios of the free-drug area under the concentration-time curve at 24 h to the MIC of the pathogen (fAUC(0-24):MIC) of ≥12.8 were associated with a faster time to fever resolution; patients with lower drug exposures had a slower time to fever resolution (P = 0.05). For safety, a multivariable logistic regression model demonstrated that a tigecycline AUC above a threshold of 6.87 mg · hr/liter (P = 0.004) and female sex were predictive of the occurrence of nausea and/or vomiting (P = 0.004). Although statistically significant, the linear relationship between tigecycline exposure and maximum change from baseline in total bilirubin is unlikely to be clinically significant.

Pharmacological and patient-specific response determinants in patients with hospital-acquired pneumonia treated with tigecycline.

Pharmacokinetic and clinical data from tigecycline-treated patients with hospital-acquired pneumonia (HAP) who were enrolled in a phase 3 clinical trial were integrated in order to evaluate pharmacokinetic-pharmacodynamic (PK-PD) relationships for efficacy. Univariable and multivariable analyses were conducted to identify factors associated with clinical and microbiological responses, based on data from 61 evaluable HAP patients who received tigecycline intravenously as a 100-mg loading dose followed by 50 mg every 12 h for a minimum of 7 days and for whom there were adequate clinical, pharmacokinetic, and response data. The final multivariable logistic regression model for clinical response contained albumin and the ratio of the free-drug area under the concentration-time curve from 0 to 24 h (fAUC(0-24)) to the MIC (fAUC(0-24):MIC ratio). The odds of clinical success were 13.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.42 times higher for patients with fAUC(0-24):MIC ratios of ≥0.9 compared to patients with fAUC(0-24):MIC ratios of <0.9 (P = 0.008). Average model-estimated probabilities of clinical success for the albumin/fAUC(0-24):MIC ratio combinations of <2.6/<0.9, <2.6/≥0.9, ≥2.6/<0.9, and ≥2.6/≥0.9 were 0.21, 0.57, 0.64, and 0.93, respectively. For microbiological response, the final model contained albumin and ventilator-associated pneumonia (VAP) status. The odds of microbiological success were 21.0 times higher for every 1-g/dl increase in albumin (P < 0.001) and 8.59 times higher for patients without VAP compared to those with VAP (P = 0.003). Among the remaining variables evaluated, the MIC had the greatest statistical significance, an observation which was not surprising given the differences in MIC distributions between VAP and non-VAP patients (MIC(50)and MIC(90) values of 0.5 and 0.25 mg/liter versus 16 and 1 mg/liter for VAP versus non-VAP patients, respectively; P = 0.006). These findings demonstrated the impact of pharmacological and patient-specific factors on the clinical and microbiological responses.

Efficacy and safety of tigecycline monotherapy compared with vancomycin-aztreonam in the treatment of complicated skin and skin structure infections in patients from India and Taiwan.

BACKGROUND: To compare the monotherapy of tigecycline with vancomycin-aztreonam in hospitalized patients from India and Taiwan with complicated skin and skin structure infections (cSSSIs). METHODS: Safety and efficacy data were analyzed for Indian (n = 86) and Taiwanese (n = 41) patients hospitalized with cSSSIs who participated in two international Phase 3, randomized, double-blind studies. RESULTS: Patients were treated for 5-14 days. Cure rates at the test-of-cure assessment (12-92 days post-therapy) were generally similar between tigecycline and vancomycin-aztreonam in the clinically evaluable populations (India, 83.3% vs. 75.8%; Taiwan, 78.6% vs. 90%) and in the clinical modified intent-to-treat populations (India, 78.6% vs. 66.7%; Taiwan, 73.3% vs. 75.0%). Nausea and vomiting occurred more frequently with tigecycline, but overall safety and tolerability were comparable between the two treatments. CONCLUSIONS: Tigecycline monotherapy is a safe and effective therapy for cSSSIs in geographically distinct populations in Asia.

Comparison of tigecycline with imipenem/cilastatin for the treatment of hospital-acquired pneumonia.

To compare efficacy and safety of a tigecycline regimen with an imipenem/cilastatin regimen in hospital-acquired pneumonia patients, a phase 3, multicenter, randomized, double-blind, study evaluated 945 patients. Coprimary end points were clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure. Cure rates were 67.9% for tigecycline and 78.2% for imipenem (CE patients) and 62.7% and 67.6% (c-mITT patients), respectively. A statistical interaction occurred between ventilator-associated pneumonia (VAP) and non-VAP subgroups, with significantly lower cure rates in tigecycline VAP patients compared to imipenem; in non-VAP patients, tigecycline was noninferior to imipenem. Overall mortality did not differ between the tigecycline (14.1%) and imipenem regimens (12.2%), although more deaths occurred in VAP patients treated with tigecycline than imipenem. Overall, the tigecycline regimen was noninferior to the imipenem/cilastatin regimen for the c-mITT but not the CE population; this difference appears to have been driven by results in VAP patients.

Efficacy and safety of tigecycline versus levofloxacin for community-acquired pneumonia.

BACKGROUND: Tigecycline, an expanded broad-spectrum glycylcycline, exhibits in vitro activity against many common pathogens associated with community-acquired pneumonia (CAP), as well as penetration into lung tissues that suggests effectiveness in hospitalized CAP patients. The aim of the present study was to compare the efficacy and safety of intravenous (IV) tigecycline with IV levofloxacin in hospitalized adults with CAP. METHODS: In this prospective, double-blind, non-inferiority phase 3 trial, eligible patients with a clinical diagnosis of CAP supported by radiographic evidence were stratified by Fine Pneumonia Severity Index and randomized to tigecycline or levofloxacin for 7-14 days of therapy. Co-primary efficacy endpoints were clinical response in the clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (Day 10-21 post-therapy). RESULTS: Of the 428 patients who received at least one dose of study drug, 79% had CAP of mild-moderate severity according to their Fine score. Clinical cure rates for the CE population were 88.9% for tigecycline and 85.3% for levofloxacin. Corresponding c-mITT population rates were 83.7% and 81.5%, respectively. Eradication rates for Streptococcus pneumoniae were 92% for tigecycline and 89% for levofloxacin. Nausea, vomiting, and diarrhoea were the most frequently reported adverse events. Rates of premature discontinuation of study drug or study withdrawal because of any adverse event were similar for both study drugs. CONCLUSION: These findings suggest that IV tigecycline is non-inferior to IV levofloxacin and is generally well-tolerated in the treatment of hospitalized adults with CAP. TRIAL REGISTRATION: NCT00081575.

A Phase 3, open-label, non-comparative study of tigecycline in the treatment of patients with selected serious infections due to resistant Gram-negative organisms including Enterobacter species, Acinetobacter baumannii and Klebsiella pneumoniae.

OBJECTIVES: To evaluate the efficacy and safety of tigecycline in patients with selected serious infections caused by resistant Gram-negative bacteria, or failures who had received prior antimicrobial therapy or were unable to tolerate other appropriate antimicrobials. Secondary objectives included an evaluation of the microbiological efficacy of tigecycline and in vitro activity of tigecycline for resistant Gram-negative bacteria. METHODS: This open-label, Phase 3, non-comparative, multicentre study assessed the efficacy and safety of intravenous tigecycline (100 mg initially, then 50 mg 12 hourly for 7-28 days) in hospitalized patients with serious infections including complicated intra-abdominal infection; complicated skin and skin structure infection (cSSSI); community-acquired pneumonia (CAP); hospital-acquired pneumonia, including ventilator-associated pneumonia; or bacteraemia, including catheter-related bacteraemia. All patients had infections due to resistant Gram-negative organisms, including extended-spectrum beta-lactamase-producing strains, or had failed on prior therapy or could not receive (allergy or intolerance) one or more agents from three classes of commonly used antibiotics. The primary efficacy endpoint was clinical response in the microbiologically evaluable (ME) population at test of cure (TOC). Safety data included vital signs, laboratory tests and adverse events (AEs). RESULTS: In the ME population at TOC, the clinical cure rate was 72.2% [95% confidence interval (CI): 54.8-85.8], and the microbiological eradication rate was 66.7% (95% CI: 13.7-78.8). The most commonly isolated resistant Gram-negative pathogens were Acinetobacter baumannii (47%), Escherichia coli (25%), Klebsiella pneumoniae (16.7%) and Enterobacter spp. (11.0%); the most commonly diagnosed serious infection was cSSSI (67%). The most common treatment-emergent AEs were nausea (29.5%), diarrhoea (16%) and vomiting (16%), which were mild or moderate in severity. CONCLUSIONS: In this non-comparative study, tigecycline appeared safe and efficacious in patients with difficult-to-treat serious infections caused by resistant Gram-negative organisms.

Integrated results of 2 phase 3 studies comparing tigecycline and levofloxacin in community-acquired pneumonia.

Tigecycline (TGC), a glycylcycline, has expanded activity against Gram-positive and Gram-negative, anaerobic, and atypical bacteria. Two phase 3 studies were conducted. Hospitalized patients with community-acquired pneumonia (CAP) were randomized to intravenous (IV) TGC (100 mg followed by 50 mg bid) or IV levofloxacin (LEV) (500 mg bid). In 1 study, patients could be switched to oral LEV after at least 3 days intravenously. The coprimary efficacy end points were as follows: clinical response in clinically evaluable (CE) and clinical modified intent-to-treat (c-mITT) populations at test-of-cure (TOC). The secondary end points were as follows: microbiologic efficacy and susceptibility to TGC for CAP bacteria. Safety evaluations were included. Eight hundred ninety-one were patients screened: 846 mITT (TGC 424, LEV 422), 574 CE (TGC 282, LEV 292). Most patients had Fine Pneumonia Severity Index II to IV (80.7% TGC, 74.4% LEV, mITT). At TOC (CE), TGC cured 253/282 patients (89.7%) and LEV cured 252/292 patients (86.3%); the absolute difference of TGC-LEV was 3.4% (95% confidence interval [CI], -2.2 to 9.1, noninferior [P < 0.001]). In c-mITT, TGC cured 319/394 patients (81.0%) and LEV cured 321/403 patients (79.7%); the absolute difference of TGC-LEV was 1.3% (95% CI -4.5 to 7.1, noninferior [P < 0.001]). The drug-related adverse events (AEs) of nausea (20.8% TGC versus 6.6% LEV) and vomiting (13.2% TGC versus 3.3% LEV) were significantly higher in TGC; elevated alanine aminotransferase (2.8% TGC versus 7.3% LEV) and aspartate aminotransferase (2.6% TGC versus 6.9% LEV) were significantly higher in LEV. Discontinuations for AEs were low (TGC, 26 patients [6.1%]; LEV, 34 patients [8.1%]). TGC appeared safe and achieved cure rates similar to LEV in hospitalized patients with CAP.

Safety and efficacy of tigecycline in treatment of skin and skin structure infections: results of a double-blind phase 3 comparison study with vancomycin-aztreonam.

In a randomized, double-blind, controlled trial, 546 patients with complicated skin and skin structure infections received tigecycline 100 mg/day (a 100-mg initial dose and then 50 mg intravenously twice daily) or the combination of vancomycin 2 g/day (1 g intravenously twice daily) and aztreonam 4 g/day (2 g intravenously twice daily) for up to 14 days. The primary end point was the clinical response in the clinical modified intent-to-treat (c-mITT) and clinically evaluable (CE) populations at the test-of-cure visit 12 to 92 days after the last dose. The microbiologic response at the test-of-cure visit was also assessed. Safety was assessed by physical examination, laboratory results, and adverse event reporting. Five hundred twenty patients were included in the c-mITT population (tigecycline group, n = 261; combination group, n = 259), and 436 were clinically evaluable (tigecycline group, n = 223; combination group, n = 213). The clinical responses in the tigecycline and the combination vancomycin and aztreonam groups were similar in the c-mITT population (84.3% versus 86.9%; difference, -2.6% [95% confidence interval, -9.0, 3.8]; P = 0.4755) and the CE population (89.7% versus 94.4%; difference, -4.7% [95% confidence interval, -10.2, 0.8]; P = 0.1015). Microbiologic eradication (documented or presumed) occurred in 84.8% of the patients receiving tigecycline and 93.2% of the patients receiving vancomycin and aztreonam (difference, -8.5 [95% confidence interval, -16.0, -1.0]; P = 0.0243). The numbers of patients reporting adverse events were similar in the two groups, with increased nausea and vomiting rates in the tigecycline group and an increased incidence of rash and increases in alanine aminotransferase and aspartate aminotransferase levels in the combination vancomycin and aztreonam group. Tigecycline was shown to be safe and effective for the treatment of complicated skin and skin structure infections.

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.