This article appears in the following Journal of Antimicrobial Chemotherapy issue: Tigecycline, a therapeutic option from a new antimicrobial class (the glycylcyclines) in an era of increasing resistance [View the issue table of contents]
Articles |
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
1 Clinic of Endoscopic Surgery, Military Medical Academy, 3, Georgi Sofiiski Str, 1606 Sofia, Bulgaria 2 Institute of Antimicrobial Chemotherapy of Smolensk State Medical Academy, 28 Krupskaya Str, 214019 Smolensk, Smolensk Regional Hospital, 27 Prospekt, Gagarina, 214018 Smolensk, Russia 3 Clinical County Hospital Cluj-Napoca Str, Cliniclor nr. 3-5 Cluj-Napoca, Romania 4 Hospital Clinico San Carlos, 28040 Madrid, Spain 5 North Estonia Regional Hospital, Mustamae Centre, Sutiste tee 19, Tallinn 13419, Estonia 6 Wyeth Research, Collegeville, PA, USA 7 Wyeth Research, Paris, France
* Corresponding author. Tel: +1-484-865-8818; Fax: +1-484-865-9262; E-mail: babinct{at}wyeth.com
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
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 β-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.
Keywords: tetracyclines , multidrug resistance , clinical trials
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
Infections due to antimicrobial-resistant Gram-negative bacteria are associated with increased mortality, morbidity, hospital stay and costs, compared with infections caused by susceptible organisms.1–4 In Gram-negative bacteria, resistance to β-lactams is a particular concern, especially when mediated by extended-spectrum β-lactamases (ESBLs), AmpC β-lactamases or carbapenemases.5–14 ESBL-producing Gram-negative pathogens are seen worldwide, often arising in focal outbreaks, with variable temporal and geographical prevalence.2,5,15 The prevalence of ESBL-producing Klebsiella pneumoniae in the USA and Canada is 7.6% and 4.9%, respectively, with higher rates being seen in Europe (22.6%), the Western Pacific (24.6%) and Latin America (45.4%).16 ESBL-producing Escherichia coli have also been reported from the USA (3.3%) and Latin America (8.5%), whereas ESBL-producing Proteus mirabilis have been reported from the Western Pacific, Canada and USA (1.8%), Europe (11%) and Latin America (22.4%).16 The prevalence of ESBL- producing K. pneumoniae shows regional differences in the USA, being more common in the North-east and South-Central regions, than in the West.
The risk factors associated with infection/colonization with resistant pathogens, including ESBL-producing strains, include prolonged hospital stay, hospital or neonatal intensive care stay and residency in long-term care facilities.5 Transmission/persistence is determined by availability of vulnerable patients with risk factors (e.g. severe disease, decubitus ulcers, recent surgery, indwelling devices and total care dependency) as well as selective pressure from total antimicrobial use (particularly third-generation cephalosporins, trimethoprim/sulfamethoxazole and ciprofloxacin) and delay in initiating appropriate antimicrobial therapy.2,5,15
International surveillance has shown that in complicated intra-abdominal infections (cIAIs), ESBL phenotypes are found primarily in E. coli (10%), Klebsiella spp. (17%) and Enterobacter spp. (22%). Ciprofloxacin and levofloxacin were the least reliably active agents against E. coli overall with the lowest activity seen in Asia/Pacific (64.5% and 66% susceptible, respectively) and Latin America (72.1% and 74.3% susceptible, respectively).17 In complicated skin and skin structure infections (cSSSIs), the prevalence of ESBL-producing E. coli and Klebsiella spp. was greatest in Latin America (15% and 48%, respectively).18 Among respiratory isolates, the prevalence of ESBL-producing E. coli in Latin America was 25.4%, whereas those for K. pneumoniae and P. mirabilis were 44 and 35.5%, respectively.19 In bacteraemia isolates (1997–2001), the prevalence of ESBL-producing Klebsiella spp. rose in Europe (from 14.6% to 21.4%), but decreased in Latin America (from 48% to 37%) and in North America (from 7% to 6%).19 Overall, ESBL-producing E. coli and Klebsiella spp. have increased in Europe, and ESBL-producing Enterobacter spp. have increased in the USA.20 Acinetobacter baumannii strains are of serious concern in nosocomial pneumonia, complicating the management of ventilated ICU patients.12,21,22
Nosocomial infections with ESBL-producing Gram-negative pathogens complicate and limit treatment options.23 Strategies to combat antimicrobial resistance require stringent infection control; accurate, prompt diagnosis and treatment; and judicious antimicrobial stewardship programmes.2,24,25 Effective empirical therapy has been achieved with carbapenems.25 However, efficacy has been compromised by the emergence of resistant strains.24–28 Reported successful treatment with the fourth-generation cephalosporin, cefepime,23 suggests that this may offer an alternative for selected infections. With increasing prevalence of resistant Gram-negative pathogens, alternative antimicrobials with greater potency, stability to common resistance mechanisms, favourable pharmacokinetics/pharmacodynamics and lower potential for resistance selection are required.29
Tigecycline has potent in vitro activity against Enterobacteriaceae, inhibiting multidrug-resistant (MDR) ESBL- and AmpC-producing strains (MICs 
2 mg/L), and exhibits good activity against A. baumannii strains (>98% susceptible; MIC90 1.0 mg/L).26–28,30–32 Tigecycline resistance is uncommon, although the drug has limited activity against Pseudomonas aeruginosa and Proteus spp.33,34 Tigecycline efficacy and safety in patients with serious infections with resistant Gram-negative pathogens were evaluated in this trial.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
This trial was designed as an open-label, non-comparative, multicentre study to evaluate the efficacy and safety of tigecycline in patients with infections due to resistant Gram-negative organisms.
Patients were enrolled based upon presumed disease in the pertinent indications, namely cSSSI, cIAI, community-acquired pneumonia (CAP), hospital-acquired pneumonia (HAP) and bacteraemia, and evidence of a resistant organism in prior cultures. If baseline cultures taken at the time of enrolment did not yield the previously identified resistant organisms, these patients were not included in the microbiologically evaluable (ME) population, which comprised patients who had: (i) clinical evidence of infection as defined in the inclusion criteria; (ii) a baseline culture of a resistant Gram-negative pathogen(s) that was susceptible to tigecycline; (iii) sufficient information available to allow a determination of microbiological response; and (iv) completed an evaluation for efficacy [test of cure (TOC)] 12–37 days after the last dose of tigecycline. Full inclusion and exclusion criteria were similar to previously published comparative trials (Figure 1).35–37 All patients were to have specimens obtained at baseline, including two sets of blood cultures and aerobic and anaerobic (if appropriate) cultures from the primary site of infection. For the purpose of study inclusion at baseline, resistance in vitro was documented based on local laboratory results from the baseline culture. All aerobic and anaerobic bacterial pathogens, regardless of the source of cultured material, were identified and tested at a central laboratory (Covance Laboratory Services, Inc.) using standard procedures approved by the CLSI. The presence of an ESBL or related mechanism, which limits the therapeutic alternatives for the treatment of the complicated infection, was documented with the CLSI confirmatory test using Etest.
|
For purposes of eligibility, a patient was considered to have a resistant Gram-negative organism if: (i) the organism was an ESBL-producer; or (ii) the patient had failed clinically, the organism was resistant (in vitro) to, or the patient could not receive (because of allergy or intolerance), at least one antimicrobial agent from three or more different classes commonly prescribed for these organisms, namely penicillins (β-lactam/β-lactamase inhibitor combinations), third- or fourth-generation cephalosporins, carbapenems, quinolones and aminoglycosides. Patients with an infection caused by A. baumannii could be entered into the trial without having to meet the latter criteria because of the tendency of these organisms to be MDR. Given the patient population for this study, and the requirement to have failed other therapies or to have an organism that was resistant to agents from at least three classes of antibiotics, the selection of a single antibiotic that could be an appropriate comparator therapy for all patients was not possible.
This study had the approval of a properly constituted Institutional Review Board (IRB) or independent Ethics Committee (IEC) recognized by national and applicable local or regional health authorities for approving clinical studies. It was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practice (GCP) and the applicable regulatory requirements. The study was conducted according to the International Conference on Harmonisation guideline for GCP in the European Community and according to the guidelines for the Statement of Investigator, Food and Drug Administration (FDA) Form 1572 [21 Code of Federal Regulations 312 Part 53 (c)]. In addition, as the study was a worldwide study, local laws or local guidelines were also considered.
An IRB/IEC-approved informed consent form was administered, which was signed and dated by the patient or by his or her legally authorized representative before any screening procedures specific to this study were performed.
Tigecycline was dosed as an initial intravenous dose of 100 mg followed by 50 mg every 12 h. Patients were to receive tigecycline for a minimum of 7 days and up to 28 days based on the severity of the infection and the investigator's judgement. An analysis of safety was performed for any patient who received at least one dose of tigecycline [the modified intent-to-treat (mITT) population]. Safety was monitored by means of scheduled physical examinations and vital sign measurements, assessment of clinical signs and symptoms of the infection, clinical laboratory determinations and recorded adverse experiences.
The primary efficacy endpoint was the clinical response rate in the ME population. The co-primary efficacy population of the microbiological mITT (m-mITT) population consisted of all patients who had clinical evidence of infection and one or more identified baseline resistant Gram-negative isolates. Cure was defined as resolution or improvement of the infection such that no further antibacterial therapy was required. No additional antibiotic therapy was allowed from the end of treatment through to the TOC. Failure was defined as the continued presence of signs and symptoms of infection requiring additional surgical or radiological intervention or additional antibiotic therapy to cure the infection, or death after study day 2 because of the infection or a treatment-related adverse event (AE) (as a primary reason). The use of non-study antibacterial agents (either systemic, or topical at the site of the primary infection) or irrigants was prohibited. The receipt of oral follow-on antibiotic therapy was considered a clinical failure. Indeterminate response was defined as the patient being lost to follow-up (failure to have an assigned clinical response), having died within 2 days after the first dose of tigecycline for any reason, or having died after study day 2, but before the TOC assessment because of non-infectious reasons.
The microbiological response at the pathogen level was determined according to the following definitions: (i) eradication (documented or presumed; the baseline isolate was absent in repeat cultures obtained from the original site of infection, or a clinical response of cure made a repeat culture unnecessary); (ii) persistence (documented or presumed; the baseline isolate was present in repeat cultures obtained from the original site of infection, or the patient's clinical response was failure and no repeat microbiological data were available); (iii) indeterminate (the patient was lost to follow-up, died within 2 days after the first dose of tigecycline for any reason, or died after study day 2, but before the TOC assessment because of non-infectious reasons). A superinfection was defined as a new isolate that emerged during therapy at the original site of infection with emergence or worsening of clinical signs and symptoms of infection.
Because of the study design, no formal statistical analysis could be performed. The evaluation consisted of summary displays (i.e. descriptive statistics). The clinical and microbiological response rates were estimated, and 95% confidence intervals (CIs) for the true proportions were calculated. The study design was a result of discussions with regulatory agencies and their endorsement of a ‘high-quality–low quantity’ approach for studying resistant organisms.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
The study enrolled 115 patients (Figure 2). Three patients did not receive tigecycline so 112 patients made up the mITT population. Table 1 describes the demographic and baseline characteristics of these patients. Table 2 describes the primary diagnosis and infection type. A total of 75 patients made up the m-mITT population, 25 patients failed to meet minimal disease criteria and 12 patients had no baseline isolate identified and were excluded. The ME population comprised 36 patients who met the inclusion/exclusion criteria, had at least one isolate that met the definition of resistance and was susceptible to tigecycline, and completed the TOC assessment within the appropriate time frame. The most common reason for exclusion from the ME population (30 patients) was the absence of a baseline isolate that met the resistance criteria or the requirement for susceptibility to tigecycline. In general, the m-mITT population represented patients with moderate-to-severe disease: 42.7% of the patients were in the ICU for some period during the hospitalization, the median APACHE score was 10 and the median duration of treatment was 12 days.
|
|
|
For patients with resistant isolates, clinical cure was achieved in 26/36 (72.2%, 95% CI: 54.8–85.8) of ME patients and 40/75 (53.3%, 95% CI: 41.4–64.9) of m-mITT patients treated with tigecycline (Table 3). Microbiological response rates were similar with 24/36 (66.7%, 95% CI: 49.0–81.4) organisms eradicated (generally presumed) in the ME population and 37/75 (49.3%, 95% CI: 37.6–61.1) in the m-mITT population (Table 4). Microbiological response rates in the ME population (excluding contaminants) were also similar whether infections were monomicrobial (73.3%) or polymicrobial (61.9%). Tables 5 and 6 summarize the clinical cure rates and microbiological eradication at TOC ME and m-mITT populations by diagnosis and organism.
|
|
|
|
Infections due to particular pathogens
E. coli. The clinical cure rate for patients with resistant E. coli in the ME population was 4/9 (44.4%, 95% CI: 13.7–78.8). Microbiological eradication was also 4/9. In the case of cIAI, a surgical review board (SRB) composed of investigators and non-investigators was used to assess the adequacy of source control in the initial surgical or interventional radiology procedure in patients who were clinical failures, had further surgery or whose deaths were considered indeterminate. The SRB reviewed data to determine whether the initial surgical intervention was adequate (surgical source control) and to determine whether the outcome judged by the investigator was appropriate. If cases deemed by the SRB to have inadequate source control were excluded, the clinical cure rate for E. coli was 4/6 (66.7%.).
In addition to cIAI, resistant E. coli was isolated from five patients with cSSSIs. The overall clinical cure rate for these patients was 3/5 (60%.).
K. pneumoniae. The clinical cure rate for patients with resistant K. pneumoniae in the ME population was 5/6 (83.3%, 95% CI: 35.9–99.6). MDR K. pneumoniae was most frequently isolated from patients with cSSSIs, usually in a polymicrobial setting. Clinical cure was achieved in each of three patients with infections involving the skin and in one patient with a cIAI. All six patients were cured microbiologically.
The lone clinical failure in this group was a 43-year-old woman with an APACHE II score of 11, systemic lupus erythematosus, diabetes, hypertension, Cushing's syndrome and multiple sclerosis, who presented with a primary K. pneumoniae bacteraemia resistant to all antibiotics tested except tigecycline. The baseline bacteraemia cleared with the start of tigecycline therapy; however, she required additional antibiotics for her underlying conditions prior to the TOC assessment and was, therefore, classified as a clinical failure.
Enterobacter spp. The clinical cure rate for patients with resistant Enterobacter spp. in the ME population was 3/4 (75%, 95% CI: 19.4–99.4). cSSSIs were most frequently involved, with 3/3 or 100% clinical cure in these patients. One patient with resistant Enterobacter as part of a polymicrobial CAP infection was considered a failure. Microbiological response was identical to the clinical response in these patients, with 3/4 isolates documented or presumed to be eradicated.
A. baumannii. A. baumannii were the most frequently isolated organisms in the trial. The clinical cure rate for patients with resistant Acinetobacter infections in the ME population was 14/17 (82.4%, 95% CI: 56.6–96.2). cSSSIs were most frequently involved with 11/13 (84.6%) of patients with these infections achieving a clinical cure. Microbiological eradication was similar to the clinical response with 11/17 (64.7%) of infecting organisms documented or presumed to be eradicated at TOC assessment. The clinical cure and microbiological eradication rate at TOC in both the ME and m-mITT populations with HAP and baseline A. baumannii were 3/4 (75.0%) and 5/11 (45.5%), respectively.
AEs during the study were similar to those observed in the Phase 3 registration studies of tigecycline. Of the 112 patients in the mITT population, 90 (80.4%) reported one or more treatment-emergent AEs (TEAEs) during the study. The most frequently reported events were nausea (29.5%), vomiting (16.1%) and diarrhoea (16.1%). All of the events were reported as mild-to-moderate in severity [NCI scoring grades 1 or 2 (NCI scoring was used just for nausea and vomiting)],38 with the exception of one report of severe (grade 3) nausea. TEAEs considered by investigators to be related to tigecycline therapy were reported in 39 patients (34.8%); most commonly, in >3% m-ITT population, nausea (20, 17.9%), vomiting (12, 10.7%), diarrhoea (9, 8.0%) and infection, increased serum glutamic pyruvic transaminase and rash (each 4, 3.6%) were reported. Only one patient in the trial discontinued tigecycline because of nausea or vomiting. Concomitant medications to treat or prevent nausea and vomiting were received by 22.3% of the patients, with metoclopramide being used most commonly. In the mITT population, 15 (13.4%) patients discontinued tigecycline because of an AE during the study.
Serious AEs were reported by 34/112 (30.4%) patients during the study. Only two of these events were considered by the investigator to be possibly related to tigecycline, both of which resulted in the discontinuation of treatment. One event was reported as a possible allergic reaction on day 7 during infusion of tigecycline. The other event was reported as thrombocytopenia beginning on day 1 of therapy. Overall, the types of serious AEs reported among this study population were consistent with the severity of illness and underlying disease.
The overall mortality rate for the trial was 20/112 (17.9%) patients. However, as not all patients in the mITT population had baseline isolates meeting the criteria for resistance, these rates are not necessarily those for resistant pathogens. None of these deaths was considered by the investigator to be related to tigecycline treatment, and all were consistent with the patient's underlying disease or a concomitant medical condition. No isolates with decreased susceptibility to tigecycline were identified in these cases.
One patient developed Clostridium difficile infection during therapy. The case was complicated by 7 days of antibiotic therapy with cefazolin, piperacillin/tazobactam, gentamicin and vancomycin prior to the initiation of tigecycline therapy. The patient recovered following treatment with oral vancomycin.
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
In this study of patients with serious infections caused by difficult-to-treat resistant Gram-negative bacteria, an effective clinical cure rate of 72.2% and a microbiological eradication rate of 66.7% were observed with tigecycline therapy in the ME population. Microbiological eradication rates were similar in both monomicrobial (73.3%) and polymicrobial infections (61.9%). The most commonly isolated resistant Gram-negative pathogens in this population were A. baumannii (47%), E. coli (25%), K. pneumoniae (16.7%) and Enterobacter spp. (11.0%), and the most commonly diagnosed serious infections were cSSSIs (67%).
The intrinsic resistance of A. baumannii to many or all currently available antimicrobials is a cause for concern.9,14,24 A high frequency of MDR A. baumannii bloodstream isolates, including those with carbapenem resistance, has been reported from service personnel sustaining traumatic injuries in Afghanistan and Iraq (2002–04), with at least one strain being responsible for further infections in UK and US hospitals receiving these casualties.39,40 Tigecycline Evaluations Surveillance Trial (TEST) data (2004–05) from hospitalized US patients report tigecycline to have the lowest MIC90 against A. baumannii (1 mg/L) compared with imipenem (16 mg/L), and a greater prevalence of imipenem resistance (11.5%) compared with 2004 MYSTIC data (8.5%).41 Against an international collection of bacterial pathogens from skin and soft tissue infections (2000–04), tigecycline inhibited 97% Acinetobacter spp. (MICs 2 mg/L).42 In this present study, in cSSSI patients with baseline isolates of A. baumannii, an effective clinical cure rate (84.6%) and a microbiological eradication rate (61.5%) were observed with tigecycline therapy in the ME population.
TEST data (2004–05) showed that tigecycline activity was unaffected by ESBL production and had the lowest MIC90 (2 mg/L) when compared with other antimicrobials for ESBL-producing K. pneumoniae.28 Tigecycline was the only antimicrobial retaining activity in vitro against >90% of the ESBL producers. Tigecycline efficacy against ESBL-producing organisms may be due to its novel mode of action.43 It is not affected by classical tetracycline resistance mechanisms (ribosomal protection and efflux pumps) and binds to bacterial ribosomes with a >100-fold higher affinity than tetracycline. Tigecycline is thought to share the same mode of action as the tetracyclines in inhibiting bacterial protein synthesis by binding to the A site of the 30S subunit. However, the ability of tigecycline to overcome tetracycline resistance due to ribosomal protection may result from increased binding affinity from interactions with other regions of the A site of the 30S subunit by substantial hydrogen bonding and van der Waal's forces.
Inappropriate antimicrobial therapy is one factor that has led to the increase in resistant Gram-negative bacterial infections in hospitalized patients and is an important determinant of mortality in serious infections.44 Appropriate initial empirical therapy needs to cover the most likely pathogens while limiting the emergence of antibacterial resistance, based on local guidelines, illness severity, presence of risk factors [previous antibiotic exposure, onset and duration of pneumonia (Acinetobacter infection risk increases in pneumonia presenting after patient hospitalization for >5 days)], local pathogen prevalence and antibacterial susceptibility. The American Thoracic Society (ATS) consensus statement for HAP therapy suggests limiting unnecessary antimicrobial utilization by de-escalation and by changing to a more targeted antimicrobial agent in responding patients as culture data become available, with prolonged prophylaxis avoided.45 In this study, in ME patients with HAP, treated with tigecycline, the overall clinical cure and microbiological eradication rates were both 80% (4/5), with rates for patients with baseline K. pneumoniae, both 100% (1/1) and A. baumannii, both 75.0% (3/4).
The safety profile of tigecycline was consistent with the previous studies.35–37 TEAEs in the m-ITT population were most commonly nausea (29.5%), diarrhoea (16.1%) and vomiting (16.1%) and were generally mild or moderate in severity.
The findings in this study were limited by the inability to identify patients with resistant organisms for inclusion into the study until the initial culture results were known, in some cases up to 72 h after presentation. As such, 25 patients did not meet the stringent criteria for the disease under study at the time of enrolment due to improvement in their clinical condition during this time. This requirement also impacted on the ME population, as some of these qualifying organisms could not be re-cultured at the baseline visit at the time of enrolment, even though prior cultures indicated the presence of an ESBL-producing isolate (12 patients). Also, the assessment of clinical response was determined 12–37 days following completion of therapy in order to allow sufficient time for failure. This window includes both the 14 and 28 day follow-up periods often used to assess clinical response. In the non-comparative study design, the impact of these limitations should be minimal and reflects the best attempts to maintain consistency across patient types and study sites.
In this non-comparative trial, tigecycline appeared safe and efficacious in the treatment of selected serious infections caused by resistant Gram-negative bacteria, for which other antimicrobial therapy had failed or in patients unable to tolerate other appropriate antimicrobial therapies. The data from this study are consistent with larger pivotal studies of tigecycline treatment of serious infections.35–37 Tigecycline may be useful as an addition to the clinician's antimicrobial therapy options for difficult-to-treat resistant Gram-negative pathogens associated with serious nosocomial infections and as a part of an overall infection control and pharmacy intervention suggested in the current guidelines.46,47 This study represents a significant population of patients with more severe disease and prior antibiotic failures that are not captured in the Phase 3 registration trials for each indication. These results need to be interpreted in the context of similar studies.
|
Members of the 309 Study Group |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
Jack M. Bernstein (Dayton Veteran's Affairs Medical Center, Dayton, OH, USA); Salah Bibi (Memorial Medical Center, Modesto, CA, USA); Emily A. Blumberg (Hospital of the University of Pennsylvania, Philadelphia, PA, USA); J. Breedt (Bougainville Centre, Pretoria, Republic of South Africa); Petre Iacob Calistru (Clinical Hospital of Infectious Diseases ‘Victor Babes’, Bucharest, Romania); Maria Isabel Campos (Hospital de Urgencia Asistencia Publica, Santiago, Chile); Liliana Ofelia Clara (Hospital Italiano de Buenos Aires, Argentina); Claudia Maria Dantas de Malo Carrilho (Hospital Univeritario Regional Norte do Parana, Brazil); Pieter Depuydt (UZ Gent, Gent, Belgium); Alexey Datsenko (Kharkiv Medical Academy of Post Graduate Education, Kharkov, Ukraine); Professor Peter Fomin (University named after A. A. Bogomolets, Kyviv, Ukraine); Amalia Rodriguez French (Hospital Santo Tomas, Panama); Antonio Tarcisiode Faria Friere (Santa Casa de Belo Horizonte, Brazil); Maria Cristina Ganaha (Sanatorio Guemes, Buenos Aires, Argentina); Helen Giamarellou (Attikon University Hospital of Western Athens, Greece); Donald Graham (Springfield Clinic, Springfield, IL, USA); Daniel L. Herr (Washington Hospital Center, Washington, DC, USA); Don Iradell (Westmead Hospital, NSW, Australia); Luis Ernesto Jauregi-Peredo (St Vincent Mercy Medical Center, Toledo, OH, USA); Manjari Joshi (R. Adams Cowley Shock Trauma Center, Baltimore, MD, USA); Thomas Adam Kaspar (DeTar Hospital, Victoria, TX, USA); Krzysztof Kolomecki (Klinika Chirurgii Endokrynologicznej, Lodz, Poland); Jaime Alejandro Labarca (Hospital Clinico de la Pontifica Universidad, Santiago, Chile); Flavia Ribeiro Machado (Hospital Sao Paulo da UNIFESP—Escola Paulista de Medicina, Brazil); Jack McCue (Franklin Square Hospital Center, Baltimore, MD, USA); Ana Luisa Corona Nakamura (UMAE Hospital de Especialidades ‘Lic. Ignacio Garcia Tellez’, Jalisco, Mexico); Borislav Tzvetanov Ninov (First Surgery Clinic Multiprofile Hospital for Active Treatment, Bulgaria); Eduardo Rodriguez Noriega (Antiguo Hospital Civil de Guadalajara ‘Fray Antonio Alcalde’, Jal, Mexico); Maria Eugenia Oliva (Hospital San Martin, Parana-Provincia de Entre Rios, Argentina); Remus Orasan (Clinical County Hospital Cluj-Napoca, Cluj-Napoca, Romania); Marek Ostrowski (Klinika Chirurgii Ogolnej I Transplantacyjnej, Szczecin, Poland); Guilermo M. Palacios (Institution Nacional de Ciencias Medicas y Nutricion ‘Salvador Zubiran’, Mexico D.F. Mexico); Philip J. Palmieri (Upstate Infectious Disease Associates LLP, NY, USA); Lance Peterson (Evanston Hospital, Evanston, IL, USA); Annette C. Reboli (Cooper University Hospital, Camden, NJ, USA); John F. Reinhardt (Christiana Care Health Services, Newark, NJ, USA); Miguel Sanchez (Hospital Universitario Principe de Asturias, Madrid, Spain); Galina K. Reshedko (Institute of Antimicrobial Chemotherapy of Smolensk State Medical Academy, Smolensk, Russia); Silvana Maria de Barros Richardo (Hospital Governador Israel Pinheiro, Brazil); Claudia Gabriela Rodriguez (Hospital General de Agudos Dr Cosme Argerich, Buenos Aires, Argentina); Diana Brasil Pedral Sampaio (Universidalde Federal da Bahia—Hospital, Universitario Prof Edgard Santos, Bahia, Brazil); Priscilla Siosan (Jackson- Madison County General Hospital, Jackson, TN, USA); Joseph M. Sirvent (Hospital Univeritari de Girona Doctor Josep Trueta, Girona, Spain); Latha Srinath (Bethesda Memorial Hospital, Boynton Beach, FL, USA); Byungse Suh (Temple University Hospital, Philadelphia, PA, USA); Jihad Slim (St Michael Medical Center, Newark, NJ, USA); S. Sudhindran (Amrita Institute of Medical Sciences and Research Centre, Cochin, India); Elena Rosa Temporiti (CEMIC, Buenos Aires, Argentina); Juri Teras (North Estonia Regional Hospital, Tallinn, Estonia); Krasimir Stefanov Vasilev (Clinic of Endoscopic Surgery, Military Medical Academy, Sofia, Bulgaria); Silvestrs Zebolds (Hospital of Traumatology and Orthopedics, Riga, Latvia).
|
Funding |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
This study was supported by Wyeth Research.
|
Transparency declarations |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
This article is part of a Supplement sponsored by Wyeth. K. V., G. R., R. O., M. S. and J. T. have no conflicts of interest to disclose. G. D., T. B., R. O. and A. C. are employees and shareholders of Wyeth Pharmaceuticals, USA. N. D. and H. G. are employees of Wyeth Research, France. E. E-G. is a former employee of Wyeth Research, USA. K. V., G. R., R. O., M. S. and J. T. conducted the study, contributed to data acquisition and reviewed the draft manuscript. G. D., T. B., N. D., H. G., R. O., E. E-G. and A. C. contributed to, reviewed, and approved the draft manuscript. T. B and K. V. reviewed and approved the final version. Wyeth employees had full access to, and take responsibility for the data and analyses.
Editorial assistance during the preparation of this manuscript was provided by Hessam Alimohammedi (Upside Endeavors, Sanatoga, USA).
|
Footnotes |
|---|
Present address: e2g Biopharmaceutical Consulting, 994 Skelp Level Road, Downingtown, PA 19335, USA 
|
Acknowledgements |
|---|
We would like to thank Wyeth Research employee Patricia Bradford for microbiological analyses and Upside Endeavors for editorial support with the manuscript.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionMembers of the 309...FundingTransparency declarationsReferences |
|---|
1 Tumbarello M, Spanu T, Sanguinetti M, et al. Bloodstream infections caused by extended-spectrum-beta-lactamase-producing Klebsiella pneumoniae: risk factors, molecular epidemiology, and clinical outcome. Antimicrob Agents Chemother (2006) 50:498–504.
2 Strausbaugh LJ, Siegel JD, Weinstein RA. Preventing transmission of multidrug-resistant bacteria in health care settings: a tale of 2 guidelines. Clin Infect Dis (2006) 42:828–35.[CrossRef][Web of Science][Medline]
3
Kang CI, Kim SH, Park WB, et al. Bloodstream infections due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae: risk factors for mortality and treatment outcome, with special emphasis on antimicrobial therapy. Antimicrob Agents Chemother (2004) 48:4574–81.
4 Paterson DL. Resistance in Gram-negative bacteria: Enterobacteriaceae. Am J Infect Control (2006) 34:S20–8. discussion S64–73.[CrossRef][Web of Science][Medline]
5 Pfaller MA, Segreti J. Overview of the epidemiological profile and laboratory detection of extended-spectrum beta-lactamases. Clin Infect Dis (2006) 42(Suppl 4):S153–63.[CrossRef][Web of Science][Medline]
6 Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med (2006) 119:S3–10. discussion S62–70.[Medline]
7 Rice LB. Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa. Clin Infect Dis (2006) 43(Suppl 2):S100–5.[CrossRef][Web of Science][Medline]
8 Deshpande LM, Rhomberg PR, Sader HS, et al. Emergence of serine carbapenemases (KPC and SME) among clinical strains of Enterobacteriaceae isolated in the United States Medical Centers: report from the MYSTIC Program (1999–2005). Diagn Microbiol Infect Dis (2006) 56:367–72.[CrossRef][Web of Science][Medline]
9 Livermore DM, Woodford N. The beta-lactamase threat in Enterobacteriaceae, Pseudomonas and Acinetobacter. Trends Microbiol (2006) 14:413–20.[CrossRef][Web of Science][Medline]
10
Lolans K, Rice TW, Munoz-Price LS, et al. Multicity outbreak of carbapenem-resistant Acinetobacter baumannii isolates producing the carbapenemase OXA-40. Antimicrob Agents Chemother (2006) 50:2941–5.
11 Pottumarthy S, Moland ES, Juretschko S, et al. NmcA carbapenem-hydrolyzing enzyme in Enterobacter cloacae in North America. Emerg Infect Dis (2003) 9:999–1002.[Web of Science][Medline]
12
Pournaras S, Markogiannakis A, Ikonomidis A, et al. Outbreak of multiple clones of imipenem-resistant Acinetobacter baumannii isolates expressing OXA-58 carbapenemase in an intensive care unit. J Antimicrob Chemother (2006) 57:557–61.
13 Poirel L, Nordmann P. Carbapenem resistance in Acinetobacter baumannii: mechanisms and epidemiology. Clin Microbiol Infect (2006) 12:826–36.[CrossRef][Web of Science][Medline]
14 Fournier PE, Vallenet D, Barbe V, et al. Comparative genomics of multidrug resistance in Acinetobacter baumannii. PLoS Genet (2006) 2:e7.[CrossRef][Medline]
15
Paterson DL, Bonomo RA. Extended-spectrum beta-lactamases: a clinical update. Clin Microbiol Rev (2005) 18:657–86.
16 Winokur PL, Canton R, Casellas JM, et al. Variations in the prevalence of strains expressing an extended-spectrum beta-lactamase phenotype and characterization of isolates from Europe, the Americas, and the Western Pacific region. Clin Infect Dis (2001) 32(Suppl 2):S94–103.[CrossRef][Web of Science][Medline]
17
Rossi F, Baquero F, Hsueh PR, et al. In vitro susceptibilities of aerobic and facultatively anaerobic Gram-negative bacilli isolated from patients with intra-abdominal infections worldwide: 2004 results from SMART (Study for Monitoring Antimicrobial Resistance Trends). J Antimicrob Chemother (2006) 58:205–10.
18 Moet GJ, Jones RN, Biedenbach DJ, et al. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Diagn Microbiol Infect Dis (2007) 57:7–13.[CrossRef][Web of Science][Medline]
19 Jones RN. Global epidemiology of antimicrobial resistance among community-acquired and nosocomial pathogens: a five-year summary from the SENTRY Antimicrobial Surveillance Program (1997–2001). Semin Respir Crit Care Med (2003) 24:121–34.[CrossRef][Web of Science][Medline]
20 Goossens H, Grabein B. Prevalence and antimicrobial susceptibility data for extended-spectrum beta-lactamase- and AmpC-producing Enterobacteriaceae from the MYSTIC Program in Europe and the United States (1997–2004). Diagn Microbiol Infect Dis (2005) 53:257–64.[CrossRef][Web of Science][Medline]
21 Fournier PE, Richet H. The epidemiology and control of Acinetobacter baumannii in health care facilities. Clin Infect Dis (2006) 42:692–9.[CrossRef][Web of Science][Medline]
22 Robenshtok E, Paul M, Leibovici L, et al. The significance of Acinetobacter baumannii bacteraemia compared with Klebsiella pneumoniae bacteraemia: risk factors and outcomes. J Hosp Infect (2006) 64:282–7.[CrossRef][Web of Science][Medline]
23 Ramphal R, Ambrose PG. Extended-spectrum beta-lactamases and clinical outcomes: current data. Clin Infect Dis (2006) 42(Suppl 4):S164–72.[CrossRef][Web of Science][Medline]
24 McGowan JJE. Resistance in nonfermenting Gram-negative bacteria: multidrug resistance to the maximum. Am J Med (2006) 119:S29–36.[Medline]
25 Owens RC Jr, Rice L. Hospital-based strategies for combating resistance. Clin Infect Dis (2006) 42(Suppl 4):S173–81.[CrossRef][Web of Science][Medline]
26 Biedenbach DJ, Beach ML, Jones RN. In vitro antimicrobial activity of GAR-936 tested against antibiotic-resistant Gram-positive blood stream infection isolates and strains producing extended-spectrum beta-lactamases. Diagn Microbiol Infect Dis (2001) 40:173–7.[CrossRef][Web of Science][Medline]
27 Fritsche TR, Strabala PA, Sader HS, et al. Activity of tigecycline tested against a global collection of Enterobacteriaceae, including tetracycline-resistant isolates. Diagn Microbiol Infect Dis (2005) 52:209–13.[CrossRef][Web of Science][Medline]
28
Waites KB, Duffy LB, Dowzicky MJ. Antimicrobial susceptibility among pathogens collected from hospitalized patients in the United States and in vitro activity of tigecycline, a new glycylcycline antimicrobial. Antimicrob Agents Chemother (2006) 50:3479–84.
29 Fraise AP. Tigecycline: the answer to beta-lactam and fluoroquinolone resistance? J Infect (2006) 53:293–300.[CrossRef][Web of Science][Medline]
30 Bouchillon S, Stevens T, Johnson B, et al. Tigecycline evaluation surveillance trial (TEST)—United States in vitro antibacterial activity against selected species of glucose non-fermenting organisms. In: Clin Microbiol Infect (2005) 11. Abstracts of 15th European Congress of Clinical Microbiology and Infectious Diseases, 2005: Copenhagen, Denmark. (Suppl 2):243. Abstract P814. ESCMID.[CrossRef][Web of Science][Medline]
31 Johnson B, Bouchillon S, Stevens T, et al. A global surveillance to determine tigecycline's in vitro activity against multi-drug resistant Enterobacteriaceae. Abstracts of Infectious Disease Society of America, San Francisco, USA, 2005. Abstract 445. Infectious Diseases Society of America, Arlington, VA, USA.
32
Pachon-Ibanez ME, Jimenez-Mejias ME, Pichardo C, et al. Activity of tigecycline (GAR-936) against Acinetobacter baumannii strains, including those resistant to imipenem. Antimicrob Agents Chemother (2004) 48:4479–81.
33
Dean CR, Visalli MA, Projan SJ, et al. Efflux-mediated resistance to tigecycline (GAR-936) in Pseudomonas aeruginosa PAO1. Antimicrob Agents Chemother (2003) 47:972–8.
34
Visalli MA, Murphy E, Projan SJ, et al. AcrAB multidrug efflux pump is associated with reduced levels of susceptibility to tigecycline (GAR-936) in Proteus mirabilis. Antimicrob Agents Chemother (2003) 47:665–9.
35 Babinchak T, Ellis-Grosse E, Dartois N, et al. The efficacy and safety of tigecycline for the treatment of complicated intra-abdominal infections: analysis of pooled clinical trial data. Clin Infect Dis (2005) 41(Suppl 5):S354–67.[CrossRef][Web of Science][Medline]
36 Dukart G, Dartois N, Cooper CA, et al. Integrated results of 2 phase 3 studies comparing tigecycline (TGC) with levofloxacin (LEV) in patients (Pts) with community-acquired pneumonia (CAP). Abstracts of 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2006: San Francisco, USA. American Society of Microbiology. Abstract L-14540, p. 379.
37 Ellis-Grosse EJ, Babinchak T, Dartois N, et al. The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis (2005) 41(Suppl 5):S341–53.[CrossRef][Web of Science][Medline]
38 Rhodes VA, McDaniel RW. The index of nausea, vomiting, and retching: a new format of the index of nausea and vomiting. Oncol Nurs Forum (1999) 26:889–94.[Medline]
39 Centers for Disease Control and Prevention. Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002–2004. MMWR Morb Mortal Wkly Rep (2004) 53:1063–6.[Medline]
40
Turton JF, Kaufmann ME, Gill MJ, et al. Comparison of Acinetobacter baumannii isolates from the United Kingdom and the United States that were associated with repatriated casualties of the Iraq conflict. J Clin Microbiol (2006) 44:2630–4.
41 Rhomberg PR, Fritsche TR, Sader HS, et al. Comparative antimicrobial potency of meropenem tested against Gram-negative bacilli: report from the MYSTIC surveillance program in the United States (2004). J Chemother (2005) 17:459–69.[Web of Science][Medline]
42 Fritsche TR, Sader HS, Stilwell MG, et al. Potency and spectrum of tigecycline tested against an international collection of bacterial pathogens associated with skin and soft tissue infections (2000–2004). Diagn Microbiol Infect Dis (2005) 52:195–201.[CrossRef][Web of Science][Medline]
43
Olson MW, Ruzin A, Feyfant E, et al. Functional, biophysical, and structural bases for antibacterial activity of tigecycline. Antimicrob Agents Chemother (2006) 50:2156–66.
44 Kollef M. Appropriate empirical antibacterial therapy for nosocomial infections: getting it right the first time. Drugs (2003) 63:2157–68.[CrossRef][Web of Science][Medline]
45 Hospital-acquired pneumonia in adults: diagnosis, assessment of severity, initial antimicrobial therapy, and preventive strategies. A consensus statement, American Thoracic Society, November 1995. Am J Respir Crit Care Med (1996) 153:1711–25.[Web of Science][Medline]
46 Harris AD, McGregor JC, Furuno JP. What infection control interventions should be undertaken to control multidrug- resistant Gram-negative bacteria? Clin Infect Dis (2006) 43(Suppl 2):S57–61.[CrossRef][Web of Science][Medline]
47 Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis (2007) 44:159–77.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. G. Zhanel, P. J. Baudry, F. Tailor, L. Cox, D. J. Hoban, and J. A. Karlowsky Determination of the pharmacodynamic activity of clinically achievable tigecycline serum concentrations against clinical isolates of Escherichia coli with extended-spectrum {beta}-lactamases, AmpC {beta}-lactamases and reduced susceptibility to carbapenems using an in vitro model J. Antimicrob. Chemother., October 1, 2009; 64(4): 824 - 828. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Nicasio, J. L. Crandon, and D. P. Nicolau In Vivo Pharmacodynamic Profile of Tigecycline against Phenotypically Diverse Escherichia coli and Klebsiella pneumoniae Isolates Antimicrob. Agents Chemother., July 1, 2009; 53(7): 2756 - 2761. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Koomanachai, A. Kim, and D. P. Nicolau Pharmacodynamic evaluation of tigecycline against Acinetobacter baumannii in a murine pneumonia model J. Antimicrob. Chemother., May 1, 2009; 63(5): 982 - 987. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. C. Gordon and D. W. Wareham A review of clinical and microbiological outcomes following treatment of infections involving multidrug-resistant Acinetobacter baumannii with tigecycline J. Antimicrob. Chemother., April 1, 2009; 63(4): 775 - 780. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||