Should we stop using fluoroquinolone in non-tuberculosis patients? A study to assess the drug resistance profile of rifampicin-resistant pulmonary tuberculosis

INTRODUCTION

Multidrug-resistant tuberculosis (MDR-TB) accounted for about half a million of the 9.9 million new TB cases that were anticipated to occur globally in 2020.¹ Drug-resistant TB (DR-TB) urgency has been threatening international public health efforts for TB elimination.² In 2017, anti-tubercular drug resistance surveillance data demonstrated that 3.5% of new & 18% of previously treated TB cases globally were assessed as having multidrug-resistant or rifampicin-resistant TB (MDR/RR-TB). In 2017, about 230,000 people died from MDR/RR-TB, while an estimated 558,000 new cases of the disease were reported globally. China, as well as India, accounted for the majority of cases & deaths. MDR-TB cases had (8.5%) extensively drug-resistant TB (XDR-TB). This emphasizes the urgency of effective treatment strategies & interventions. Only 34% of XDR-TB patients responded successfully to treatment.³

Fluoroquinones (FQs) have been demonstrated to be successful in treating TB since 1984.⁴ FQs are broad-spectrum antibiotics, used particularly for cases that are resistant to drug-sensitive TB treatment. Resistance to FQs in Mycobacterium tuberculosis (MTB) is primarily associated with mutations in DNA gyrase, a tetramer composed of two A & two B subunits encoded by gyrA & gyrB genes, respectively.⁵ Emergence of fluoroquinolone resistance is considered a major issue for TB elimination.

FQs resistant data are limited among nations with a significant TB burden. Although most available data on FQs resistance to DR-TB have emerged from India, China, and Pakistan.⁶ There is scepticism regarding the role of FQs in managing infections other than TB, especially urinary tract infections & community-acquired pneumonia, which may be a contributing factor in this resistance.⁶ According to a recent meta-analysis evaluating the relationship between use of FQs prior to diagnoses and the development of FQ-resistance in tubercular patients revealed a threefold higher risk of developing FQs-resistant MTB.⁷ Multiple FQ prescriptions or prolonged FQ exposure, over ten days of treatment, are substantial risk for resistance development.⁸

Due to genetic diversity, different drug-resistance mutations may be present in different geographical regions in patients with TB. Therefore, epidemiological research benefits from assessing drug resistance based on MTB gene mutations and strain diversity common in a given geographic location. In India, numerous studies have been conducted to assess the genetic variability and pattern of drug resistance among MTB isolates from pulmonary TB patients.^9–12 However, additional information on TB research ought to be accessible. Our objective for this research is to determine drug resistance patterns along with molecular characteristics of MTB that are prevalent among pulmonary TB patients in our surrounding area. The institutional ethics committee granted its approval for this initiative.

MATERIAL AND METHODS

The retrospective observational research was conducted at our tertiary care with large number of referral patients in Northern India, having a Nodal DR-TB centre. All newly diagnosed RR-TB patients of pulmonary TB were admitted to our Nodal DR-TB center for various indications in the investigation period January 2021 to December 2023, recruited in this research. RR-TB patients with extrapulmonary TB were excluded from the research. Molecular drug sensitivity testing (DST) data (Cartridge-based nucleic acid amplification test and line probe assay [LPA]) of RR-TB patients were taken from pre-existing patient records and analyzed. Data of additional drug resistance determined by first- and second-line LPA for individual RR-TB patients was further analyzed to determine the proportion of patients having additional resistance to isoniazid (INH), FQs (Either moxifloxacin or levofloxacin or both), second-line injectables (SLIs) (Kanamycin, capreomycin or amikacin), and their different combinations.

All the above molecular tests were done on morning sputum samples of good quality, which was assured by applying bacterial selection criteria. This was done by examination of the sputum specimen to confirm a sufficient bacterial load in the sputum (microscopy grade 1 on at least one direct smear). A concentration test using smear microscopy was performed on each sample. Fluorescence staining was used for smear microscopy on these samples. Smear-positive samples were treated employing N-acetyl-L-cysteine sodium hydroxide decontamination technique.

Data Analysis: Sociodemographic information, clinical data, and laboratory results are entered into the Excel sheet. Mean, number, standard deviation, & percentage have been employed to represent the data.

RESULTS

Out of a total of 607 RR-TB patients of pulmonary TB, 349 (57.49%) were male & 258 (42.51%) were female, with a male-to-female ratio of 1.35. The mean age of all participants was 30.53±14.03 years, with the majority of patients in the age group of 15–39 years [Table 1].

Among 607 patients of rifampicin resistant pulmonary tuberculosis (RR-TB), a percentage of additional resistance was reported based on LPA. First-line (FL) LPA revealed INH resistance in 477 patients (78.5%), and second-line LPA revealed FQ resistance in 352 patients (57.9%). On further evaluation of data to determine the different combinations of anti-tubercular drug resistance, we found that rifampicin-INH resistance was present in 158 (26%), rifampicin-INH-FQs resistance in 240 (39.5%), rifampicin-INH-FQs-SLI resistance in 89 (13%), and rifampicin-FQs resistance in 33 (5.4%) patients [Figure 1].

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Figure 1:

Additional drug-resistant pattern in RR-TB. RR-TB: Rifampicin resistant pulmonary tuberculosis, FL-LPA: First line - Line probe assay, SL-LPA: Second line - Line probe assay, INH: Isoniazid, FQ: Fluoroquinolone, SLI: Second line injectable.

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FL LPAs allowed swift drug resistance testing for rifampicin & INH in sputum samples containing MTB. Table 2, showing FL-LPA results, clearly states that 130 (21.5%) patients did not have additional INH resistance.

In our results of second-line (SL) LPA, the percentages of FQs- Not Resistant, FQ-resistant, SLI- Not Resistant, SLI-resistant, FQs-SLI -Resistant, FQ-resistant and SLI- Not Resistant, FQ- Not Resistant and SLI-resistant, were 42.1%, 57.9%, 85.7%, 14.3%, 13%, 44.9%, and 1.3%, respectively [Table 3, Figure 2].

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Figure 2:

Proportion of different combinations of anti-TB drug resistance

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DISCUSSION

Efforts to eradicate drug-resistant TB remain a global health issue. Fast & precise detection of disease, effective patient care, reduces the spread of disease, & halts drug-resistant strains of TB. National TB control & elimination programs, along with management of individual patients for MDR/RR-TB, are greatly hampered by new drug resistance emergence. FQs resistance to TB emerged as a result of widespread FQs administration for various infections, including genitourinary, skin, ocular infections, respiratory & gastrointestinal.¹³ This clinical scenario is concerning, as FQs resistance is identified as a significant risk factor for bacteriologically unfavorable outcomes for DR-TB treatment.

The research indicated that individuals aged 15–39 years comprised the predominant group of patients with pulmonary drug-resistant TB (72.14%), followed by those aged 40–59 years (18.79%). The entire study population's mean age was 30.53±14.03 years, highlighting the fact that the economically productive age group of our population is most affected. A similar study by Tripathy et al. (2015) reported that about 71% of MDR-TB cases involved young patients aged 16–30 years.¹⁴ The study by Dholakia et al. (2013) in Mumbai found that 67% of MDR-TB cases occurred in young patients (15–35 years).¹⁵

The present study investigated LPAs for drug susceptibility testing to detect resistance to INH, Rifampicin, FQs, and SLI drugs. As already stated, the proportion of FQs-sensitive, FQs-resistant, SLI-sensitive & SLI-resistant, detected by second line LPA was 42.1%, 57.9%, 85.7%, and 14.3%, respectively. These findings demonstrated that approximately 57.9% of MDR-TB patients were resistant to FQs, much higher than the global average level of 18%.¹⁶ FQ-resistance prevalence among MDR-TB patients varies significantly across different geographical regions. The range is from 9% in Australia to 56% in India.¹⁷ It may also reflect the extent of restrictions on the sale and ease of availability of fluoroquinolones in different countries.

The study by Dreyer et al. (2022) in Mumbai (India) reported around 36% of MDR TB strains had FQs resistance, again reflecting a high proportion of XDR-TB & pre-XDR.⁹ The study by Singh PK et al.¹⁰ (2015) in Lucknow (India) determines the proportion of strains resistant to only FQs 50.1%, to SLI-drugs at 1.5%, and to FQs plus SLI drugs was 8.3%. This high proportion of FQ resistance (with or without SLI resistance) rendered about 58.4% of patients not eligible for the shorter regimen of DR-TB and increased the burden of providing a longer regimen for DR-TB, but without FQs, which is a very important Group A anti-TB drug for DR-TB. All these issues add to difficulties in treating TB in our country.

FQ resistance was demonstrated to be less prevalent in MDR-TB patients in older Indian research. Selvakumar et al.¹³ (2015) from Tamil Nadu & Jain et al.¹¹ (2012) from Lucknow, North India, reported that FQ resistance within MDR-TB patients have been 29 & 26%, respectively. In Gujarat, research by Ramachandran et al.¹² (2009) determined that FQ resistance was 24%. The results of this research explain an elevated incidence of FQ resistance.

FQ resistance has a high prevalence in RR-TB & its significant correlation with adverse treatment outcomes presents a concerning scenario for our region. This issue has been discussed under programmatic management of drug-resistance tuberculosis through the implementation of universal DST for the prompt identification of resistance to FQs & SLI drugs. However, the challenge of FQs-resistant RR-TB cases remains significant due to the inclusion of this important Group A drug class in all recommended regimens for DR-TB.

CONCLUSION

A high proportion of FQ resistance in RR-TB cases in our geographical area raises a grave issue of unrestricted use of these drugs for non-tubercular indications, which in turn may adversely impact the national efforts of TB elimination. Hence, it can be concluded that the use of FQs should always be judicious, particularly for non-tubercular indications.