ABSTRACT
We evaluated the activity of minocycline and comparator agents against a large number of Stenotrophomonas maltophilia (n = 1,289), Acinetobacter baumannii-Acinetobacter calcoaceticus species complex (n = 1,081), and Burkholderia cepacia complex (n = 101) isolates collected from 2014 to 2018 from 87 U.S. medical centers spanning all 9 census divisions. The isolates were collected primarily from hospitalized patients with pneumonia (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall). Against the A. baumannii-A. calcoaceticus species complex, colistin was the most active agent, exhibiting MIC50/90 values at ≤0.5/2 μg/ml and 92.4% susceptibility. Minocycline ranked second in activity, with MIC50/90 values at 0.25/8 μg/ml and susceptibility at 85.7%. Activity for these two agents was reduced against extensively drug-resistant and multidrug-resistant isolates of the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex. Only two agents showed high levels of activity (susceptibility, >90%) against S. maltophilia, minocycline (MIC50/90, 0.5/2 μg/ml; 99.5% susceptible) and trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/1 μg/ml; 94.6% susceptible). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant S. maltophilia isolates. Various agents exhibited susceptibility rates of nearly 90% against the B. cepacia complex isolates; these were trimethoprim-sulfamethoxazole (MIC50/90, ≤0.5/2 μg/ml; 93.1% susceptible), ceftazidime (MIC50/90, 2/8 μg/ml; 91.0% susceptible), meropenem (MIC50/90, 2/8 μg/ml; 89.1% susceptible), and minocycline (MIC50/90, 2/8 μg/ml; 88.1% susceptible). These results indicate that minocycline is among the most active agents for these three problematic potential pathogen groups when tested against U.S. isolates.
INTRODUCTION
Stenotrophomonas maltophilia, the Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, and the Burkholderia cepacia complex are nonfermentative Gram-negative bacteria that are typically resistant to many antimicrobials (1–8). Infections from S. maltophilia and the A. baumannii-A. calcoaceticus species complex often occur in intensive care units and in immunocompromised patients. These organisms are associated with a variety of infections, but most commonly, bloodstream infections and pneumonia in hospitalized patients (7, 9–11). The multidrug-resistant (MDR; resistant to three or more classes of agents) nature of these organisms makes them serious treatment challenges (3, 9–12).
MDR Acinetobacter pathogens are included in the 2013 CDC list of pathogens posing a serious health risk and the 2017 WHO list of bacteria for which new antibiotics are a critical priority (13, 14). S. maltophilia has occurred in numerous hospital outbreaks, increasingly causing ventilator-associated pneumonia (7, 9, 12). S. maltophilia was among the 10 most common bacterial pathogens causing pneumonia in hospitalized patients from Europe, China, and the United States (15). The B. cepacia complex is a serious problem for cystic fibrosis patients and is increasingly occurring in hospital outbreaks in intensive care settings (5, 16–18).
Tetracycline agents have historically exhibited broad-spectrum antibacterial activity (19, 20). These agents were expanded from the original class representative, tetracycline, to later-generation agents with expanded activity, either oral or intravenous, and with improved safety (19–22). Doxycycline, minocycline, omadacycline, eravacycline, and tigecycline are examples of later-generation tetracyclines (23–27). Of these agents, minocycline has been shown to have the best activity against S. maltophilia, the A. baumannii-A. calcoaceticus species complex, and the B. cepacia complex (28).
The aim of this study was to evaluate the in vitro activity of minocycline and comparator agents against a large collection of contemporary U.S. isolates consisting of S. maltophilia, the A. baumannii-A. calcoaceticus species complex, and the Burkholderia cepacia complex. These isolates were collected from 2014 to 2018 from 87 U.S. medical centers spanning all nine census divisions.
RESULTS
A total of 1,081 isolates of the Acinetobacter baumannii-A. calcoaceticus species complex, 1,289 isolates of Stenotrophomonas maltophilia, and 101 isolates of the Burkholderia cepacia complex from the SENTRY Antimicrobial Surveillance Program collection were evaluated, representing 87 medical centers in the 9 U.S. census divisions from 2014 to 2018 (Table 1). The isolates were collected primarily from specimens from pneumonia in hospitalized patients (1,632 isolates; 66.0% overall), skin and skin structure infections (354 isolates; 14.3% overall), bloodstream infections (266 isolates; 10.8% overall), urinary tract infections (126 isolates; 5.1% overall), intra-abdominal infections (61 isolates; 2.5% overall), and other infections (32 isolates; 1.3% overall).
Antimicrobial activity of minocycline tested against the main organisms and organism groups
Table 1 shows the MIC distributions for these organisms, including a breakdown of the distributions for MDR and extensively drug resistant (XDR) A. baumannii-A. calcoaceticus species complex isolates. Susceptibility profiles for minocycline and comparator agents are presented in Table 2.
Activity of minocycline and comparators when tested against Acinetobacter baumannii-Acinetobacter calcoaceticus species complex, Stenotrophomonas maltophilia, and Burkholderia cepacia complex isolates from the United States (2014 to 2018)
Activity against the Acinetobacter baumannii-A. calcoaceticus species complex.Colistin was the most active agent against the A. baumannii-A. calcoaceticus species complex, exhibiting MIC50/90 values at ≤0.5/2 μg/ml (Table 2) with 92.4% of isolates susceptible (Table 2). Colistin activity was slightly decreased for MDR and XDR isolates with an MIC90 value of 4 μg/ml for each resistance phenotype (Table 2). Minocycline ranked second in activity against all A. baumannii-A. calcoaceticus species complex isolates with MIC50/90 results at 0.25/8 μg/ml and susceptibility at 85.7% (Table 2). Against MDR and XDR isolates, susceptibility was reduced to 71.2% and 67.3%, respectively, for minocycline (Table 2). Activity for the carbapenems, third- and fourth-generation cephalosporins, and the β-lactam/β-lactamase inhibitor combinations piperacillin-tazobactam and ampicillin-sulbactam ranged from 50.2% to 62.4% for all A. baumannii-A. calcoaceticus species complex isolates and was much lower for MDR (7.1% to 25.8% susceptible) and XDR (0.2% to 11.2% susceptible) isolates. Susceptibility for amikacin was at 79.2% for all isolates and at 58.7% and 48.9% for MDR and XDR isolates, respectively (Table 2).
Activity against Stenotrophomonas maltophilia.Only seven agents (ticarcillin-clavulanate, ceftazidime, cefidericol, minocycline, levofloxacin, trimethoprim-sulfamethoxazole, and chloramphenicol) have susceptibility interpretive criteria for Stenotrophomonas maltophilia in CLSI M100 (2019), four of which (ceftazidime, minocycline, levofloxacin, and trimethoprim-sulfamethoxazole) are included in this study (29). Among the agents not tested, cefiderocol is still in clinical development and has not yet been approved for marketing in the United States, ticarcillin-clavulanate was discontinued by the manufacturer in the United States in 2015, and chloramphenicol has markedly poor activity against this organism. Two of the tested agents showed high levels of activity (susceptibility, >90%). The highest susceptibility rate was minocycline (99.5%) with MIC50/90 values at 0.5/2 μg/ml (Table 2). Trimethoprim-sulfamethoxazole activity was 94.6% susceptible with MIC50/90 values at ≤0.5/1 μg/ml (Table 2). Levofloxacin (75.8% susceptible) showed moderate activity, and ceftazidime exhibited poor activity (26.8% susceptible; Table 2). Minocycline was active against 92.8% (MIC90, 4 μg/ml) of trimethoprim-sulfamethoxazole-resistant isolates (Tables 1 and 2). The three other agents with published interpretive criteria against this species, ticarcillin-clavulanate, cefiderocol, and chloramphenicol, were not tested.
Activity against Burkholderia cepacia.As with S. maltophilia, only seven agents (ticarcillin-clavulanate, ceftazidime, meropenem, minocycline, levofloxacin, trimethoprim-sulfamethoxazole, and chloramphenicol) have interpretive criteria for Burkholderia cepacia in CLSI M100 (2019), five of which (ceftazidime, levofloxacin, meropenem, minocycline, and trimethoprim-sulfamethoxazole) were tested in the present study (29). A total of 88.1% of isolate MIC values for minocycline were ≤4 μg/ml (MIC50/90 at 2/8 μg/ml; 88.1% susceptible; Tables 1 and 2). Other active agents included trimethoprim-sulfamethoxazole (93.1% susceptible), ceftazidime (91.0%), and meropenem (89.1%) (Table 2). Susceptibility to levofloxacin was 71.3% (Table 2). Ticarcillin-clavulanate and chloramphenicol were not tested.
DISCUSSION
The only agent that demonstrated a high level of susceptibility against all three organism groups of S. maltophilia, the A. baumannii-A. calcoaceticus species complex, and the B. cepacia complex was minocycline. Colistin was the most active agent against the A. baumannii-A. calcoaceticus species complex (92.4% susceptible, MIC90, 2 μg/ml), and minocycline was the next most active agent (85.7% susceptible, MIC90, 8 μg/ml).
Although we have identified 22 different species of Acinetobacter in the course of the SENTRY Program (7), we do not routinely go beyond complex for the Acinetobacter baumannii-A. calcoaceticus species complex. In general, A. baumannii sensu stricto was less susceptible to the agents tested than the other members of the Acinetobacter baumannii-A. calcoaceticus species complex (data not shown).
Colistin showed significant in vitro activity; however, concerns exist about its safety and efficacy due to its narrow therapeutic window and the suboptimal and uncertain pharmacokinetics (11, 30). In addition, there are concerns about the development of resistance (11, 30). Colistin has been used in combination treatment; however, optimization of dosing regimens and whether those will prevent the emergence of resistance is still a question (31, 32). In contrast, minocycline has been shown to have few adverse events (AE; primarily central nervous system [dizziness, lightheadedness, and vertigo] and gastrointestinal [nausea and diarrhea]), favorable pharmacokinetic (PK)/pharmacodynamic (PD) profiles (oral and parenteral formulations, dosing flexibility, low protein binding, good tissue distribution, and long half-life), and stability to many tetracycline resistance mechanisms (18–22). Although the combinations of minocycline and several other agents have been studied, there is no consensus as to the optimal combination and its clinical utility (7, 31).
Typically, trimethoprim-sulfamethoxazole is very active against S. maltophilia (3, 7, 28). Minocycline has also been shown to be one of the more active agents (3, 7, 28). In our study, minocycline was the most active agent in terms of susceptibility (99.5% susceptible), followed closely by trimethoprim-sulfamethoxazole (94.6%). Due to problems in maintaining a supply of intravenous trimethoprim-sulfamethoxazole, Hand et al. conducted a retrospective chart review and concluded that treatment failure did not differ among patients taking monotherapy with trimethoprim-sulfamethoxazole or minocycline for S. maltophilia infections (4).
Agents that might be considered for use in treatment of B. cepacia complex infections in the lung include trimethoprim-sulfamethoxazole, meropenem, ciprofloxacin or levofloxacin, minocycline, or chloramphenicol (33). In this study, high levels of susceptibility occurred with trimethoprim-sulfamethoxazole (93.1% susceptible), ceftazidime (91.0% susceptible), meropenem (89.1% susceptible), and minocycline (88.1% susceptible).
More than 20 testable agents have CLSI susceptibility interpretive criteria for the A. baumannii-A. calcoaceticus species complex (29). Unfortunately, due to the large number of resistance mechanisms that include efflux pumps, which may provide resistance across multiple classes of antibiotics, the actual number of antimicrobials that might test as susceptible may be very limited. For example, in this study, 37.1% of A. baumannii-A. calcoaceticus species complex isolates were an XDR phenotype and 49.9% were an MDR phenotype.
The number of antimicrobial agents that laboratories can test and provide antimicrobial susceptibility category results for S. maltophilia or the B. cepacia complex is quite limited (29). Notably, two of the testable agents for these organism groups are chloramphenicol and ticarcillin-clavulanate (discontinued by the manufacturer in the United States in 2015), neither of which represent an optimal choice.
Given the limited number of agents available with robust activity against S. maltophilia, the A. baumannii-A. calcoaceticus species complex, and the Burkholderia cepacia complex, developing new antimicrobials with activity against these organisms, as well as gaining a better understanding of the role and optimization of combinations of agents, is needed. In this study, four agents tested (ceftazidime, levofloxacin, minocycline, and trimethoprim-sulfamethoxazole) have established CLSI interpretive criteria against all S. maltophilia, A. baumannii-A. calcoaceticus species complex, and Burkholderia cepacia species complex isolates. Of the four agents, minocycline exhibited the best overall susceptibility at 99.5%, 85.7%, and 88.1%, respectively.
MATERIALS AND METHODS
Isolate collection.A total of 2,471 isolates were selected from a collection of isolates recovered from documented infections from the nine U.S. census divisions from 2014 to 2018. The isolates chosen consisted of the A. baumannii-A. calcoaceticus species complex (for the purpose of this study, isolates identified as A. baumannii, A. calcoaceticus, A. nosocomialis, A. pittii, and the A. baumannii-A. calcoaceticus complex were collectively designated A. baumannii-A. calcoaceticus complex isolates), S. maltophilia, and the B. cepacia complex. Isolates were from a variety of infection types that included bloodstream, skin and skin structure, pneumonia in hospitalized patients, urinary tract, intra-abdominal, and others. Bacterial species were identified by the submitting laboratories and confirmed by JMI Laboratories using standard microbiology methods and matrix-assisted laser desorption ionization–time of flight mass spectrometry (Bruker Daltonics, Bremen, Germany).
Susceptibility testing.Broth microdilution methods for antimicrobial susceptibility were performed and interpreted following CLSI guidelines (29). CLSI interpretive criteria for minocycline are as follows: susceptible, ≤4 μg/ml; intermediate, 8 μg/ml; resistant, ≥16 μg/ml (29). JMI Laboratories produced the frozen-form 96-well panels used to test minocycline and the comparator agents. The testing medium was cation-adjusted Mueller-Hinton broth. Amikacin, ampicillin, cefepime, ceftazidime, gentamicin, imipenem, levofloxacin, meropenem, minocycline, sulbactam, tazobactam, tetracycline, and trimethoprim were obtained from United States Pharmacopeia (North Bethesda, MD, USA). Colistin, piperacillin, and sulfamethoxazole were obtained from Sigma-Aldrich (St. Louis, MO, USA).
Resistance phenotype definitions.The A. baumannii-A. calcoaceticus species complex isolates were defined as MDR if organisms were nonsusceptible to three or more drug classes and as XDR if all but two or fewer drug classes had a nonsusceptible drug (7, 28). The drug classes used were extended-spectrum cephalosporins (ceftazidime and cefepime), carbapenems (imipenem and meropenem), antipseudomonal penicillins plus a β-lactamase inhibitor (piperacillin-tazobactam), fluoroquinolones (levofloxacin), aminoglycosides (amikacin and gentamicin), polymyxins (colistin), tetracyclines (tetracycline and minocycline), and penicillins plus β-lactamase inhibitors (ampicillin-sulbactam).
ACKNOWLEDGMENTS
We thank Jennifer M. Streit and Lori Flanigan for their assistance in, respectively, coordinating the SENTRY Program and editorial review of the manuscript.
This study was performed by JMI Laboratories and supported by Melinta Therapeutics, which included funding for services related to preparing the manuscript.
JMI Laboratories contracted to perform services in 2018 for Achaogen, Inc., Albany College of Pharmacy and Health Sciences, Allecra Therapeutics, Allergan, AmpliPhi Biosciences Corp., Amplyx, Antabio, American Proficiency Institute, Arietis Corp., Arixa Pharmaceuticals, Inc., Astellas Pharma Inc., Athelas, Basilea Pharmaceutica Ltd., Bayer AG, Becton, Dickinson and Company, bioMérieux SA, Boston Pharmaceuticals, Bugworks Research Inc., CEM-102 Pharmaceuticals, Cepheid, Cidara Therapeutics, Inc., CorMedix, Inc., DePuy Synthes, Destiny Pharma, Discuva Ltd., Dr. Falk Pharma GmbH, Emery Pharma, Entasis Therapeutics, Eurofarma Laboratorios SA, U.S. Food and Drug Administration, Fox Chase Chemical Diversity Center, Inc., Gateway Pharmaceutical LLC, GenePOC, Inc., Geom Therapeutics, Inc., GlaxoSmithKline plc, Harvard University, Helperby, HiMedia Laboratories, F. Hoffmann-La Roche Ltd., ICON plc, Idorsia Pharmaceuticals Ltd., Iterum Therapeutics plc, Laboratory Specialists, Inc., Melinta Therapeutics, Inc., Merck & Co., Inc., Microchem Laboratory, Micromyx, MicuRx Pharmaceuticals, Inc., Mutabilis Co., Nabriva Therapeutics plc, NAEJA-RGM, Novartis AG, Oxoid Ltd., Paratek Pharmaceuticals, Inc., Pfizer, Inc., Polyphor Ltd., Pharmaceutical Product Development, LLC, Prokaryotics, Inc., Qpex Biopharma, Inc., Ra Pharmaceuticals, Inc., Roivant Sciences Ltd., Safeguard Biosystems, Scynexis, Inc., SeLux Diagnostics, Inc., Shionogi and Co., Ltd., SinSa Labs, Spero Therapeutics, Summit Pharmaceuticals International Corp., Synlogic, T2 Biosystems, Inc., Taisho Pharmaceutical Co., Ltd., TenNor Therapeutics Ltd., Tetraphase Pharmaceuticals, The Medicines Company, Theravance Biopharma, University of Colorado, University of Southern California-San Diego, University of North Texas Health Science Center, VenatoRx Pharmaceuticals, Inc., Vyome Therapeutics, Inc., Wockhardt, Yukon Pharmaceuticals, Inc., Zai Lab, Zavante Therapeutics, Inc. There are no speakers’ bureaus or stock options to declare.
FOOTNOTES
- Received 4 June 2019.
- Returned for modification 29 June 2019.
- Accepted 12 August 2019.
- Accepted manuscript posted online 19 August 2019.
- Copyright © 2019 American Society for Microbiology.
