Tigecycline Evaluation Surveillance Trial Research Articles

Prevalence of RND efflux pump regulator variants associated with tigecycline resistance in carbapenem-resistant Acinetobacter baumannii from a worldwide survey

To determine the most common tigecycline resistance mechanisms in carbapenem-resistant Acinetobacter baumannii isolates obtained during the global Tigecycline Evaluation Surveillance Trial (TEST). Tigecycline MICs were determined by broth microdilution. WGS was used to screen for the previously identified tigecycline resistance mechanisms, as well as mutations in resistance-nodulation-cell division (RND)-type efflux pump regulators. From a total 313 isolates, 113 genetically unique tigecycline-resistant isolates were analysed. The most frequent and worldwide distributed mechanism associated with tigecycline resistance was disruption of adeN, which encodes the repressor of the RND efflux pump AdeIJK, either by IS elements or nucleotide deletions causing premature stop codons. However, mutations leading to amino acid substitutions and disruption by IS elements within the two-component regulatory system adeRS, which regulates expression of the AdeABC efflux pump, correlate with higher tigecycline MICs, but these were found less frequently and were mainly restricted to Southern European countries. Furthermore, an altered version of tviB was identified in several tigecycline-resistant isolates that did not have putative resistance mutations within RND-type regulators. The resistance determinants tet(A) and tet(X), as well as resistance mutations in putative resistance determinants trm, plsC, rrf, msbA and genes encoding 30S ribosomal proteins, were not identified in any isolate. The most prevalent tigecycline resistance mechanisms were caused by alterations in the regulators of RND-type efflux pumps. These data provide the basis for further characterization of regulator alterations and their contribution to increased efflux and tigecycline resistance, and also should be taken into account in drug discovery programmes to overcome the contribution of efflux pumps.

Distribution of Streptococcus pneumoniae serotypes in isolates collected from sterile body sites in the United States (US), 2004-2015

Background: Streptococcus pneumoniae remains a leading cause of disease in children and adults. Serotypes differ in invasiveness, virulence and antibiotic resistance; therefore, serotype surveillance is necessary to monitor the seroepidemiology of invasive pneumococcal disease. The serotypes and antibiotic susceptibilities of 2,105 S. pneumoniae isolates (from sterile body sites) collected in the US through the Tigecycline Evaluation Surveillance Trial, (TEST) 2004-2015, were evaluated. Methods & Materials: Serotypes were determined by PCR; isolates non-typeable by PCR were serotyped by the Quellung reaction. Minimum inhibitory concentrations were determined by broth microdilution and interpreted using CLSI guidelines. Results: In the US, in the 2010-2015 time period, serotypes 19A (27.3%), 35B (18.2%), 3 (9.1%), and 34 (6.8%) were the most common in children under 2 y. In adults ≥65 y, serotypes 19A (10.0%), 22F (8.2%), 23A (8.2%), 35B (7.8%), and 3 (7.3%) were most common. Overall, the proportion of isolates with PCV13 serotypes declined when comparing the pre-PCV13 and post-PCV13 time periods [Figure 1]. The proportion of isolates of serotype 19A that were penicillin-susceptible (PSSP) decreased in the post-PCV13 period (74.8% (2004-2009) compared to 44.6% (2010-2015)). However, the overall proportion of PSSP changed only modestly between 2004-2009 (92.5%) and 2010-2015 (91.2%). The proportion of erythromycin-resistant isolates increased in the later time period and shifted in serotype distribution, with the highest percentages found in serotypes 19A, 33F, 15A, 33A, and 35B in 2010-2015, compared to 15A, 9 V, 19F, 14, and 19A in 2004-2009. Conclusion: These data, although limited in numbers, demonstrate that vaccination of infants with PCVs has resulted in reductions in invasive disease caused by PCV7/13 serotypes, but some residual disease remains in all age groups. The 2014 recommendation to vaccinate all adults ≥65 with PCV13 was warranted to further reduce invasive disease in this age group. Susceptibility of S. pneumoniae to antimicrobial agents commonly used as part of empiric therapy further documents the value of vaccination programs and the need for ongoing monitoring of the seroepidemiology of this important pathogen.

Tigecycline Susceptibility Trends Among Pathogens Isolated from Complicated Skin and Soft-Tissue Infections in North and Latin America: 2012–2016

Background The Tigecycline Evaluation Surveillance Trial (TEST) monitors the activity of tigecycline and other antimicrobials against clinically-relevant pathogens collected globally. This study reports the activity of tigecycline (TGC) against Gram-positive and Gram-negative isolates collected in North and Latin America from patients with complicated skin and soft-tissue infections (CSSTI).Methods Hospital sites from North America (NA) and Latin America (LA) collected non-duplicate clinical Gram-positive and -negative isolates from various complicated skin and skin structure infection sources during 2012–2016. Organism identification and antibiotic susceptibility (S) testing was performed by the local laboratories. Susceptibility testing was determined using the broth microdilution method according to CLSI guidelines and categorical interpretation of results was done using CLSI or FDA (tigecycline) breakpoint criteria where appropriate. Cefoxitin disk testing was performed for all S. aureus to determine methicillin susceptibility (i.e., MRSA and MSSA).ResultsThe table provides %S and MIC90 data for TGC against CSSTI isolates Region, n, %S, MIC 90 (µg/ml) North America Latin America Organism n %S MIC 90 n %S MIC 90 S. aureus 22701000.123101000.25 Enterobacter spp. 92596.4115992.52 P. aeruginosa 758na*> 8165na> 8 E. coli 71699.90.252411000.25 Enterococcus spp. 69199.30.121351000.12 S. agalactiae 5031000.12581000.06 K. pneumoniae 47194.9215291.52 S. marcescens 34796.826797.02 A. baumannii 310na*297na1 K. oxytoca 20499.00.5151001*na = not applicable or no breakpoints available for this species.ConclusionBased on %S and MIC90 data TGC exhibited potent activity against isolates of all organism groups from complicated skin and soft-tissue infections, regardless of the geographic region. However, given the potential many of these organisms have for developing resistance, continued and careful surveillance monitoring is warranted.Disclosures M. Renteria, IHMA, Inc.: Employee, Salary. H. Leister-Tebbe, Pfizer: Employee, Salary

In Vitro Susceptibility Profiles of Klebsiella spp. Isolated from ICU and non-ICU Wards in North and Latin America (TEST Program 2012–2016)

Klebsiella spp. are one of the most frequently isolated Gram-negative pathogens infecting seriously ill patients in intensive care units. Increasing resistance mechanisms associated with this species group has led to the inclusion of K. pneumoniae as a member of the ESKAPE pathogens as determined by the Infectious Disease Society of America (IDSA). Regional variations of susceptibility to several classes of antimicrobial agents can provide guidance when selecting appropriate antimicrobial therapy. Data from Tigecycline Evaluation Surveillance Trial (TEST) program 2012-2016 were used to determine antimicrobial susceptibility patterns in Klebsiella spp.in patients in ICUs and non-ICUs in both Latin America (LA) and North America (NA). Klebsiella spp. isolates were identified locally and antimicrobial susceptibility testing was done using broth microdilution according to CLSI guidelines at each participating institution in NA and LA. CLSI or FDA (tigecycline) breakpoint criteria were applied to define susceptibility status. Susceptibility by region and patient location are shown in the following table. Klebsiella spp. infections are becoming a treatment challenge due to several resistance mechanisms, particularly β-lactamases. Decreased activities among all agents were observed among Klebsiella spp. isolates collected in LA compared with NA. Isolates of Klebsiella spp. collected from patients in ICU wards demonstrated comparable susceptibility to those from non-ICU wards in both North America and Latin America. Because resistance patterns can vary with patient locations continued monitoring of antimicrobial trends based on location parameters is warranted. M. Renteria, IHMA, Inc.: Employee, Salary. H. Leister-Tebbe, Pfizer: Employee, Salary

In vitro activity of tigecycline and comparators against carbapenem-resistant Enterobacteriaceae in Africa-Middle East countries: TEST 2007-2012.

Multidrug-resistant (MDR) Enterobacteriaceae are an emerging concern for healthcare providers. Infections caused by MDR pathogens are associated with increased costs, length of hospital stay, and morbidity and mortality rates. Carbapenem-resistant Enterobacteriaceae (CRE) continue to increase, and infections with these organisms are observed worldwide not only as hospital-acquired infections but also as community-acquired infections. Increasing antimicrobial resistance dictates the need for continued surveillance studies of common and MDR pathogens. The Tigecycline Evaluation Surveillance Trial (TEST) examined the susceptibility of pathogens isolated in Africa and the Middle East from 2007 to 2012. A total of 4155 Enterobacteriaceae isolates were evaluated to determine the in vitro activity and changes in resistance patterns for tigecycline and comparators. Carbapenem resistance was found in 191 (4.6%) of the isolates tested. Klebsiella pneumoniae was the most common CRE (64.9%), followed by Enterobacter cloacae (14.1%) and Escherichia coli (9.9%). Tigecycline MIC90 values (minimum inhibitory concentration required to inhibit 90% of the isolates) were 2μg/mL against all of these enteric species, with susceptibility rates of 96.8%, 92.6% and 100%, respectively. Tigecycline had in vitro activity against CRE, with a 95.3% susceptibility rate.

Serotype prevalence and antibiotic resistance in Streptococcus pneumoniae clinical isolates among global populations

Streptococcus pneumoniae remains a leading cause of disease in children and adults. Serotypes differ in invasiveness, virulence, and antibiotic resistance; therefore, serotype surveillance is necessary to monitor the burden of pneumococcal disease, especially in the setting of pneumococcal vaccination programs. The Tigecycline Evaluation Surveillance Trial, (TEST), is an on-going global antibiotic susceptibility surveillance program. Serotypes and antibiotic susceptibilities of 2173 invasive S. pneumoniae in this existing database during 2004–2008 were evaluated. Worldwide, serotypes 19A (28%), 19F (10%) and 14 (9%) were the most common in children under 5 years. In adults over 16 years, 19A (13%), 3, 6A and 7F (all 7%) were most common. Serotypes 19A, 6A, 19F, 6B, 15A, 9V, and 14 exhibited significantly higher levels of erythromycin resistance (P<0.05), while 19A, 19F, 35B, 6A, 6B, 23A, 9V, 15A, and 14 demonstrated higher rates of penicillin resistance (P<0.05). This analysis of an existing pathogen database provides a snapshot of global serotype data and describes the consequential issue of antibiotic resistance in specific serotypes, many of which are increasingly common causes of invasive pneumococcal disease.

Trending 7 years of in vitro activity of tigecycline and comparators against Gram-positive and Gram-negative pathogens from the Asia-Pacific region: Tigecycline Evaluation Surveillance Trial (TEST) 2004–2010

A total of 10948 clinical isolates was collected throughout the Asia-Pacific region as part of the Tigecycline Evaluation Surveillance Trial (TEST) during 2004–2010, consisting of 7549 Gram-negative and 3399 Gram-positive pathogens. Susceptibility trends for all species demonstrated several significant species-dependent susceptibility changes to multiple antibiotics. The most notable was minocycline, for which significant decreases in susceptibility (P<0.001) were observed for six of the ten species studied. In contrast, statistically significant susceptibility changes for tigecycline were observed in only two of the ten species, namely Klebsiella pneumoniae and Serratia marcescens. Seven years following the introduction of tigecycline into clinical use, this agent remains highly active against a wide range of pathogens from the Asia-Pacific region.

Resistance trends and in vitro activity of tigecycline and 17 other antimicrobial agents against Gram-positive and Gram-negative organisms, including multidrug-resistant pathogens, in Germany

To document the development of resistance to tigecycline in comparison with 17 other antimicrobials, the susceptibilities of 2,741 isolates comprising 16 bacterial species recovered from hospitalised patients in 15 German centres in 2009 were assessed. The results were compared with those of previous trials (German Tigecycline Evaluation Surveillance Trial, G-TEST I and II, performed in 2005 and 2007, respectively) conducted prior to and shortly after the introduction of tigecycline in Germany. Moreover, the in vitro activities of tigecycline against the subset of multidrug-resistant (MDR) pathogens recovered within all three sampling periods (n = 4,988) were evaluated in comparison to the corresponding non-MDR isolates. All susceptibility tests were performed by broth microdilution. Between 2005 and 2009, tigecycline retained its high activity against Gram-positive and Gram-negative organisms, including MDR pathogens. By contrast, an in part marked increase in resistance to broad-spectrum beta-lactams and fluoroquinolones was observed for many Enterobacteriaceae and for non-fermenting Gram-negative bacteria. Against a background of a steadily increasing number of multiresistant pathogens, the activity of tigecycline remained unaltered. With the exception of Acinetobacter isolates with decreased susceptibility to carbapenems, tigecycline's activity profile was not notably affected by organisms resistant to other drug classes and, thus, holds promise as an important therapeutic agent, particularly for situations in which MDR organisms are suspected.

Comparative Evaluation of Tigecycline and other Antimicrobials in the United States Against Multi-drug Resistant (MDR) Staphylococcus aureus

Objectives: Worldwide methicillin-resistant S.aureus (MRSA) are increasing dramatically with corresponding resistance to multiple drug classes (MDR). Tigecycline, a new glycylcycline offers the potential of enhanced activity against MDR S. aureus. The tigecycline evaluation surveillance trial (T.E.S.T.) evaluated the activity of tigecycline and comparators to MDR S. aureus(including MR + MS strains) isolated in the United States. Methods: 193 hospital sites in the United States, between 2004 and 2007, collected 5280 clinically significant S. aureus. MICs were performed as specified by CLSI at each site. Results: MIC90 of tigecycline and comparators to S. aureus resistant groups 0–3+ are shown in the following table: Conclusions: Tigecycline demonstrated in vitro activity comparable to that of linezolid and vancomycin against all multidrug resistant groups of S. aureus. Tigecycline in vitro activity is unaffected by multidrug resistant phenotypes of S. aureus and offers an alternative in the treatment of infections due to S. aureus where approved indications apply.

In Vitro Potency of Tigecycline Against Pathogens from Most Common Body Sites: A Study in Asia/Pacific Rim

Objectives: Surveillance studies can identify patterns of resistance and assist in empiric antibiotic choices as resistance can vary by organism and body site isolation. The Tigecycline Evaluation Surveillance Trial (T.E.S.T.) is an ongoing global study that can serve to help recognize resistance by body site. This report evaluates differences in susceptibility of strains from different body sites, collected in Asia/Pacific Rim 2004–2007. Methods: 4057 strains isolated from 8 specimen types were collected and identified from 2004 to 2007 at 23 hospitals in 9 countries in Asia/Pacific Rim. MICs for each strain were determined per CLSI guidelines at each facility using broth microdilution. MIC50/90 values were analyzed to identify any significant differences in antibiograms from different sources. Results: Tigecycline (TIG) MIC50 values for almost all organism/specimen pairings were ±2 dilutions of each other, with no single source giving a higher MIC50 than others. The same was seen for TIG MIC90 values, which were almost always within 1–2 dilutions of the MIC50. Comparator drugs generally showed similar absence of variability in activity vs. isolates from various body sites; however, their MIC90/MIC50 ratios were usually much higher than those of TIG. Even imipenem had such high ratios with Acinetobacter and Enterococus spp. Conclusions: Bacteria isolated from more than 10 different body sites had generally similar antibiograms, with no single source showing significantly different sensitivity patterns. TIG demonstrated a broad spectrum of activity and consistently low MIC90/50 ratios, including strains resistant to other drugs (MRSA, ESBL-producers, and imipenem-resistant Acinetobacter).

Multi-Drug Resistant (MDR) S. aureus Against Tigecycline and Comparators: A Global Evaluation

Background: Worldwide S. aureus are increasingly displaying resistance to multiple drug classes. Therapeutic options to multi-drug resistant (MDR) S. aureus phenotypes are limited. Tigecycline, a new glycylcycline offers the potential of enhanced activity against MDR S. aureus. The tigecycline evaluation surveillance trial (T.E.S.T.) evaluated the activity of tigecycline and comparators to MDR S. aureus isolated worldwide. Methods: 335 hospital sites in 47 countries between 2004 and 2007 collected 7,557 clinically significant S. aureus. MICs were determined using broth microdilution panels and results interpreted as specified by CLSI at each site. S. aureus strains were categorized into groups according to the number of drug classes to which they were resistant (MDR groups 0 to 4). Results: MIC90 of tigecycline and comparators for MDR groups 0 to 4 are shown in the table. Conclusions: Tigecycline in comparison to 10 relevant comparators exhibited the lowest MIC90 against S. aureus isolated worldwide irrespective of MDR phenotype and multiple drug class resistance.

Tigecycline Comparison with Minocycline Resistance Pathogens. A Worldwide Perspective

Objectives: Tigecycline, a new glycylcycline is an analogue of tetracycline that demonstrates activity against bacterial strains carrying tetracycline (minocycline) resistance mechanisms. This report documents the activity of TIG against minocycline resistant isolates collected worldwide, 2004–2007, as part of the Tigecycline Evaluation Surveillance Trial (TEST) study. Methods: Between 2004 and 2007, 387 hospital sites in 48 countries collected significant pathogens associated with 8 specimen types, were identified to species level and MICs performed for each strain to a supplied panel of antibiotics and interpreted according to CLSI guidelines. Results: The table below illustrates the activity of tigecycline to minocycline resistant pathogens. Conclusions: Tigecycline MIC90s were ≤0.5 mcg/ml for minocycline resistant gram-positive pathogens such as Enterococcus and S. aureus (including MRSA) and ≤8 mcg/ml for minocycline resistant gram-negative pathogens such as Enterobacteriaceae, including ESBL producers. Tigecycline demonstrated minimal activity against P. aeruginosa. Tigecycline demonstrates enhanced activity to many minocycline resistant pathogens.

P2047 Tigecycline Evaluation Surveillance Trial (T.E.S.T.)–United States in vitro antibacterial activity against selected species of Enterococcus spp.

P2047 Tigecycline Evaluation Surveillance Trial (T.E.S.T.)–United States in vitro antibacterial activity against selected species of Enterococcus spp.

A7.5 In Vitro antibacterial activity against Gram-positive and Gram-negative pathogens in Asia - Tigecycline evaluation surveillance trial (T.E.S.T.)

A7.5 In Vitro antibacterial activity against Gram-positive and Gram-negative pathogens in Asia - Tigecycline evaluation surveillance trial (T.E.S.T.)

A7.8 In Vitro antimicrobial activity against Gram-positive and Gram-negative pathogens in the united states — tigecycline evaluation surveillance trial (T.E.S.T.)

A7.8 In Vitro antimicrobial activity against Gram-positive and Gram-negative pathogens in the united states — tigecycline evaluation surveillance trial (T.E.S.T.)

A7.9 Global in vitro antibacterial activity against Gram-positive and Gram-negative pathogens — tigecycline evaluation surveillance trial (T.E.S.T.)

A7.9 Global in vitro antibacterial activity against Gram-positive and Gram-negative pathogens — tigecycline evaluation surveillance trial (T.E.S.T.)

A7.7 In Vitro antibacterial activity against Gram-positive and Gram-negative pathogens in Europe — tigecycline evaluation surveillance trial (T.E.S.T.)

A7.7 In Vitro antibacterial activity against Gram-positive and Gram-negative pathogens in Europe — tigecycline evaluation surveillance trial (T.E.S.T.)