Associate Professor Pinyo Rattanaumpawan, MD, MSCE, PhD
Associate Professor of Medicine
Division of Infectious Diseases and Tropical Medicine, Department of Medicine
Faculty of Medicine Siriraj Hospital, Mahidol University
Bangkok, Thailand

The overuse and misuse of antimicrobials has contributed to the rapid emergence of antimicrobial resistance (AMR). There are no new antimicrobial agents in the market. Data show that new-generation fluoroquinolones (FQs) such as sitafloxacin are active against many antimicrobial-resistant pathogens such as the extended-spectrum beta-lactamase (ESBL)-producing pathogen, Acinetobacter baumannii. Sitafloxacin has been approved for oral treatment of urinary tract infections (UTIs) and lower respiratory tract infections (LRTIs) in Thailand since 2011.¹

Associate Professor Pinyo Rattanaumpawan shares insights into the role of FQs in the treatment of infections caused by antimicrobial-resistant pathogens.

Q1. What is the prevalence of AMR in Thailand? What are the key factors for the emergence of AMR?

Based on data from the National Antimicrobial Resistance Surveillance Center, Thailand (NARST) 2020, the prevalence of penicillin-resistant Streptococcus pneumoniae (PRSP) and methicillin-resistant Staphylococcus aureus (MRSA) locally were approximately 30% and 7%, respectively.² The problem of AMR is more intensified among Gram-negative bacteria. The prevalence of FQ resistance was approximately 50% among Escherichia coli, 30% among Klebsiella pneumoniae, 67% among Acinetobacter spp., and 15.2% among Pseudomonas aeruginosa isolates. Approximately half of both E. coli and K. pneumoniae isolates were ESBL-producing strains (identified by the cefotaxime disc screening test). Carbapenem-resistance was documented in 3% of E. coli, 12% of K. pneumoniae, 70% of Acinetobacter spp., and 20% of P. aeruginosa isolates.²

In a recent study of 1,288 clinical isolates from two tertiary care hospitals in Thailand, the sitafloxacin susceptibility rate was 72.69% for all E. coli (n = 216) (68.26% for E. coli with ESBL and 86.96% for E. coli without ESBL), 39.31% for all K. pneumoniae (n = 173) (50% for K. pneumoniae with ESBL, 61.11% for K. pneumoniae without ESBL) and 13.11% for the carbapenem-resistant Enterobacteriaceae (CRE) strains of K. pneumoniae, 60.66% for P. aeruginosa (n = 366), 66.32% for A. baumannii (n = 386), and 93.94% for S. maltophilia (n = 33).³

AMR is driven by multiple factors including inappropriate antimicrobial therapy, inadequate laboratory and microbiology surveillance systems, insufficient infection control, poor sanitation, and antimicrobial use in agriculture and farming. In my opinion, the major driving factor is inappropriate antimicrobial therapy. In Thailand, many antimicrobial agents can be freely purchased at the drugstore without a doctor’s prescription.

Q2. How has the emergence of AMR changed the way clinicians approach the treatment of infections caused by antimicrobial-resistant pathogens?

Because of the high prevalence of AMR in Thailand, clinicians tend to prescribe broad-spectrum antimicrobial agents as empirical therapy. Some physicians may adopt the de-escalation strategy after obtaining the susceptibility results of the causative pathogen. However, some may not modify the treatment regimen based on the susceptibility results; this practice will ultimately result in the emergence of AMR.

For example, ciprofloxacin was previously considered the treatment of choice for acute pyelonephritis in Thailand. Due to the increasing trend of FQ resistance among uropathogens (especially E. coli), ciprofloxacin is now no longer recommended as an empirical option for treatment of acute pyelonephritis. Physicians tend to prescribe a broad spectrum antibiotic such as ceftriaxone or ertapenem. However, ciprofloxacin is still being used for intravenous-to-oral (IV-to-PO) switching if the causative pathogen is later known to be a FQ-susceptible strain.

Q3. Do you have any criteria to prescribe fluroquinolones for infection compared with the other antimicrobials?

Yes. Several points should be considered before prescribing FQ antibiotics:

• Antimicrobial susceptibility

Due to the increasing trend of FQ resistance among uropathogens, I rarely prescribe FQ antibiotics as an empirical therapy for UTIs. I prefer to use FQ antibiotics as IV-to-PO switching therapy instead (after knowing susceptibility results). However, the prevalence of FQ-resistant S. pneumoniae in Thailand is not high. Therefore, I am still confident about prescribing respiratory FQ antibiotics as empirical therapy for community-acquired pneumonia.

• Tissue penetration

FQ antibiotics are well known in terms of good penetration into bone and joint tissues, reaching concentrations exceeding the minimum inhibitory concentration (MIC) and/or MIC90 breakpoints of common bone and joint infection pathogens.⁴ Therefore, I prefer to choose FQ antibiotics over other antibiotic groups for treatment of bone and joint infections (if the drug is active against the causative pathogen).

• Contraindications

FQ antibiotics should be avoided in young children and pregnant women.

Q4. What is the role of FQs (e.g., sitafloxacin) in the treatment of infections caused by antimicrobial-resistant pathogens? What are the benefits/advantages?

In my opinion, new FQ antibiotics (especially sitafloxacin) play two major roles in treatment of multidrug-resistant (MDR) pathogens:

• Use as IV-to-PO switching

After obtaining the susceptibility results, the broad-spectrum antibiotic may be switched to oral FQs (if susceptible). Given that approximately two-thirds of ESBL+ E. coli and 50% of ESBL+ K. pneumoniae in Thailand may be susceptible to sitafloxacin, the drug may be used as a switch therapy for treatment of UTIs caused by ESBL+ pathogens. Additionally, treatment of non-bacteraemic acute pyelonephritis caused by ESBL-E.coli with carbapenem followed by oral sitafloxacin was found to be effective and well tolerated in a small randomised controlled trial conducted in Thailand (n = 37).⁵

• Use as combination therapy

In my opinion, A. baumannii is the most problematic MDR pathogen. Based on the 2020 NARST data, approximately 70% of A. baumannii isolates were carbapenem resistant (CR-AB).² Colistin and aminoglycoside seem to be the most active agents against CR-AB that are available in the Thai market.

A recent study conducted in Thailand reported that approximately 60% of A. baumannii were susceptible to sitafloxacin.⁴ Although the number is not high, the colistin-sitafloxacin combination has been shown to exhibit synergy in MDR-AB, CR-AB and colistin-resistant-AB isolates in a recent study using the broth micro-dilution checkerboard and time-kill methods.⁶ Therefore, I frequently prescribe a combination of colistin plus sitafloxacin to treat patients with serious infections caused by CR-AB.

Q5. What are the considerations and precautions when prescribing sitafloxacin?

• When administered orally, all FQ antibiotics, not only sitafloxacin, require appropriate administration to ensure adequate absorption. Concurrent administration of antacids (aluminium hydroxide or magnesium hydroxide), calcium supplement or iron supplement leads to reduced absorption.⁷ Furthermore, patients with unstable vital signs or gastrointestinal bleeding may have poor gastrointestinal absorption and should not be treated with oral antibiotics.
• Always check for drug-drug interactions. Using FQs together with warfarin may result in prolonged international normalised ratio (INR) and bleeding tendency. Using FQs together with macrolides may cause QT prolongation.⁸
• When using sitafloxacin for the treatment of MDR pathogens, a higher dose (i.e. 100 mg twice a day) may be needed.⁵

References

1. Paiboonvong T, Rodjun V, Houngsaitong J, et al. Pharm Sci Asia. 2020;47:37-52. doi:10.29090/psa.2020.01.019.0012.
2. National Antimicrobial Resistance Surveillance Center, Thailand. http://narst.dmsc.moph.go.th/data/AMR%202000-2020-12M.pdf. Accessed 28 Aug 2021.
3. Tantisiriwat W, Linasmita P. J Med Assoc Thai. 2017;100(4):469-78.
4. Thabit AK, Fatani DF, Bamakhrama MS, et al. Int J Infect Dis. 2019;81:128-136. doi: 10.1016/j.ijid.2019.02.005.
5. Malaisri C, Phuphuakrat A, Wibulpolprasert A, et al. J Infect Chemother. 2017;23(8):556-562. doi: 10.1016/j.jiac.2017.05.005.
6. Rodjun V, Houngsaitong J, Montakantikul P, et al. Antibiotics (Basel). 2020;9(8):516. doi: 10.3390/antibiotics9080516.
7. Pitman SK, Hoang UTP, Wi CH, et al. Antibiotics (Basel). 2019;8(3):108. doi: 10.3390/antibiotics8030108.
8. Mehlhorn AJ, Brown DA. Ann Pharmacother. 2007;41(11):1859-66. doi: 10.1345/aph.1K347.