Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by β-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC50/90 values were 0.12/0.25 mg/liter, and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/liter; the highest MIC value was only 2 mg/liter.
KEYWORDS: Haemophilus influenzae, ceftolozane-tazobactam, cephalosporin, susceptibility testing
ABSTRACT
Nine hundred Haemophilus influenzae clinical isolates from 83 U.S. and European medical centers were tested for susceptibility by reference broth microdilution methods against ceftolozane-tazobactam and comparators. Results were stratified by β-lactamase production and infection type. Overall, ceftolozane-tazobactam MIC50/90 values were 0.12/0.25 mg/liter, and 99.0% of isolates were inhibited at the susceptible breakpoint of ≤0.5 mg/liter; the highest MIC value was only 2 mg/liter. Our results support using ceftolozane-tazobactam to treat H. influenzae infections.
TEXT
Haemophilus influenzae is an important cause of infections, including pneumonia, exacerbated chronic obstructive pulmonary disease (COPD), persistent bacterial bronchitis, cystic fibrosis, neonatal sepsis, meningitis, otitis media, and bacterial sinusitis, across all age groups (1–4). Moreover, bacterial pneumonia is one of the most common and severe infections among hospitalized patients and is associated with increased morbidity and mortality. Implementing timely and effective antimicrobial therapy is critical to decrease complications and mortality (5–7).
Ceftolozane-tazobactam is approved by the FDA and the European Medicines Agency for the treatment of patients aged ≥18 years with hospital-acquired bacterial pneumonia, including ventilator-associated bacterial pneumonia, complicated intra-abdominal infections (in combination with metronidazole), and complicated urinary tract infections, including pyelonephritis (8–10).
Because H. influenzae may cause respiratory tract infections that may require hospitalization and intravenous antimicrobial therapy and ceftolozane-tazobactam represents a valuable option to treat these types of infections, it is important to understand the in vitro activity ceftolozane-tazobactam against contemporary H. influenzae clinical isolates. Furthermore, clinical microbiology laboratories may not be able to evaluate the susceptibility of H. influenzae isolates against ceftolozane-tazobactam because this drug-organism combination has not been incorporated into most of the automated susceptibility systems (11, 12). Results from a large multicenter surveillance program may be helpful to guide empirical therapy. In this investigation, we evaluated the in vitro activity of ceftolozane-tazobactam and many comparator agents against a large collection of H. influenzae isolates from U.S. and European medical centers.
A total of 900 H. influenzae clinical isolates were collected from 83 medical centers located in the United States (34 centers) and in 25 countries in Europe and the Mediterranean region (49 centers) from 2011 to 2018 as part of the Program to Assess Ceftolozane-Tazobactam Susceptibility (PACTS). PACTS monitors the in vitro activity of ceftolozane-tazobactam and numerous antimicrobial agents against Gram-negative bacteria worldwide (13). The countries surveyed were (no. of isolates) Austria (10), Belarus (3), Belgium (10), Czech Republic (6), Denmark (12), Finland (9), France (59), Germany (63), Greece (4), Hungary (3), Ireland (30), Israel (7), Italy (32), the Netherlands (10), Norway (2), Poland (18), Portugal (15), Russia (14), Slovenia (2), Spain (48), Sweden (29), Switzerland (10), Turkey (20), Ukraine (5), the United Kingdom (71), and the United States (408). The bacterial isolates were collected consecutively (1 per infection episode) according to the infection type and sent to a monitoring laboratory (JMI Laboratories, North Liberty, IA), where they were tested for susceptibility by reference broth microdilution methods against most antimicrobial agents currently used to treat H. influenzae infections.
The bacterial isolates were collected from patients with community-acquired respiratory tract infections (n = 506, 56.2%), pneumonia (n = 273, 30.3%), bloodstream infections (n = 67, 7.4%), and other infection types (n = 54, 6.0%) according to defined protocols. Only isolates determined to be significant by local criteria as the reported probable cause of infection were included in the program. Species identification was confirmed by standard biochemical tests and use of the MALDI Biotyper (Bruker Daltonics, Billerica, MA) according to the manufacturer’s instructions, when necessary.
Broth microdilution test methods conducted according to CLSI guidelines determined the antimicrobial susceptibility of ceftolozane-tazobactam (inhibitor at fixed concentration of 4 mg/liter) and comparator agents (14). MIC panels were manufactured at JMI Laboratories (2015 to 2018) or purchased from Thermo Fisher Scientific (Cleveland, OH) (2011 to 2014). Organisms were tested in Haemophilus test medium (Thermo Fisher Scientific). Concurrent quality control testing was performed to ensure proper test conditions and procedures. Quality control strains included H. influenzae ATCC 49247 and 49766. FDA breakpoint criteria were used to determine susceptibility/resistance rates for ceftolozane-tazobactam and tigecycline (15), whereas CLSI and EUCAST susceptibility interpretive criteria were applied for other comparator agents (16, 17).
Ceftolozane-tazobactam was highly active against H. influenzae infection, with overall MIC50/90 values of 0.12/0.25 mg/liter and 99.0% of isolates inhibited at the FDA susceptible breakpoint of ≤0.5 mg/liter (Tables 1 and 2). The highest ceftolozane-tazobactam MIC value was only 2 mg/liter. Ceftolozane-tazobactam was equally active against isolates from the United States and Europe, with MIC50/90 values of 0.12/0.25 mg/liter and 99.0% susceptibility in both geographic regions (Tables 1 and 2). Moreover, ceftolozane-tazobactam activities against β-lactamase-positive isolates (MIC50/90, 0.12/0.25 mg/liter; 98.9% susceptible) and β-lactamase-negative isolates (MIC50/90, 0.12/0.25 mg/liter; 99.0% susceptible) were virtually identical (Table 1). No major differences were noted in the ceftolozane-tazobactam activity when isolates were stratified by infection type, with MIC50/90 values of 0.12/0.25 mg/liter for isolates from all infection types and susceptibility rates ranging from 98.6% to 100.0% (Table 1).
TABLE 1.
Antimicrobial activity of ceftolozane-tazobactam against H. influenzae isolates from the United States and Europe, 2011 to 2018
| Location, β-lactamase production, infection type | No. of isolates (cumulative %) inhibited at ceftolozane-tazobactam MIC (mg/liter) ofb
: |
|||||||
|---|---|---|---|---|---|---|---|---|
| ≤0.015 | 0.03 | 0.06 | 0.12 | 0.25 | 0.5 | 1 | 2 | |
| Region | ||||||||
| United States (n = 408) | 3 (0.7) | 12 (3.7) | 95 (27.0) | 218 (80.4) | 62 (95.6) | 14 (99.0) | 2 (99.5) | 2 (100.0) |
| Europe (n = 492) | 1 (0.2) | 15 (3.3) | 143 (32.3) | 242 (81.5) | 70 (95.7) | 16 (99.0) | 5 (100.0) | |
| β-Lactamase production | ||||||||
| Negative (n = 720) | 3 (0.4) | 20 (3.2) | 171 (26.9) | 391 (81.2) | 104 (95.7) | 24 (99.0) | 6 (99.9) | 1 (100.0) |
| Positive (n = 180) | 1 (0.6) | 7 (4.4) | 67 (41.7) | 69 (80.0) | 28 (95.6) | 6 (98.9) | 1 (99.4) | 1 (100.0) |
| Infection typea | ||||||||
| CARTI (n = 506) | 2 (0.4) | 12 (2.8) | 134 (29.2) | 250 (78.7) | 79 (94.3) | 22 (98.6) | 5 (99.6) | 2 (100.0) |
| Pneumonia (n = 273) | 2 (0.7) | 9 (4.0) | 77 (32.2) | 143 (84.6) | 34 (97.1) | 6 (99.3) | 2 (100.0) | |
| BSI (n = 67) | 0 (0.0) | 3 (4.5) | 16 (28.4) | 38 (85.1) | 9 (98.5) | 1 (100.0) | ||
| Others (n = 54) | 0 (0.0) | 3 (5.6) | 11 (25.9) | 29 (79.6) | 10 (98.1) | 1 (100.0) | ||
| All isolates (n = 900) | 4 (0.4) | 27 (3.4) | 238 (29.9) | 460 (81.0) | 132 (95.7) | 30 (99.0) | 7 (99.8) | 2 (100.0) |
CARTI, community-acquired respiratory tract infection; BSI, bloodstream infection.
Last 2 columns beyond susceptible breakpoint (≤0.5 mg/liter).
TABLE 2.
Activity of ceftolozane-tazobactam and comparator antimicrobial agents against H. influenzae isolates collected from medical centers in the United States and Europe, 2011 to 2018
| Antimicrobial agent, by location | MIC (mg/liter) |
Susceptibility (%) according toa
: |
|||||
|---|---|---|---|---|---|---|---|
| CLSI |
EUCAST |
||||||
| MIC50 | MIC90 | Range | S | R | S | R | |
| All isolates (n = 900) | |||||||
| Ceftolozane-tazobactam | 0.12 | 0.25 | ≤0.015 to 2 | 99.0b | |||
| Amoxicillin-clavulanic acid | ≤1 | 2 | ≤1 to >8 | 99.7 | 0.3 | 97.7 | 2.3 |
| Azithromycin | 1 | 2 | ≤0.12 to >4 | 99.0 | 99.0c | ||
| Ceftazidime | 0.06 | 0.12 | ≤0.015 to 1 | 100.0 | |||
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 | 100.0 | 100.0 | 0.0 | |
| Ciprofloxacin | ≤0.03 | ≤0.03 | ≤0.03 to >1 | 99.7 | 99.0 | 1.0 | |
| Levofloxacin | ≤0.12 | ≤0.12 | ≤0.12 to >2 | 99.7 | |||
| Meropenem | ≤0.06 | 0.12 | ≤0.06 to 0.5 | 100.0 | 100.0d | 0.0 | |
| Piperacillin-tazobactam | ≤0.5 | ≤0.5 | ≤0.5 to ≤0.5 | 100.0 | 0.0 | ||
| Tigecycline | 0.12 | 0.25 | 0.06 to 1 | 90.6b | |||
| United States (n = 408) | |||||||
| Ceftolozane-tazobactam | 0.12 | 0.25 | ≤0.015 to 2 | 99.0b | |||
| Amoxicillin-clavulanic acid | ≤1 | 2 | ≤1 to >8 | 99.5 | 0.5 | 97.8 | 2.2 |
| Azithromycin | 1 | 2 | ≤0.03 to >4 | 99.3 | 99.3c | ||
| Ceftazidime | 0.06 | 0.12 | ≤0.015 to 1 | 100.0 | |||
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 | 100.0 | 100.0 | 0.0 | |
| Ciprofloxacin | ≤0.03 | ≤0.03 | ≤0.03 to >1 | 99.8 | 99.0 | 1.0 | |
| Levofloxacin | ≤0.12 | ≤0.12 | ≤0.12 to >2 | 99.8 | |||
| Meropenem | ≤0.06 | 0.12 | ≤0.06 to 0.25 | 100.0 | 100.0d | 0.0 | |
| Piperacillin-tazobactam | ≤0.5 | ≤0.5 | ≤0.5 to ≤0.5 | 100.0 | 0.0 | ||
| Tigecycline | 0.25 | 0.5 | 0.06 to 1 | 89.2b | |||
| Europe (n = 492) | |||||||
| Ceftolozane-tazobactam | 0.12 | 0.25 | ≤0.015 to 1 | 99.0b | |||
| Amoxicillin-clavulanic acid | ≤1 | 2 | ≤1 to 8 | 99.8 | 0.2 | 97.6 | 2.4 |
| Azithromycin | 1 | 2 | ≤0.12 to >4 | 98.8 | 98.8c | ||
| Ceftazidime | 0.06 | 0.12 | ≤0.015 to 0.5 | 100.0 | |||
| Ceftriaxone | ≤0.06 | ≤0.06 | ≤0.06 to 0.12 | 100.0 | 100.0 | 0.0 | |
| Ciprofloxacin | ≤0.03 | ≤0.03 | ≤0.03 to >1 | 99.6 | 99.0 | 1.0 | |
| Levofloxacin | ≤0.12 | ≤0.12 | ≤0.12 to >2 | 99.6 | |||
| Meropenem | ≤0.06 | 0.12 | ≤0.06 to 0.5 | 100.0 | 100.0d | 0.0 | |
| Piperacillin-tazobactam | ≤0.5 | ≤0.5 | ≤0.5 to ≤0.5 | 100.0 | 0.0 | ||
| Tigecycline | 0.12 | 0.25 | 0.06 to 1 | 91.7b | |||
Most comparator agents were very active against the collection of H. influenzae isolates evaluated in this investigation (Table 2). All isolates were susceptible to ceftriaxone (MIC50/90, ≤0.06/≤0.06 mg/liter) and meropenem (MIC50/90, ≤0.06/0.12 mg/liter) per CLSI and EUCAST criteria (nonmeningitis EUCAST breakpoints were applied). Moreover, ceftazidime (MIC50/90, 0.06/0.12 mg/liter) and piperacillin-tazobactam (MIC50/90, ≤0.5/≤0.5 mg/liter) exhibited 100.0% susceptibility per CLSI criteria; and azithromycin (MIC50/90, 1/2 mg/liter), ciprofloxacin (MIC50/90, ≤0.03/≤0.03 mg/liter), and levofloxacin (MIC50/90, ≤0.12/≤0.12 mg/liter) showed susceptibility rates of ≥99.0% per CLSI and EUCAST criteria. Susceptibility rates for amoxicillin-clavulanate (MIC50/90, ≤1/2 mg/liter) were 99.7% and 97.7% per CLSI and EUCAST criteria, respectively (Table 2). No major differences were observed between isolates from the United States and Europe regarding the activities of the comparator agents (Table 2).
Prompt initiation of effective antimicrobial therapy is critical for managing severe lower respiratory tract infections, especially pneumonia and exacerbated COPD, and empirical antimicrobial regimens should be guided primarily by understanding the causative pathogens and their antimicrobial resistance profiles (5, 7, 18). Ceftolozane-tazobactam has demonstrated good activity and broad spectrums against Enterobacterales and Pseudomonas aeruginosa causing pneumonia (19, 20). These results expand available data about the in vitro activity of ceftolozane-tazobactam against H. influenzae isolates, an important cause of respiratory tract infections in hospitalized patients (1–4). A total of 900 clinical isolates from 83 U.S. and European medical centers were tested, and 99.0% were susceptible to ceftolozane-tazobactam. The results presented here indicate that H. influenzae infection is typically susceptible to ceftolozane-tazobactam and support the empirical use of this compound to treat H. influenzae infections until susceptibility results can be obtained.
ACKNOWLEDGMENTS
Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ.
JMI Laboratories contracted to perform services in 2018 to 2019 for Accelerate Diagnostics, Inc.; Achaogen, Inc.; Acurx Pharmaceuticals, LLC; Albany College of Pharmacy and Health Sciences; Alifax S.r.l.; Allecra Therapeutics; Allergan; American Proficiency Institute; Amicrobe Advanced Biomaterials; AmpliPhi Biosciences Corp.; Amplyx Pharmaceuticals, Inc.; Antabio SAS; Arietis Corp.; Arixa Pharmaceuticals, Inc.; Armata Pharmaceuticals, Inc.; Artugen Therapeutics USA, Inc.; Astellas Pharma Global Development; Athelas Therapeutics, Inc.; Bako Diagnostics; Basilea Pharmaceutica Ltd.; Bayer AG; Becton, Dickinson and Company; bioMérieux SA; BioVersys AG; Boston Pharmaceuticals; Bravos Biosciences; Bugworks Research Inc.; CEM-102 Pharmaceuticals; Cepheid; Cidara Therapeutics, Inc.; ContraFect Corporation; CorMedix Inc.; Creighton University; DePuy Synthes; Destiny Pharma; Discuva Ltd.; Dr. Falk Pharma GmbH; Eagle Analytical Services, Inc.; Emery Pharma; Entasis Therapeutics; Eurofarma Laboratorios SA; Evobiotics, LLC; F. Hoffmann-La Roche Ltd.; Fimbrion Therapeutics, Inc.; Forge Therapeutics, Inc.; Fox Chase Chemical Diversity Center, Inc.; Gateway Pharmaceutical LLC; GenePOC Inc.; Geom Therapeutics, Inc.; GlaxoSmithKline plc; Guardian Therapeutics, Inc.; Harvard University; Helperby Therapeutics Ltd.; Hennessy Research Associates; HiMedia Laboratories; ICON plc; Idorsia Pharmaceuticals Ltd.; Iterum Therapeutics plc; Janssen Vaccines & Prevention B.V.; KBP Biosciences Co. Ltd.; LabConnect, LLC; Laboratory Specialists, Inc.; Louisiana State University; MAIA Pharmaceuticals, Inc.; Mayo Clinic; Meiji Seika Pharma Co., Ltd.; Melinta Therapeutics, Inc.; Merck & Co., Inc.; Microchem Laboratory; Micromyx; MicuRx Pharmaceuticals, Inc.; Mutabilis Co.; Nabriva Therapeutics plc; NAEJA-RGM; National Institutes of Health; Northeastern University; Novartis AG; NovoBiotic Pharmaceuticals, LLC.; NTS Ventures LLC; Omnix Medical Ltd.; Oxoid Ltd.; Paratek Pharmaceuticals, Inc.; Pfizer, Inc.; Polyphor Ltd.; Pharmaceutical Product Development, LLC; Prokaryotics Inc.; Qpex Biopharma, Inc.; Ra Pharmaceuticals, Inc.; Recida Therapeutics, Inc.; Roche Molecular Systems, Inc.; Roivant Sciences, Ltd.; Safeguard Biosystems; Savara Inc.; Scynexis, Inc.; SeLux Diagnostics, Inc.; Sfunga Therapeutics, Inc.; Shionogi and Co., Ltd.; SinSa Labs; Sonoran Biosciences, Inc.; Spero Therapeutics; Summit Pharmaceuticals International Corp.; Suzhou Sinovent Pharmaceuticals Co., Ltd.; Synlogic Inc.; T2 Biosystems, Inc.; Taisho Pharmaceutical Co., Ltd.; TenNor Therapeutics Ltd.; Tetraphase Pharmaceuticals; The Medicines Company San Diego, LLC; Theravance Biopharma; Thermo Fisher Scientific; The US Food and Drug Administration; University of Colorado; University of California; San Francisco; University of Southern California-San Diego; University of North Texas Health Science Center; Vast Therapeutics, Inc.; VenatoRx Pharmaceuticals, Inc.; Viosera Therapeutics; Vyome Therapeutics Inc.; Waksman Institute for Microbiology; Washington University in St. Louis; Wockhardt Bio AG; Yale University; Yukon Pharmaceuticals, Inc.; Zai Lab (Hong Kong) Ltd.; Zavante Therapeutics, Inc. We have no speakers’ bureaus or stock options to declare.
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