Abstract
Background
Fluoroquinolones are used for infection prevention in high-risk patients with haematological malignancies. Fluoroquinolones are active against many Gram-negative bacilli (GNB) but are less active against Gram-positive organisms. We evaluated the in vitro activity of delafloxacin and selected comparators against 560 bacterial pathogens isolated exclusively from patients with cancer.
Methods
Antimicrobial susceptibility testing and time-kill studies were performed using CLSI-approved methodology and interpretive criteria for 350 Gram-positive organisms and 210 GNB that had been recently isolated from patients with cancer.
Results
Delafloxacin was more active than ciprofloxacin and levofloxacin against Staphylococcus aureus and CoNS. Overall, 63% of staphylococcal isolates were susceptible to delafloxacin, 37% to ciprofloxacin and 39% to levofloxacin. Activity of delafloxacin against most Enterobacterales was similar to that of ciprofloxacin and levofloxacin. Escherichia coli and MDR Pseudomonas aeruginosa isolates had low susceptibility rates to the three tested fluoroquinolones. In time-kill studies delafloxacin and levofloxacin decreased the bacterial load to 3.0 log10 in 8 and 13 h, respectively, using 8 × MIC.
Conclusions
Delafloxacin is more active than ciprofloxacin and levofloxacin against S. aureus but has substantial gaps in coverage against GNB. Resistance to all three fluoroquinolones could be high among leading GNB such as E. coli and P. aeruginosa, particularly in cancer centres where these agents are widely used as prophylactic agents.
Introduction
Immunocompromised patients with cancer often develop bacterial infections, especially during episodes of neutropenia. Consequently, antibiotics are used frequently and for several indications in this patient population including antimicrobial prophylaxis, pre-emptive therapy, definitive therapy, maintenance therapy and suppressive therapy.1–3 Fluoroquinolones, broad-spectrum antibiotics frequently used in this population, generally contain a fluorine atom in their chemical structure and have activity against both Gram-negative bacilli (GNB) and Gram-positive organisms (GPOs).4,5
Delafloxacin, previously named ABT-492, is one of the most recently approved fluoroquinolones for use in the USA and Europe.6–8 Delafloxacin targets both bacterial DNA gyrase and topoisomerase IV enzymes of GPOs and GNB.9,10 Delafloxacin can be given IV or orally and has excellent oral bioavailability.11 Although fluoroquinolone prophylaxis has been shown to be effective in reducing infection rates among neutropenic patients, the increasing rate of fluoroquinolone resistance in bacteria causing infections in patients with cancer has significantly impacted the efficacy of these agents.12,13
The primary objective of the current study was to determine the in vitro activity of delafloxacin against a wide variety of GPOs and GNB pathogens recently isolated from patients with cancer, and to compare delafloxacin activity with that of ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, cefpodoxime, cefixime, ertapenem and tigecycline. Comparator agents were chosen based on their use in prophylaxis and treatment, especially in reducing rates of significant bacterial infection (particularly GNB) and sepsis in high-risk febrile neutropenic patients.
Materials and methods
We evaluated the in vitro activity of delafloxacin and seven comparator agents against 350 GPOs and 210 GNB recently isolated (2018–2020) from patients with cancer at The University of Texas MD Anderson Cancer Center. Samples were processed by the clinical microbiology laboratory and stored in an Institutional Research Board-approved research repository at MD Anderson. All of these bacteria were exclusively blood culture isolates. Only one isolate per patient was tested (i.e. no duplicate isolates). Among GNB, 10 ESBL-producing and 20 MDR isolates were tested. ESBL positivity was based on data from the MD Anderson microbiology laboratory as generated by the Vitek2 system.14 MDR was defined in accordance with CDC recommendations.15 These classes include: fluoroquinolones (such as levofloxacin and ciprofloxacin), fourth-generation cephalosporins (such as cefepime and ceftazidime), antipseudomonal carbapenems (such as meropenem and imipenem) and antipseudomonal penicillins (such as piperacillin/tazobactam). Delafloxacin powder was provided by the sponsor, Melinta Therapeutics, and the comparator agents were obtained commercially. Appropriate ATCC control organisms (Staphylococcus aureus ATCC-29213 and Enterococcus faecalis ATCC-29212 for GPOs, and Escherichia coli ATCC-25922 and Pseudomonas aeruginosa ATCC-27853 for GNB) were included in each run to ensure the accuracy and validity of our results. Lysed horse blood (5% v/v) was used in broth microdilution susceptibility testing of streptococci.
MIC values were determined using CLSI-approved microdilution methods.16 MIC50, MIC90, MIC ranges and percentage of susceptibility calculations were made according to CLSI 2020.17 Because there are no CLSI breakpoints for delafloxacin we used the FDA breakpoints, which are susceptible-only breakpoints. The in vitro activity of each agent was reported using MIC. MIC50 and MIC90 values were calculated when ≥10 isolates of a particular species were available for testing. When <10 isolates were available, MIC ranges were reported. The chi-square test was used to statistically compare delafloxacin activity with that of ciprofloxacin and levofloxacin; P < 0.05 was considered statistically significant.
Time-kill studies were performed on four viridans group streptococci (VGS) isolates (Streptococcus mitis/oralis) using CLSI-approved broth microdilution techniques at concentrations of each agent that were equivalent to MIC and four and eight times the respective MIC. Levofloxacin was used as a comparator agent, and the test was performed according to CLSI M26-A.18
Results
The in vitro activity of delafloxacin and seven comparator agents against 350 GPOs and 210 GNB from patients with cancer is shown in Tables 1 and 2. Statistical comparison of delafloxacin with ciprofloxacin and levofloxacin was made when breakpoints for all three fluoroquinolones were available, as shown in Table 3. The overall susceptibility rates of all isolates with available breakpoints to delafloxacin, ciprofloxacin and levofloxacin were 59.3%, 48.1% and 51.1%, respectively, and the overall susceptibility rate to delafloxacin was significantly higher than that for ciprofloxacin (P = 0.015).
Table 1.
In vitro activity of delafloxacin and seven comparators against 350 Gram-positive organisms isolated from patients with cancer
| Organism | No. tested | Agent | % S | MIC (mg/L) | ||
|---|---|---|---|---|---|---|
| MIC50 | MIC90 | Range | ||||
| Bacillus spp. | 20 | Delafloxacin | NA | 0.06 | 0.06 | ≤0.03 to 0.125 |
| Ciprofloxacin | NA | 0.25 | 0.25 | ≤0.06 to 0.25 | ||
| Levofloxacin | NA | 0.125 | 0.125 | ≤0.06 to 0.25 | ||
| Trimeth/sulfa | NA | 4/76 | 4/76 | ≤0.03/0.6 to 4/76 | ||
| Cefpodoxime | NA | >64 | >64 | 8 to >64 | ||
| Cefixime | NA | >64 | >64 | 8 to >64 | ||
| Ertapenem | NA | 4 | 4 | ≤0.06 to 8 | ||
| Tigecycline | NA | ≤0.125 | ≤0.125 | ≤0.125 to 0.25 | ||
| β-Haemolytic streptococci group A | 4 | Delafloxacin | 75 | NA | NA | ≤0.03 to 0.25 |
| Ciprofloxacin | 100 | NA | NA | 0.125 to 0.5 | ||
| Levofloxacin | 100 | NA | NA | 0.125 to 0.5 | ||
| Trimeth/sulfa | 100 | NA | NA | ≤0.03/0.6 to 0.125 | ||
| Cefpodoxime | NA | NA | NA | ≤0.06 to ≤0.06 | ||
| Cefixime | NA | NA | NA | ≤0.06 to ≤0.06 | ||
| Ertapenem | NA | NA | NA | ≤0.03 to ≤0.03 | ||
| Tigecycline | NA | NA | NA | ≤0.125 to ≤0.125 | ||
| β-Haemolytic streptococci group B | 12 | Delafloxacin | 100 | ≤0.03 | ≤0.03 | ≤0.03 |
| Ciprofloxacin | 100 | 0.5 | 1 | 0.25 to 1 | ||
| Levofloxacin | 100 | 0.5 | 1 | 0.5 to 1 | ||
| Trimeth/sulfa | 100 | 0.125/2.4 | 0.125/2.4 | ≤0.03/0.6 to 0.125/2.4 | ||
| Cefpodoxime | NA | ≤0.06 | 1 | ≤0.06 to 2 | ||
| Cefixime | NA | 0.5 | 8 | 0.25 to 16 | ||
| Ertapenem | NA | ≤0.03 | 0.5 | ≤0.03 to 0.5 | ||
| Tigecycline | NA | ≤0.125 | ≤0.125 | ≤0.125 | ||
| Corynebacterium spp. | 30 | Delafloxacin | NA | 0.06 | 2 | ≤0.03 to 4 |
| Ciprofloxacin | NA | 0.25 | 16 | ≤0.06 to >64 | ||
| Levofloxacin | NA | 0.25 | 32 | ≤0.06 to 64 | ||
| Trimeth/sulfa | NA | 0.25/4.8 | >32/608 | ≤0.03/0.6 to >32/608 | ||
| Cefpodoxime | NA | 4 | >64 | 0.5 to >64 | ||
| Cefixime | NA | 32 | >64 | 2 to >64 | ||
| Ertapenem | NA | 1 | 2 | 0.25 to >32 | ||
| Tigecycline | NA | 0.25 | 0.5 | ≤0.125 to 0.5 | ||
| Enterococcus faecalis (VSE) | 15 | Delafloxacin | 60 | 0.125 | >32 | ≤0.03 to >32 |
| Ciprofloxacin | 40 | 2 | >64 | 0.125 to >64 | ||
| Levofloxacin | 53 | 2 | >64 | 0.5 to >64 | ||
| Trimeth/sulfa | NA | 0.06/1.2 | >32/608 | ≤0.03/0.6 to >32/608 | ||
| Cefpodoxime | NA | >64 | >64 | 0.25 to >64 | ||
| Cefixime | NA | >64 | >64 | 0.25 to >64 | ||
| Ertapenem | NA | 16 | >32 | 0.125 to >32 | ||
| Tigecycline | NA | 0.5 | 1 | ≤0.125 to 1 | ||
| Enterococcus faecium (VSE) | 15 | Delafloxacin | NA | >32 | >32 | 0.06 to >32 |
| Ciprofloxacin | 13 | >64 | >64 | 0.5 to >64 | ||
| Levofloxacin | 20 | >64 | >64 | 1 to >64 | ||
| Trimeth/sulfa | NA | 0.125/2.4 | >32/608 | ≤0.03/0.6 to >32/608 | ||
| Cefpodoxime | NA | >64 | >64 | >64 to >64 | ||
| Cefixime | NA | >64 | >64 | >64 to >64 | ||
| Ertapenem | NA | >32 | >32 | 16 to >32 | ||
| Tigecycline | NA | 0.25 | 0.5 | ≤0.125 to 0.5 | ||
| Listeria monocytogenes | 6 | Delafloxacin | NA | NA | NA | ≤0.03 to 0.06 |
| Ciprofloxacin | NA | NA | NA | 0.25 to 1 | ||
| Levofloxacin | NA | NA | NA | 0.25 to 1 | ||
| Trimeth/sulfa | NA | NA | NA | ≤0.03 to 0.125 | ||
| Cefpodoxime | NA | NA | NA | 16 to >64 | ||
| Cefixime | NA | NA | NA | 0.5 to >64 | ||
| Ertapenem | NA | NA | NA | 0.25 to 1 | ||
| Tigecycline | NA | NA | NA | ≤0.125 to 0.25 | ||
| Micrococcus spp. | 20 | Delafloxacin | NA | ≤0.03 | 0.06 | ≤0.03 to 0.06 |
| Ciprofloxacin | NA | 0.5 | 1 | 0.5 to 2 | ||
| Levofloxacin | NA | 1 | 1 | 0.5 to 1 | ||
| Trimeth/sulfa | NA | 0.25/4.8 | 0.5/9.6 | ≤0.03/0.6 to 1/19 | ||
| Cefpodoxime | NA | 1 | 4 | 0.25 to 8 | ||
| Cefixime | NA | 16 | >64 | 2 to >64 | ||
| Ertapenem | NA | 0.125 | 0.25 | 0.06 to 0.5 | ||
| Tigecycline | NA | ≤0.125 | 0.25 | ≤0.125 to 0.25 | ||
| MRSA | 30 | Delafloxacin | 40 | 0.5 | 4 | ≤ 0.015 to 4 |
| Ciprofloxacin | 6.7 | >64 | >64 | 0.25 to >64 | ||
| Levofloxacin | 6.7 | 32 | >64 | 0.125 to >64 | ||
| Trimeth/sulfa | 100 | 0.03/0.6 | 0.125/2.4 | ≤0.015/0.3 to 0.125/2.4 | ||
| Cefpodoxime | NA | >64 | >64 | 16 to >64 | ||
| Cefixime | NA | >64 | >64 | 64 to >64 | ||
| Ertapenem | NA | 8 | 64 | 1 to >64 | ||
| Tigecycline | NA | 0.5 | 1 | 0.5 to 2 | ||
| MSSA | 20 | Delafloxacin | 80 | ≤0.015 | 0.5 | ≤0.015 to 4 |
| Ciprofloxacin | 55 | 0.25 | >64 | 0.125 to >64 | ||
| Levofloxacin | 65 | 0.125 | 16 | ≤0.03 to >64 | ||
| Trimeth/sulfa | 100 | 0.06/1.2 | 0.25/4.8 | 0.03/0.6 to 1/19 | ||
| Cefpodoxime | NA | 2 | >64 | 2 to >64 | ||
| Cefixime | NA | 32 | 64 | 4 to 64 | ||
| Ertapenem | NA | 0.125 | 16 | ≤0.06 to 64 | ||
| Tigecycline | NA | ≤0.125 | ≤0.125 | ≤0.125 to 0.25 | ||
| CoNS-OR | 20 | Delafloxacin | 50 | 0.25 | 2 | ≤0.03 to 2 |
| Ciprofloxacin | 10 | 16 | 32 | 0.125 to 64 | ||
| Levofloxacin | 10 | 8 | >64 | ≤0.06 to >64 | ||
| Trimeth/sulfa | 25 | 4/76 | 8/152 | 0.125/2.4 to 32/608 | ||
| Cefpodoxime | NA | 32 | 64 | 1 to >64 | ||
| Cefixime | NA | 64 | >64 | 2 to >64 | ||
| Ertapenem | NA | 16 | >32 | 2 to >32 | ||
| Tigecycline | NA | ≤0.125 | 0.5 | ≤0.125 to 1 | ||
| CoNS-OS | 20 | Delafloxacin | 95 | ≤0.03 | 0.25 | ≤0.03 to 1 |
| Ciprofloxacin | 60 | 0.125 | 16 | ≤0.06 to 16 | ||
| Levofloxacin | 60 | 0.125 | 4 | ≤0.06 to 8 | ||
| Trimeth/sulfa | 70 | 0.125/2.4 | 16/304 | 0.06/1.2 to >32/608 | ||
| Cefpodoxime | NA | 1 | 2 | 0.25 to >64 | ||
| Cefixime | NA | 2 | 4 | 1 to 64 | ||
| Ertapenem | NA | 0.125 | 0.25 | ≤0.06 to 64 | ||
| Tigecycline | NA | ≤0.125 | 0.5 | ≤0.125 to 1 | ||
| Staphylococcus lugdunensis | 10 | Delafloxacin | 60 | ≤0.03 | 0.125 | ≤0.03 to 0.25 |
| Ciprofloxacin | 100 | 0.125 | 0.25 | ≤0.06 to 0.25 | ||
| Levofloxacin | 100 | 0.25 | 0.25 | 0.125 to 0.5 | ||
| Trimeth/sulfa | 90 | 1/19 | 2/38 | 0.25/4.8 to 32/608 | ||
| Cefpodoxime | NA | 2 | >64 | 1 to >64 | ||
| Cefixime | NA | 8 | 8 | 2 to >64 | ||
| Ertapenem | NA | 0.5 | 0.5 | 0.25 to 2 | ||
| Tigecycline | NA | ≤0.125 | 0.25 | ≤0.125 to 0.25 | ||
| Streptococcus pneumoniae (penicillin-susceptible) | 20 | Delafloxacin | 55 | ≤0.03 | 0.125 | ≤0.03 to 0.125 |
| Ciprofloxacin | NA | 0.5 | 1 | 0.125 to 2 | ||
| Levofloxacin | 95 | 0.25 | 2 | ≤0.06 to 4 | ||
| Trimeth/sulfa | 60 | 0.25/4.8 | 4/76 | ≤0.03/0.6 to 32/608 | ||
| Cefpodoxime | 35 | 1 | 16 | ≤0.06 to 16 | ||
| Cefixime | NA | 8 | 64 | ≤0.06 to 64 | ||
| Ertapenem | 60 | 0.25 | 32 | ≤0.03 to 32 | ||
| Tigecycline | NA | ≤0.125 | 0.25 | ≤0.125 to 0.5 | ||
| Rhodococcus equi | 5 | Delafloxacin | NA | NA | NA | 0.125 to 0.5 |
| Ciprofloxacin | NA | NA | NA | 0.25 to 0.5 | ||
| Levofloxacin | NA | NA | NA | 0.5 to 1 | ||
| Trimeth/sulfa | NA | NA | NA | 0.5 to 1 | ||
| Cefpodoxime | NA | NA | NA | 8 to 32 | ||
| Cefixime | NA | NA | NA | 32 to >64 | ||
| Ertapenem | NA | NA | NA | 0.5 to 1 | ||
| Tigecycline | NA | NA | NA | 0.25 to 0.5 | ||
| Rothia spp. | 30 | Delafloxacin | NA | ≤0.03 | 0.06 | ≤0.03 to 0.06 |
| Ciprofloxacin | NA | 0.125 | 0.5 | ≤0.06 to 1 | ||
| Levofloxacin | NA | 0.125 | 1 | ≤0.06 to 2 | ||
| Trimeth/sulfa | NA | ≤0.03/0.6 | 0.25/4.8 | ≤0.03/0.6 to 0.5/9.6 | ||
| Cefpodoxime | NA | ≤0.06 | 1 | ≤0.06 to 16 | ||
| Cefixime | NA | 8 | 32 | 0.125 to 64 | ||
| Ertapenem | NA | 0.5 | 2 | ≤0.03 to 4 | ||
| Tigecycline | NA | ≤0.125 | 0.25 | ≤0.125 to 0.25 | ||
| Viridans group streptococci | 73 | Delafloxacin | NA | 0.06 | 0.06 | ≤0.03 to 0.5 |
| Ciprofloxacin | NA | 2 | 16 | ≤0.06 to 64 | ||
| Levofloxacin | 78 | 1 | 4 | ≤0.06 to 16 | ||
| Trimeth/sulfa | 75 | 0.25/4.8 | 8/152 | ≤0.03/0.6 to >32/608 | ||
| Cefpodoxime | NA | 0.25 | 16 | ≤0.06 to >64 | ||
| Cefixime | NA | >64 | >64 | ≤0.06 to >64 | ||
| Ertapenem | NA | 0.25 | 4 | ≤0.03 to >32 | ||
| Tigecycline | NA | ≤0.125 | 0.5 | ≤0.125 to 1 | ||
US FDA susceptibility breakpoints to delafloxacin are as follows: staphylococci ≤0.25 (except S. lugdunensis, which is ≤0.03); E. faecalis ≤0.12; S. pneumoniae ≤0.03; and β-haemolytic streptococci ≤0.06. NA indicates not applicable either because breakpoints have not been established for that antimicrobial drug/bacteria combination or because the antimicrobial drug is not expected to have activity for that bacterial species. CoNS-OR, oxacillin-resistant coagulase-negative staphylococci; CoNS-OS, oxacillin-susceptible coagulase-negative staphylococci; Trimeth/sulfa, trimethoprim/sulfamethoxazole; VSE, vancomycin-susceptible enterococci; % S, percentage of susceptibility.
Table 2.
In vitro activity of delafloxacin and seven comparators against 210 Gram-negative bacilli isolated from patients with cancer
| Organism | No. tested | Agent | % S | MIC (mg/L) | ||
|---|---|---|---|---|---|---|
| MIC50 | MIC90 | Range | ||||
| Achromobacter spp. | 15 | Delafloxacin | NA | 4 | 16 | 0.5 to 32 |
| Ciprofloxacin | NA | 4 | 64 | 1 to >64 | ||
| Levofloxacin | NA | 2 | 64 | 1 to 64 | ||
| Trimeth/sulfa | NA | 0.25/4.8 | 8/152 | 0.06/1.2 to 8/152 | ||
| Cefpodoxime | NA | >64 | >64 | >64 | ||
| Cefixime | NA | >64 | >64 | >64 | ||
| Ertapenem | NA | 0.125 | 32 | 0.06 to >32 | ||
| Tigecycline | NA | 2 | 4 | 0.5 to 4 | ||
| Acinetobacter spp. | 15 | Delafloxacin | NA | 0.06 | 0.125 | ≤0.03 to 2 |
| Ciprofloxacin | 93 | 0.25 | 2 | ≤0.06 to 32 | ||
| Levofloxacin | 93 | 0.125 | 0.25 | ≤0.06 to 64 | ||
| Trimeth/sulfa | 93 | 0.25/4.8 | 8/152 | 0.06/1.2 to 32/304 | ||
| Cefpodoxime | NA | 16 | 32 | 2 to >64 | ||
| Cefixime | NA | 32 | >64 | 8 to >64 | ||
| Ertapenem | NA | 8 | >32 | 2 to >32 | ||
| Tigecycline | NA | 0.25 | 1 | 0.125 to 4 | ||
| Citrobacter spp. | 20 | Delafloxacin | NA | 0.06 | 2 | ≤0.03 to 8 |
| Ciprofloxacin | 55 | 0.25 | 8 | ≤0.06 to 64 | ||
| Levofloxacin | 80 | 0.25 | 8 | ≤0.06 to 64 | ||
| Trimeth/sulfa | 75 | 0.125/2.4 | 4/76 | ≤0.03/0.6 to 32/608 | ||
| Cefpodoxime | 30 | 32 | >64 | 0.125 to >64 | ||
| Cefixime | 10 | >64 | >64 | 0.125 to >64 | ||
| Ertapenem | 85 | 0.125 | 1 | ≤0.03 to 16 | ||
| Tigecycline | 95 | 0.5 | 2 | ≤0.06 to 4 | ||
| Klebsiella aerogenes (known as Enterobacter aerogenes) | 20 | Delafloxacin | NA | 0.125 | 0.25 | ≤0.03 to 16 |
| Ciprofloxacin | 90 | ≤0.06 | ≤0.06 | ≤0.06 to 16 | ||
| Levofloxacin | 90 | ≤0.06 | 0.125 | ≤0.06 to 4 | ||
| Trimeth/sulfa | 95 | 0.125/2.4 | 0.25/4.8 | 0.06/1.2 to >32/608 | ||
| Cefpodoxime | 80 | 0.5 | 64 | 0.25 to >64 | ||
| Cefixime | 80 | 1 | >64 | 0.25 to >64 | ||
| Ertapenem | 90 | 0.06 | 1 | ≤0.03 to >32 | ||
| Tigecycline | 100 | 1 | 1 | 0.25 to 2 | ||
| Enterobacter cloacae | 20 | Delafloxacin | 85 | 0.06 | 1 | ≤0.03 to 8 |
| Ciprofloxacin | 85 | ≤0.06 | 1 | ≤0.06 to 8 | ||
| Levofloxacin | 85 | ≤0.06 | 1 | ≤0.06 to 8 | ||
| Trimeth/sulfa | 70 | 0.5/9.5 | 32/608 | 0.06/1.2 to >32/608 | ||
| Cefpodoxime | 40 | 4 | >64 | 0.125 to >64 | ||
| Cefixime | 10 | 4 | >64 | 0.125 to >64 | ||
| Ertapenem | 70 | 0.125 | 1 | ≤0.03 to 4 | ||
| Tigecycline | 95 | 0.5 | 1 | 0.25 to 4 | ||
| Escherichia coli (ESBL-positive) | 10 | Delafloxacin | 0 | 8 | 32 | 1to 32 |
| Ciprofloxacin | 0 | 32 | >64 | 2 to >64 | ||
| Levofloxacin | 0 | 64 | 64 | 1 to 32 | ||
| Trimeth/sulfa | 30 | >32/608 | >32/608 | 0.125/2.4 to >32/608 | ||
| Cefpodoxime | 30 | >64 | >64 | 1 to >64 | ||
| Cefixime | 20 | >64 | >64 | 1 to >64 | ||
| Ertapenem | 70 | ≤0.03 | >32 | ≤0.03 to >32 | ||
| Tigecycline | 100 | 0.25 | 0.5 | 0.25 to 0.5 | ||
| E. coli (non-ESBL) | 10 | Delafloxacin | 30 | 1 | 16 | ≤0.03 to 16 |
| Ciprofloxacin | 30 | 1 | 32 | ≤0.06 to >64 | ||
| Levofloxacin | 40 | 1 | 16 | ≤0.06 to 32 | ||
| Trimeth/sulfa | 70 | ≤0.03/0.6 | >32/608 | ≤0.03/0.6 to >32/608 | ||
| Cefpodoxime | 100 | 0.5 | 1 | 0.25 to 1 | ||
| Cefixime | 90 | 0.5 | 1 | 0.125 to 4 | ||
| Ertapenem | 100 | ≤0.03 | ≤0.03 | ≤0.03 | ||
| Tigecycline | 100 | 0.25 | 0.25 | ≤0.03 to 0.25 | ||
| Klebsiella oxytoca | 20 | Delafloxacin | NA | 0.125 | 8 | 0.06 to 32 |
| Ciprofloxacin | 80 | ≤0.06 | 16 | ≤0.06 to >64 | ||
| Levofloxacin | 80 | ≤0.06 | 16 | ≤0.06 to 64 | ||
| Trimeth/sulfa | 80 | 0.25/4.8 | >32/608 | 0.06/1.2 to >32/608 | ||
| Cefpodoxime | 65 | 0.125 | 64 | ≤0.06 to >64 | ||
| Cefixime | 70 | ≤0.06 | >64 | ≤0.06 to >64 | ||
| Ertapenem | 95 | ≤0.03 | 0.125 | ≤0.03 to 4 | ||
| Tigecycline | 100 | 0.5 | 2 | 0.5 to 2 | ||
| Klebsiella pneumoniae (non-ESBL) | 20 | Delafloxacin | 70 | 0.125 | 1 | ≤0.03 to 16 |
| Ciprofloxacin | 80 | 0.125 | 2 | ≤0.06 to 16 | ||
| Levofloxacin | 90 | ≤0.06 | 0.5 | ≤0.06 to 16 | ||
| Trimeth/sulfa | 70 | 0.25/4.8 | >32/608 | 0.125/2.4 to >32/608 | ||
| Cefpodoxime | 85 | 0.125 | 4 | ≤0.06 to >64 | ||
| Cefixime | 85 | ≤0.06 | 8 | ≤0.06 to >64 | ||
| Ertapenem | 100 | ≤0.03 | ≤0.03 | ≤0.03 to 0.06 | ||
| Tigecycline | 95 | 1 | 1 | 0.5 to 4 | ||
| Proteus mirabilis | 10 | Delafloxacin | NA | 0.06 | 8 | ≤0.03 to 16 |
| Ciprofloxacin | 60 | ≤0.06 | >64 | ≤0.06 to >64 | ||
| Levofloxacin | 60 | ≤0.06 | 64 | ≤0.06 to 64 | ||
| Trimeth/sulfa | 30 | >32/608 | >32/608 | 0.06/1.2 to >32/608 | ||
| Cefpodoxime | 70 | ≤0.06 | >64 | ≤0.06 to >64 | ||
| Cefixime | 60 | ≤0.06 | >64 | ≤0.06 to >64 | ||
| Ertapenem | 100 | ≤0.03 | 0.125 | ≤0.03 to 0.125 | ||
| Tigecycline | 10 | 4 | 4 | 2 to 4 | ||
| P. aeruginosa (MDR) | 20 | Delafloxacin | 5 | 8 | 32 | 0.5 to >32 |
| Ciprofloxacin | 5 | 16 | 32 | 0.5 to >64 | ||
| Levofloxacin | 5 | 16 | 64 | 1 to >64 | ||
| Trimeth/sulfa | NA | >32/608 | >32/608 | 8/152 to >32/608 | ||
| Cefpodoxime | NA | >64 | >64 | >64 | ||
| Cefixime | NA | >64 | >64 | >64 | ||
| Ertapenem | NA | >32 | >32 | 32 to >32 | ||
| Tigecycline | NA | 8 | 16 | 4 to >64 | ||
| P. aeruginosa (non-MDR) | 20 | Delafloxacin | 75 | 0.25 | 2 | 0.125 to 16 |
| Ciprofloxacin | 75 | 0.125 | 4 | ≤0.06 to 8 | ||
| Levofloxacin | 75 | 0.5 | 8 | 0.25 to 16 | ||
| Trimeth/sulfa | NA | 16/152 | >32/608 | 4/76 to >32/608 | ||
| Cefpodoxime | NA | >64 | >64 | 64 to >64 | ||
| Cefixime | NA | 64 | >64 | 32 to >64 | ||
| Ertapenem | NA | 4 | 16 | 2 to >32 | ||
| Tigecycline | NA | 8 | 8 | 1 to 16 | ||
| P. aeruginosa (combined results of both MDR and non-MDR) | 40 | Delafloxacin | 40 | 2 | 32 | 0.125 to >32 |
| Ciprofloxacin | 40 | 4 | 32 | ≤0.06 to >64 | ||
| Levofloxacin | 40 | 8 | 64 | 0.25 to >64 | ||
| Trimeth/sulfa | NA | 32/608 | >32/608 | 4/76 to >32/608 | ||
| Cefpodoxime | NA | >64 | >64 | 64 to >64 | ||
| Cefixime | NA | >64 | >64 | 32 to >64 | ||
| Ertapenem | NA | >32 | >32 | 2 to >32 | ||
| Tigecycline | NA | 8 | 16 | 1 to >64 | ||
| Serratia spp. | 10 | Delafloxacin | NA | 0.5 | 1 | 0.5 to 2 |
| Ciprofloxacin | 100 | ≤0.06 | 0.125 | ≤0.06 to 0.125 | ||
| Levofloxacin | 100 | ≤0.06 | 0.25 | ≤0.06 to 0.25 | ||
| Trimeth/sulfa | 100 | 0.5/9.6 | 0.5/9.6 | 0.25/4.8 to 1/19.2 | ||
| Cefpodoxime | 90 | 1 | 2 | 1 to 8 | ||
| Cefixime | 30 | >64 | >64 | 0.5 to >64 | ||
| Ertapenem | 90 | ≤0.03 | 0.25 | ≤0.03 to 1 | ||
| Tigecycline | 100 | 1 | 2 | 1 to 2 | ||
US FDAS susceptibility breakpoints to delafloxacin are as follows: Enterobacterales ≤0.25; Pseudomonas spp. ≤0.5. NA indicates not applicable either because breakpoints have not been established for that antimicrobial drug/bacteria combination or because the antimicrobial drug is not expected to have activity for that bacterial species. Trimeth/sulfa, trimethoprim/sulfamethoxazole; % S, percentage of susceptibility.
Table 3.
In vitro activity of delafloxacin compared with ciprofloxacin and levofloxacin against bacterial pathogens with available breakpoints, isolated from patients with cancer
| Pathogen | No. tested | No. of susceptible isolates (%) | P a | P b | ||
|---|---|---|---|---|---|---|
| Delafloxacin | Ciprofloxacin | Levofloxacin | ||||
| Staphylococci | 100 | 63 (63) | 37 (37) | 39 (39) | 0.0002 | 0.0007 |
| Streptococci | 16 | 15 (93.8) | 16 (100) | 16 (100) | >0.99 | >0.99 |
| Enterococci | 15 | 9 (60) | 6 (40) | 8 (53.3) | 0.27 | 0.71 |
| Enterobacterales | 60 | 34 (56.7) | 36 (60) | 39 (65) | 0.71 | 0.35 |
| Pseudomonas aeruginosa | 40 | 16 (40) | 16 (40) | 16 (40) | >0.99 | >0.99 |
| Total | 231 | 137 (59.3) | 111 (48.1) | 118 (51.1) | 0.015 | 0.08 |
Enterobacterales include Enterobacter cloacae, Escherichia coli and Klebsiella pneumoniae. Pseudomonas aeruginosa includes both MDR and non-MDR isolates. Staphylococci include MRSA, MSSA, CoNS and Staphylococcus lugdunensis. Streptococci include β-haemolytic streptococci group A and group B. Enterococci include vancomycin-susceptible Enterococcus faecalis.
Delafloxacin compared with ciprofloxacin (chi-square test).
Delafloxacin compared with levofloxacin (chi-square test).
Activity against staphylococci
Delafloxacin was more active than ciprofloxacin and levofloxacin against MSSA, MRSA and CoNS. We found that 40% of MRSA isolates were susceptible to delafloxacin, whereas only 6.7% of these isolates were susceptible to ciprofloxacin and levofloxacin. Also, 80% of MSSA isolates were susceptible to delafloxacin, compared with 55% to ciprofloxacin and 65% to levofloxacin. Susceptibility to delafloxacin was observed in 95% of oxacillin-susceptible CoNS isolates and 50% of oxacillin-resistant CoNS isolates, whereas the susceptibility to both ciprofloxacin and levofloxacin was 60% against oxacillin-susceptible and 10% against oxacillin-resistant CoNS isolates. In contrast, all Staphylococcus lugdunensis isolates (100%) were susceptible to both ciprofloxacin and levofloxacin, whereas only 60% of S. lugdunensis isolates were susceptible to delafloxacin using susceptible-only breakpoints. However, delafloxacin MIC values for susceptible isolates were lower than those of ciprofloxacin and levofloxacin. Significantly more staphylococcal isolates were susceptible to delafloxacin than to ciprofloxacin (63% compared with 37%; P = 0.0002) and levofloxacin (63% compared with 39%; P = 0.0007).
Activity against enterococci and streptococci
We found that 60% of vancomycin-susceptible E. faecalis isolates were susceptible to delafloxacin, whereas only 40% were susceptible to ciprofloxacin and 53% were susceptible to levofloxacin. The MIC90 values for all three tested fluoroquinolones indicated limited activity against vancomycin-susceptible Enterococcus faecium (Table 1). The MIC range of delafloxacin against 20 penicillin-susceptible Streptococcus pneumoniae isolates was ≤0.03 mg/L to 0.125 mg/L, compared with 0.125 mg/L to 2 mg/L against ciprofloxacin and ≤0.06 mg/L to 4 mg/L against levofloxacin. The MIC range of delafloxacin against 73 VGS isolates was ≤0.03 mg/L to 0.5 mg/L, compared with 0.06 mg/L to 64 mg/L for ciprofloxacin and ≤0.06 mg/L to 16 mg/L for levofloxacin. Although ciprofloxacin and levofloxacin were more active than delafloxacin against β-haemolytic streptococci group A isolates, the MIC ranges were much higher than for delafloxacin. The MIC range for delafloxacin was only ≤0.03 mg/L to 0.25 mg/L, compared with 0.125 mg/L to 0.5 mg/L for ciprofloxacin and levofloxacin. All β-haemolytic streptococci group B isolates (100%) were susceptible to all three fluoroquinolones, although the breakpoint against β-haemolytic streptococci is ≤0.06 mg/L for delafloxacin, ≤ 1 mg/L for ciprofloxacin and ≤2 mg/L for levofloxacin. There were no significant differences in susceptibility to the three tested fluoroquinolones for enterococci or streptococci.
Activity against less common GPOs
Although susceptibility breakpoints for less common GPOs are not available, the MIC ranges for delafloxacin were much lower than those for the comparators. Delafloxacin had the lowest MIC ranges for Bacillus species (≤0.03 mg/L to 0.125 mg/L), Micrococcus species (≤0.03 mg/L to 0.06 mg/L), Rothia species (≤0.03 mg/L to 0.06 mg/L), Rhodococcus equi (0.125 mg/L to 0.5 mg/L) and Listeria monocytogenes (≤0.03 mg/L to 0.06 mg/L). Delafloxacin also had lower MIC ranges against Corynebacterium species (≤0.03 mg/L to 4 mg/L) when compared with ciprofloxacin and levofloxacin, which had ≤0.06 to >64 mg/L, and ≤ 0.06 to 64 mg/L, respectively.
Activity against Enterobacterales
The in vitro activity of delafloxacin and comparator agents against 210 GNB are shown in Table 2. The susceptibility rate of Enterobacter cloacae isolates to delafloxacin was the same as that observed for ciprofloxacin and levofloxacin (85%). In non-ESBL Klebsiella pneumoniae isolates, 70% were susceptible to delafloxacin, 80% to ciprofloxacin, and 90% to levofloxacin. Notably, ESBL E.coli tested isolates had 0.0% susceptibility to all three tested fluoroquinolones, whereas 30% of non-ESBL Escherichia coli isolates were susceptible to delafloxacin and ciprofloxacin, and 40% were susceptible to levofloxacin. MIC50, MIC90 and MIC range values for delafloxacin were almost similar to those of ciprofloxacin and levofloxacin against Citrobacter species, Klebsiella aerogenes and Klebsiella oxytoca. Overall, 56.7% of Enterobacterales were susceptible to delafloxacin, 60% to ciprofloxacin and 65% to levofloxacin, but the differences in these rates were not statistically significant.
Activity against non-fermenting GNB
Susceptibility rates to the three fluoroquinolones also did not differ for P. aeruginosa isolates. Activity of delafloxacin, ciprofloxacin and levofloxacin was almost similar against Achromobacter and Acinetobacter species, although the susceptibility breakpoints are not available, as shown in Table 2.
Time-kill experiment
Because the MIC ranges were lowest for delafloxacin among comparator agents against VGS, which are the most common GPOs that cause bloodstream infections in neutropenic patients, we sought to determine whether delafloxacin would effectively kill these organisms using time-kill studies, with levofloxacin as a comparator. MIC was 0.06 mg/L for delafloxacin, and 1 mg/L for levofloxacin. Similar results were found for all four tested organisms with a representative isolate shown in Figure 1. Delafloxacin decreased the bacterial load to 3 log10 in <8 h at 8× MIC, and <10 h at 4× MIC, whereas levofloxacin needed >13 h at 8× MIC and >16 h at 4× MIC to achieve the same results. Maximum bactericidal activity for delafloxacin and levofloxacin was achieved at 8 × MIC for all tested isolates.
Figure 1.
Time-kill experiments for (a) delafloxacin and (b) levofloxacin against Streptococcus mitis/oralis MB #9957, showing the effect at 1×, 4× and 8× MIC.
Discussion
Consistent with prior studies,6,19,20 in the current examination of isolates from patients with cancer, delafloxacin showed superior in vitro activity against GPOs, including MSSA, MRSA and CoNS, compared with other conventional fluoroquinolones such as ciprofloxacin and levofloxacin (Table 3). However, delafloxacin was active against only 40% of MRSA organisms, whereas 100% of these organisms were susceptible to trimethoprim/sulfamethoxazole. In addition, delafloxacin was less active against S. lugdunensis compared with ciprofloxacin and levofloxacin.
We also found that only 55% of penicillin-susceptible S. pneumoniae isolates were susceptible to delafloxacin, which was significantly less than the 95% of isolates susceptible to levofloxacin (P = 0.004). These results are inconsistent with those of Pfaller et al.,21 who reported that 98% of S. pneumoniae isolates from the USA and Europe were susceptible to delafloxacin. The decreased activity in our study is most likely related to the emergence of resistance in cancer patients, given the wide prophylactic use of fluoroquinolones in this patient population.12,22,23 In addition, delafloxacin showed activity against most β-haemolytic streptococci, as well as against VGS and most uncommon GPOs such as Bacillus species, L. monocytogenes, Micrococcus and Rothia species, with the lowest MIC ranges among the comparators.
In general, delafloxacin had similar activity to that of ciprofloxacin and levofloxacin against a broad range of aerobic GNB. Delafloxacin and the other fluoroquinolones were not active against ESBL E. coli and showed limited activity against non-ESBL isolates, unlike ertapenem. All non-ESBL E. coli isolates and 70% of ESBL E. coli isolates were susceptible to ertapenem. These findings are consistent with the results of other studies and could also be related to the growing resistance associated with heavy prophylactic and empirical use of fluoroquinolones in the cancer patient population.12,20,21,24–26 In addition, all tested fluoroquinolones had nearly the same low level of activity against P. aeruginosa and E. coli. These findings suggest that the three fluoroquinolones tested might not be the best prophylactic agents to prevent GNB in patients with cancer.
Time-kill testing showed similar inhibitory and cidal kinetics for delafloxacin and levofloxacin against S. mitis/oralis isolates (maximum activity at 8 × MIC) as shown in Figure 1. Delafloxacin and levofloxacin decreased the bacterial load to 3.0 log10 in 8 and 13 h, respectively, using 8 × MIC.
Our study had a few limitations. Although the IDSA recommends cefepime, piperacillin/tazobactam and meropenem for the treatment of fever and neutropenia, assessment of the in vitro activity of these agents was beyond the scope of the current study. The relative numbers of E. coli isolates that were tested in this study (E. coli: 20; K. pneumoniae: 40) may not be representative of the entire spectrum of bloodstream isolates in this patient population. This may lead to biases in MIC50, MIC90 and susceptibility percentage interpretation and hence is considered a limitation. Because there are no CLSI breakpoints for delafloxacin we used the FDA breakpoints, which are susceptible-only breakpoints and thus we consider comparing susceptibility percentage for delafloxacin with levofloxacin and ciprofloxacin for various organisms as another limitation to this study.
In conclusion, our data indicate that delafloxacin could serve as a prophylactic alternative to levofloxacin in neutropenic cancer patients given its higher activity against GPOs, although clinical studies are needed to confirm these findings. Although delafloxacin could occasionally serve as a targeted or step-down therapy against susceptible pathogens, particularly in patients with polymicrobial infections,27 the main focus of this drug should be on its prophylactic use in patients with prolonged neutropenia. However, our data also showed that resistance to all three fluoroquinolones tested was high among leading GNB such as E. coli and P. aeruginosa.
Acknowledgments
We thank Dr Ruth Reitzel, Ms Salli Saxton and Ms Ying Jiang for their support in the study protocol, manuscript publishing, and for helping us in statistics analysis, respectively. Also, we thank Ms Erica Goodoff in the Research Medical Library at The University of Texas MD Anderson Cancer Center for editing the manuscript.
Contributor Information
Bahgat Gerges, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Kenneth Rolston, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Samuel A Shelburne, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA; Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Joel Rosenblatt, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Randall Prince, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Issam Raad, Department of Infectious Diseases, Infection Control and Employee Health Research, The University of Texas MD Anderson Cancer Center, 1515 Holcomb Blvd, Houston, TX 77030, USA.
Funding
This study was supported in part by Melinta Pharmaceuticals, while the rest of the work was done at our MD Anderson lab (PI: Dr. Issam Raad).
Transparency declarations
Issam Raad, University of Texas MD Anderson Cancer Center, is the inventor of the nitroglycerine-based catheter lock solution technology licensed by Novel Anti-infective Technologies, LLC, in which he and the University of Texas MD Anderson Cancer Center are shareholders. All others have no conflicts to disclose.
References
- 1. Freifeld AG, Bow EJ, Sepkowitz KAet al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: 427–31. 10.1093/cid/ciq147 [DOI] [PubMed] [Google Scholar]
- 2. Elting LS, Rubenstein EB, Rolston KVet al. Outcomes of bacteremia in patients with cancer and neutropenia: observations from two decades of epidemiological and clinical trials. Clin Infect Dis 1997; 25: 247–59. 10.1086/514550 [DOI] [PubMed] [Google Scholar]
- 3. Elting LS, Lu C, Escalante CPet al. Outcomes and cost of outpatient or inpatient management of 712 patients with febrile neutropenia. J Clin Oncol 2008; 26: 606–11. 10.1200/JCO.2007.13.8222 [DOI] [PubMed] [Google Scholar]
- 4. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother 2003; 51Suppl 1: 1–11. 10.1093/jac/dkg212 [DOI] [PubMed] [Google Scholar]
- 5. Heeb S, Fletcher MP, Chhabra SRet al. Quinolones: from antibiotics to autoinducers. FEMS Microbiol Rev 2011; 35: 247–74. 10.1111/j.1574-6976.2010.00247.x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Remy JM, Tow-Keogh CA, McConnell TSet al. Activity of delafloxacin against methicillin-resistant Staphylococcus aureus: resistance selection and characterization. J Antimicrob Chemother 2012; 67: 2814–20. 10.1093/jac/dks307 [DOI] [PubMed] [Google Scholar]
- 7. Rusu A, Lungu IA, Moldovan OLet al. Structural characterization of the millennial antibacterial (fluoro)quinolones—shaping the fifth generation. Pharmaceutics 2021; 13: 1289. 10.3390/pharmaceutics13081289 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Tulkens PM, Van Bambeke F, Zinner SH. Profile of a novel anionic fluoroquinolone—delafloxacin. Clin Infect Dis 2019; 68: S213–S22. 10.1093/cid/ciy1079 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Almer LS, Hoffrage JB, Keller ELet al. In vitro and bactericidal activities of ABT-492, a novel fluoroquinolone, against gram-positive and gram-negative organisms. Antimicrob Agents Chemother 2004; 48: 2771–7. 10.1128/AAC.48.7.2771-2777.2004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Nilius AM, Shen LL, Hensey-Rudloff Det al. In vitro antibacterial potency and spectrum of ABT-492, a new fluoroquinolone. Antimicrob Agents Chemother 2003; 47: 3260–9. 10.1128/AAC.47.10.3260-3269.2003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Hook EW Jr, Golden MR, Taylor SNet al. Efficacy and safety of single-dose oral delafloxacin compared with intramuscular ceftriaxone for uncomplicated gonorrhea treatment: an open-label, noninferiority, phase 3, multicenter, randomized study. Sex Transm Dis 2019; 46: 279–86. 10.1097/OLQ.0000000000000971 [DOI] [PubMed] [Google Scholar]
- 12. Rangaraj G, Granwehr BP, Jiang Yet al. Perils of quinolone exposure in cancer patients: breakthrough bacteremia with multidrug-resistant organisms. Cancer 2010; 116: 967–73. 10.1002/cncr.24812 [DOI] [PubMed] [Google Scholar]
- 13. Freifeld AG, Bow EJ, Sepkowitz KAet al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2011; 52: e56–93. 10.1093/cid/cir073 [DOI] [PubMed] [Google Scholar]
- 14. Spanu T, Sanguinetti M, Tumbarello Met al. Evaluation of the new VITEK 2 extended-spectrum beta-lactamase (ESBL) test for rapid detection of ESBL production in Enterobacteriaceae isolates. J Clin Microbiol 2006; 44: 3257–62. 10.1128/JCM.00433-06 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Siegel JD, Rhinehart E, Jackson Met al. Management of multidrug-resistant organisms in health care settings, 2006. Am J Infect Control 2007; 35: S165–93. https://www.cdc.gov/infectioncontrol/guidelines/mdro/background.html 10.1016/j.ajic.2007.10.006 [DOI] [PubMed] [Google Scholar]
- 16. CLSI . Methods for Dilution Antimicrobial Susceptibility Tested for Bacteria That Grow Aerobically: Eleventh Edition: M07-A10. 2018. [Google Scholar]
- 17. CLSI . Performance Standards for Antimicrobial Susceptibility Testing. Thirtieth Edition. 2020. [Google Scholar]
- 18. CLSI . Methods for Determining Bactericidal Activity of Antimicrobial Agents, Approved Guideline. M26-A. 1999. [Google Scholar]
- 19. Pfaller MA, Sader HS, Rhomberg PRet al. Erratum for Pfaller, et al., “in vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe, 2014”. Antimicrob Agents Chemother 2018; 62: e02383-17. 10.1128/AAC.02383-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. McCurdy S, Lawrence L, Quintas Met al. In vitro activity of delafloxacin and microbiological response against fluoroquinolone-susceptible and nonsusceptible Staphylococcus aureus isolates from two phase 3 studies of acute bacterial skin and skin structure infections. Antimicrob Agents Chemother 2017; 61: e00772-17. 10.1128/AAC.00772-17 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Pfaller MA, Sader HS, Rhomberg PRet al. In vitro activity of delafloxacin against contemporary bacterial pathogens from the United States and Europe, 2014. Antimicrob Agents Chemother 2017; 61: e02609-16.. 10.1128/AAC.02609-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Friedman ND, Temkin E, Carmeli Y. The negative impact of antibiotic resistance. Clin Microbiol Infect 2016; 22: 416–22. 10.1016/j.cmi.2015.12.002 [DOI] [PubMed] [Google Scholar]
- 23. Dalhoff A. Global fluoroquinolone resistance epidemiology and implications for clinical use. Interdiscip Perspect Infect Dis 2012; 2012: 1–37. 10.1155/2012/976273 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Pfaller MA, Flamm RK, McCurdy SPet al. Delafloxacin in vitro broth microdilution and disk diffusion antimicrobial susceptibility testing guidelines: susceptibility breakpoint criteria and quality control ranges for an expanded-spectrum anionic fluoroquinolone. J Clin Microbiol 2018; 56: e00339-18. 10.1128/JCM.00339-18 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Gulyás D, Kocsis B, Szabó D. Plasmid copy number and qnr gene expression in selection of fluoroquinolone-resistant Escherichia coli. Acta Microbiol Immunol Hung 2019; 66: 169–78. 10.1556/030.65.2018.049 [DOI] [PubMed] [Google Scholar]
- 26. Rodríguez-Martínez JM, Machuca J, Cano MEet al. Plasmid-mediated quinolone resistance: two decades on. Drug Resist Updat 2016; 29: 13–29. 10.1016/j.drup.2016.09.001 [DOI] [PubMed] [Google Scholar]
- 27. Rolston KV, Bodey GP, Safdar A. Polymicrobial infection in patients with cancer: an underappreciated and underreported entity. Clin Infect Dis 2007; 45: 228–33. 10.1086/518873 [DOI] [PubMed] [Google Scholar]