|Year : 2017 | Volume
| Issue : 1 | Page : 59-64
High moxifloxacin cross-resistance levels among “newly identified” ofloxacin-resistant multidrug-resistant tuberculosis patients from South India: A ticking bomb or a tricky challenge?
Praveen Sanker1, Anjana Satheesan1, Anusree P Ambika1, Vishnu T Santhosh1, Ravikrishnan Balakrishnan1, Sunil Kumar Mrithunjayan2
1 Intermediate Reference Laboratory (TB), State TB Cell, Red Cross Road, Vanchiyoor, Thiruvananthapuram, Kerala, India
2 State TB Training and Demonstration Centre-Intermediate Reference Laboratory, Vanchiyoor, Thiruvananthapuram, Kerala, India
|Date of Web Publication||24-Jul-2017|
Intermediate Reference Lab (TB), State TB Cell, Red Cross Road, Vanchiyoor, Thiruvananthapuram, Kerala
Source of Support: None, Conflict of Interest: None
Background: Fluoroquinolones (FQs) are among the most important second-line anti-tuberculosis (TB) drugs, of which 8-methyl FQs; moxifloxacin (MFX) and gatifloxacin are considered to have the most mycobactericidal and “sterilizing action.” Because of the wide and often illogical usage, FQ resistance has evolved and challenged the multidrug-resistant (MDR)/extensively drug-resistant TB (XDRTB) control activities worldwide. We have compared the baseline ofloxacin (OFX) resistance among MDR/rifampicin-resistant (RR) TB cases identified from South Tamil Nadu and Kerala states in India and then assessed the cross-resistance with different concentrations of MFX using MGIT 960. Methods: Bactec MGIT 960 method and the standard protocol as per the manufacturer modified for the multiple concentrations of the drugs were used for the susceptibility testing. Results: We found that samples from newly identified MDR/RR cases of both states have baseline OFX resistance at 16–17%. MFX cross-resistance was 33%–35% (2 mg/L), 59%–70% (1 mg/L), and 87%–93% (0.5 mg/L). Conclusions: As the cross-resistances to MFX 1 mg/L (minimum inhibitory concentration between 1 and 2 mg/L) and 2 mg/L are very high, 59%–70% and 33%–35%, respectively, among newly identified OFX-resistant MDRTB cases, we assume the sterilizing activity of MFX-containing regimens may be seriously compromised leading to higher relapse rates despite having decent cure rates. This may pose considerable technical as well as cost-wise challenges for TB control program in the future.
Keywords: Cross-resistance, extensively drug-resistant tuberculosis, fluoroquinolones, MGIT 960, minimum inhibitory concentration, multidrug-resistant tuberculosis, relapses
|How to cite this article:|
Sanker P, Satheesan A, Ambika AP, Santhosh VT, Balakrishnan R, Mrithunjayan SK. High moxifloxacin cross-resistance levels among “newly identified” ofloxacin-resistant multidrug-resistant tuberculosis patients from South India: A ticking bomb or a tricky challenge?. Biomed Biotechnol Res J 2017;1:59-64
|How to cite this URL:|
Sanker P, Satheesan A, Ambika AP, Santhosh VT, Balakrishnan R, Mrithunjayan SK. High moxifloxacin cross-resistance levels among “newly identified” ofloxacin-resistant multidrug-resistant tuberculosis patients from South India: A ticking bomb or a tricky challenge?. Biomed Biotechnol Res J [serial online] 2017 [cited 2019 Jul 16];1:59-64. Available from: http://www.bmbtrj.org/text.asp?2017/1/1/59/211418
| Introduction|| |
Fluoroquinolones (FQs) are among the most important second-line anti-tuberculosis (TB) drugs which are also, unfortunately, one of the most widely used broad-spectrum antibiotics for other bacterial infections. Resistance to quinolones is associated with mutations in gyr A and gyr B genes of bacterial genome, the former being more common, which code for two pairs of subunits of the target enzyme DNA gyrase which in turn is involved in bacterial DNA replication.,,
Because of the unregulated and often irrational use, most of the Gram-negative bacteria already acquired resistance to FQs, especially in countries like India. Among FQs, ofloxacin (OFX), levofloxacin (LFX), gatifloxacin, and moxifloxacin (MFX) [Figure 1] exhibit significant antimycobacterial activity and considered as invaluable drugs in the management of multidrug-resistant TB (MDRTB);,, the type of TB where the pathogen is resistant to rifampicin (RIF) and isoniazid, which is difficult to cure by short course standard first-line drugs.
The widespread use/misuse of FQs, either for TB or for other respiratory infections, is thought to be responsible for emerging FQ resistance in MDRTB, a situation where treatment options are further limited.,, It is believed that OFX/LFX resistance among newly identified MDRTB patients (baseline FQ resistance among MDRTB) is around 30% in most parts of India., Because of the pharmacokinetic superiority, eight methoxy FQs - MFX and gatifloxacin are considered as the FQs with the most mycobactericidal and sterilizing actions and are a treatment option for MDRTB with OFX/LFX resistance as such mycobacterial population may still be susceptible, despite having some amount of cross-resistance.,,,, Consequently, the TB Control Program of India (Revised National Tuberculosis Control Program [RNTCP]) adopted a policy of advising baseline OFX/LFX and kanamycin resistance identification for all MDR/RIF-resistant (RR) TB cases. The treatments of such patients (with standard second-line drugs) are modified later, depending on the availability of susceptibility results of OFX/LFX and kanamycin according to RNTCP drug-resistant TB (DRTB) management guidelines.
We compiled the data for all newly identified MDR/RR TB cases identified/received continuously at a certified State TB Lab in South India during the study period and assessed the proportion of “baseline” OFX resistance among them. Later, we tried to identify the proportion of MFX cross-resistance at different concentrations among OFX-resistant MDR/RR TB isolates. All the laboratory tests were done in a BSL3 lab certified and Quality assured by National Institute for Research in TB, Chennai; the WHO Supranational Reference Laboratory.
| Methods|| |
All the MDR/RR TB cases identified by WHO-approved nucleic acid amplification tests; line probe assay (LPA) - Genotype MTBDR plus or GeneXpert - Xpert MTB/RIF (Xpert) from presumptive MDRTB cases at or received at our laboratory from February 01, 2014, to July 31, 2015 were selected from the records and the proportion of OFX resistance assessed. During this period, our laboratory was the only certified laboratory in Kerala (KE) state and the neighboring Southern districts of Tamil Nadu (TN) state and was receiving samples from all newly identified MDR/RR TB cases identified by the TB Control Program. The cases were grouped into two; those from KE state and those from TN state. Later, the corresponding isolates of the cases from frozen stocks were subjected to a repeat OFX (2.0 mg/L) and MFX susceptibility testing at multiple concentrations of 0.25, 0.5, 1.0, 2.0, and 4.0 mg/L using Bactec MGIT 960 (Becton Dickinson, Maryland, USA). Standard protocol as per the manufacturer, modified for the multiple concentrations were used. The drugs: OFX was sourced from Sigma-Aldrich India (www.sigmaaldrich.com/india) and MFX hydrochloride was sourced from Molekula, Gillingham, UK (www.molekula.com).
| Results|| |
Isolates from Kerala state
Three hundred and thirteen RR cases were detected by LPA during the selected period. Of that, 283 (90.4%) were culture positive and three out of them were very slow to grow and eventually lost after repeated attempts to subculture. Among 280 cases with drug susceptibility test (DSTs) results, 48 (17.1%) were resistant to OFX and an additional five cases (1.8%) resistant to both OFX and kanamycin (extensively DRTB - XDR) [Table 1].
Of the 53 cases which were OFX resistant with or without kanamycin resistance, treatment histories were available for 52 cases. Thirty-four (65.4%) of the 52 cases were either new cases with histories of anti-TB treatment (ATT) for more than 3 months or retreatment cases. The history of treatment with added quinolones was documented only by 10 (18.9%); OFX/LFX – 7 cases and MFX – 3 cases [Table 2].
|Table 2: Treatment history of ofloxacin-resistant cases among rifampicin-resistant tuberculosis|
Click here to view
Eighteen of the 52 (34.6%) were new cases on ATT for <3 months. Of these 18 cases, six were health workers and another four had documented history of contact with proven quinolone-resistant MDRTB cases.
Among the 53 OFX-resistant MDRTB cases, 33 (62.3%) were males as opposed to a total of 216 males (77.1%) among MDRs in our data. OFX resistant RR TB isolates were more from 30 to 60 years age groups among males as expected, while in females, half of the 20 cases were contributed from the 15–30 years age group. All (10/10) the patients in the 15–30 age group among females were health workers; young nurses, nursing students, and a laboratory technician; all of them working/studying in metro cities outside KE state.
Of the 40 OFX-resistant MDRTB isolates with MFX susceptibility results, 37 (92.5%) showed cross-resistance with MFX 0.5 mg/L, while 28 (70%) isolates showed resistance up to 1 mg/L. At MFX 2.0 mg/L, the breakpoint advised by WHO, 14 (35%) showed resistance and only 4 among them gave a history of prior treatment with FQ. One case showed very high MFX resistance at 4.0 mg/L.
Isolates from Tamil Nadu state
Three hundred and eighteen RR cases diagnosed by LPA or Xpert from Southern TN were received at Intermediate Reference Laboratory (IRL), Thiruvananthapuram, during the selected period. Out of that, 280 (88.1%) were culture positive, 45 (16.1%) were OFX resistant, and three XDR (1.1%) cases [Table 1].
Of the 46 OFX-resistant cases with or without kanamycin resistance with treatment histories available, all except two were new cases on ATT for more than 3 months, or on a retreatment regimen. There were four cases with a history of exposure to OFX/LFX, and one case with contact with MDRTB [Table 2].
Females contributed only 11 cases (22.9%) among the 48 OFX-resistant MDRTB compared to a total of 55 females (19.6%) among MDRs as per our data. As expected, majority of OFX resistant were from the 4th, 5th, and 6th decades of life.
MFX results were available for 39 OFX-resistant MDRTB isolates; 34 (87.2%) demonstrated cross-resistance to MFX 0.5 mg/L, while resistance up to 1 mg/L of MFX was shown by 23 (59%) isolates. Thirteen (33.3%) were resistant up to MFX 2.0 mg/L and none of them gave a history of FQ intake although one of them was an MDRTB contact. Two (5%) isolates showed very high MFX resistance at 4.0 mg/L [Figure 2].
|Figure 2: Ofloxacin - Moxifloxacin cross-resistance: South Tamil Nadu versus Kerala states. South India|
Click here to view
| Discussion|| |
Baseline OFX resistance among newly identified MDR/RR TB cases from KE state and Southern TN were strikingly similar though lower than expected as per our data; 17.1% and 16.1%, respectively. This is probably because of the early detection of MDR/RR TB and adequate treatment due to the increasing availability of quality assured susceptibility testing facilities in this part of the country and the impact of programmatic management of DRTB implemented by RNTCP, starting 6–8 years back. Studies about FQ resistance among Mycobacterium TB in India are not common and that of MFX resistance are very rare. Drug Resistance Survey conducted in Gujarat early in 2005–2006 put OFX resistance at 24% of MDRTB cases along with 3% XDRTB cases. A similar study conducted at TN state in 2011–12 also found high levels of OFX resistance (29%) and 4% XDRTB among MDRTB cases. Globally, there are a few studies reported with variation in resistance to OFX; 25% of MDRs from China, 27% of MDRs from Taiwan, 10% of MDRs from Rwanda, and 54%–58% of MDRs from Pakistan.
There is a lot of concerns about the increasing levels of FQ resistance among TB patients due to the widespread use of the drugs including MFX for TB as well as for other infections. The use of FQs as the first-line drugs along with other TB drugs,, (to shorten ATT or as a sequential addition to a failing first-line regimen) could be responsible for the majority of FQ resistance among TB patients. Compared to that, use of FQs for shorter durations like that for treating community-acquired pneumonia or other respiratory infections may not cause acquired FQ resistance among misdiagnosed TB patients, as exposure to the drug need to be sufficiently longer (months) or repeated courses of the drug needed, for a significant resistance to be established.,, The frequent association of quinolone resistance among Mycobacterium TB complex with resistance to other first-line TB drugs is often quoted as evidence for acquired quinolone resistance while on treatment for TB.,, There are also reports of RIF increasing the metabolism of MFX when used simultaneously, thus resulting in lower serum levels indicating the combination may be less ideal.
In our study, 10 out of 52 OFX-resistant cases detected from KE had a prior history of exposure to quinolones as part of TB treatment compared to 4 out of 46 from TN samples as per the given details. Understandably, it is difficult to get the history of FQ intake along with first-line drugs as FQ is often a “strap-on prescription” outside the standard prescription (and treatment records) of first-line drugs in case the patient fails to respond “adequately” in the first few months of treatment, especially in the absence of reliable facilities for MDR/RR TB identification.
OFX-resistant MDRTB was isolated more from males from both states; KE and TN (62.3% vs. 77.1%, respectively), closely following the male predominance among MDRTB isolates (77.1% and 80.4%, respectively from KE and TN) as per our data, which is in agreement with other published studies from India.,, Interestingly, KE showed an exceptionally higher number of female cases in the 15–30 age groups. All the 10 isolates in this group were from health professionals; young nurses, nursing students, and one laboratory technician, who were/used to work/study in metro cities in India. Nursing profession is quite popular among young females of KE and a good number of them are studying or working in large Indian cities outside KE state. Some of these cities have very high MDR and FQ resistance compared to KE and South TN., DRTB as an occupational risk in such a scenario is very realistic as could be imagined from our data. However, we may need further studies with more data with structured sampling to establish the magnitude of this problem. Anticipating this possible issue much earlier, RNTCP in KE had started counting all health workers having TB as presumptive MDRs eligible for MDR screening from 2014 itself.
Moxifloxacin cross-resistance among ofloxacin-resistant rifampicin-resistant tuberculosis
WHO accepted and advised the use of dual concentrations of MFX; 0.5 and 2.0 mg/L for resistance identification as cross-resistance exist between earlier generation FQs and MFX at a lower concentration of 0.25 mg/L., FQ resistance dramatically reduces the sterilizing activity of second-line regimen. The sterilizing activity of MFX-containing regimen decreases gradually against mycobacterial strains displaying low to intermediate to high level MFX resistance. As per evidence from murine models, low MFX resistance at or below 0.5 mg/L can be treated successfully with an increased MFX dose, while a moderate resistance below 2.0 mg/L may still respond as it is given along with other active second-line drugs, but with higher relapse rates.,, Very high resistance above 3 mg/L results in a situation where FQs are not likely to be of much use as the peak MFX level seen in humans is around 3 mg/L.
FQs target the bacterial enzyme, DNA gyrase coded by gyr A and gyr B genes of mycobacterial genome. Different mutations mostly in gyr A resistance determining region (RDR which codes for the drug interacting site) and less commonly in gyr B RDR are considered to be associated with different levels of FQ resistance. Mutations involving gyr A codons 90, 91, and 94 are among the most frequently encountered in clinical samples.,,,,, Despite the identification of very high-level FQ resistance associated mutations (including MFX) such as D94G, D94N of gyr A and G512R of gyr B and moderate level FQ-resistant gyr B D500N and gyr A A90V (MFX sensitive), identification of gyr A and B mutations for predicting FQ resistance may be less specific, especially in areas with a high prevalence of “Beijing” and “Indo-Oceanic” strains with a relatively increased presence of FQ-susceptible isolates with mutations compared to Euro-American strains., The possibility of other resistance mechanisms such as efflux pumps and unknown mutation sites complicate the picture further.
As per our data, 33% of the OFX-resistant MDRTB isolates from KE and 35% from TN, demonstrated cross-resistance with MFX 2 mg/L, indicating a minimum inhibitory concentration (MIC) above that level, in which case MFX is not considered as a realistic treatment option. 3%–5% of OFX-resistant isolates exhibited cross-resistance to even higher MFX concentration (4 mg/L) with probably very poor outlook. 59%–70% isolates were resistant to MFX 1 mg/L (MIC between 1.0 and 2.0 mg/L). The mycobacterial population of such patients may respond to second-line drugs with MFX, but with higher relapse rates as the sterilizing activity of MFX is likely to be compromised. These impending MDR/XDR relapses may create a far more difficult problem in the near future with more drugs possibly detecting resistant. Such patients may need very expensive and difficult salvage regimens coupled with institutionalized, contained management. This may increase the pressure on laboratories to provide quality assured extended DST services and the program needs to anticipate the need to establish inpatient facilities with impeccable infection control practices for managing such patients. Despite all these steps, the results understandably are likely to be less spectacular. The introduction of newer sterilizing drugs in OFX/LFX-resistant MDR/RR cases and introduction of MFX earlier in the course of MDR/RR treatment could be an option.
The notable strength of this study was that the susceptibility testing was done in an RNTCP certified and quality assured BSL3 lab and the study was conducted in all MDR/RR isolates from samples of program-defined, presumed RR patients continuously for 1½ years, collected programmatically/systematically from a large geographical area reflecting more of the real situations, prevailing in these areas. Major weaknesses were the limited and unverified treatment histories (and hence absence of structured sampling of patients) received along with the culture requests and the limited numbers of FQ-resistant isolates. The patients were not followed up for their treatment response or relapses as it was not possible.
| Conclusion|| |
The baseline OFX resistance of newly identified RR TB cases from South India were low (16%–17%) as per our data and the inclusion of MFX with other second-line drugs for OFX-resistant MDRTB or XDRTB may yield less than optimal results as the cross-resistance rates of MFX above the concentration of 1 mg/L among such cases are high (59%–70%), which may result in decent cure rates but with higher relapse rates. MDR/XDR relapses which may start to report in the near future may challenge the TB control program to introduce in-patient facilities with enhanced infection control provision along with salvage regimens with remaining susceptible drugs based on quality assured laboratory reports; both may push the TB control cost further up without spectacular results.
We sincerely appreciate the efforts of the staff members in IRL and the field workers in RNTCP – KE state in this study. We are also thankful to the late Dr. J Arivoli, State TB Officer, TN state and the RNTCP staff there for their kind support. We wish to thank Dr. Hisham Moosan, Government Medical College, Palakkad, for the valuable and timely help. The study was cleared by Institutional Ethics Committee of General Hospital, Thiruvananthapuram.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]