Keywords
Lepromatous Leprosy; Ofloxacin; Multi-Drug Therapy (MDT); Bacteriological Index (BI); Morphological Index (MI); Leprosy Treatment Optimization; Indonesia
Standard multi-drug therapy (MDT) with duration of 6-12 months is generally effective for treating leprosy. However, in cases of lepromatous (LL) and borderline lepromatous (BL) patients with high bacterial loads and complicated circumstances often faces non-adherence. Ofloxacin, a fluoroquinolone, has shown promising efficacy against Mycobacterium leprae in in-vitro and in-vivo studies, therefore accelerates bacterial clearance.
This single-center retrospective cohort study investigated the effects of adding ofloxacin to MDT in 21 patients diagnosed with LL or BL leprosy at Cipto Mangunkusumo National Referral Hospital, Jakarta, Indonesia. Bacterial load and viability were tracked using the Bacteriological Index (BI) and Morphological Index (MI), and were compared before and after the patients were given ofloxacin.
Adding ofloxacin to MDT led to a significant reductions in both BI and MI. The median MI dropped to zero after six months of combined treatment (p<0.001), with significant differences between baseline and 6, 9, and 12-months. BI also significantly declined (p=0.007), with significant reductions between baseline and 3, 6, 9, and 12-month assessments. The proportion of patients reaching an MI of zero also steadily increased.
Ofloxacin as an adjunctive therapy to MDT substantially improves treatment of leprosy with high bacterial and morphological index. Faster bacterial clearance prevent prolonged treatment duration, potentially improving adherence, outcomes and reducing relapse risk. Ofloxacin is the only second-line leprosy treatment covered by the national health insurance in Indonesia. Earlier initiation of this adjunctive therapy may offer greater benefits.
Lepromatous Leprosy; Ofloxacin; Multi-Drug Therapy (MDT); Bacteriological Index (BI); Morphological Index (MI); Leprosy Treatment Optimization; Indonesia
This version incorporates several revisions to improve clarity, accuracy, and alignment between sections. The Abstract has been revised to clarify the role of ofloxacin in enhancing bacteriological clearance rather than reducing treatment duration, aligning it with the findings presented in the Discussion. A sentence on statistical methods has been removed from the Abstract to maintain conciseness.
The Methods section was corrected by removing a misplaced paragraph describing ofloxacin’s adverse effects, which has now been relocated to the Introduction for appropriate context. A statement was also added in the Discussion acknowledging the lack of systematic adverse event monitoring as a study limitation.
Figure 1 has been revised to clarify the inclusion criteria and explain why patients with BT/TT leprosy were excluded, despite initially being listed in the pharmacy records. Figure 2, showing the geographical distribution of patients, has been removed due to its limited relevance to the study aims.
In the Limitations section, we added details regarding the lack of a control group, retrospective design, and missing follow-up data, emphasizing the impact these factors may have on generalizability and interpretation.
Overall, these changes aim to improve transparency and strengthen the coherence of the manuscript while preserving the original findings.
See the authors' detailed response to the review by Maria T Ochoa
See the authors' detailed response to the review by Brandon L Adler
Despite global efforts to eliminate Leprosy, Indonesia continues to be a country with a high prevalence of the disease, with 17,251 cases reported by the Indonesian Ministry of Health in 2023. The World Health Organization (WHO) recognizes Indonesia as having one of the highest leprosy burden worldwide.1 In 2024, a total of 413 leprosy cases have been registered at Dr. Cipto Mangunkusumo National Hospital.2 The more severe and contagious form of leprosy – lepromatous leprosy (LL) and borderline lepromatous leprosy (BL) – are especially concerning due to their high bacterial loads and may lead to significant morbidity if not properly treated.3 Since 1981, multi-drug therapy (MDT) combining rifampicin, dapsone, and clofazimine by the World Health Organization (WHO) has been used as the standard treatment for leprosy.4
While MDT is effective, its use alone can lead to prolonged treatment durations, particularly in patients with high bacterial loads, which may contribute to poor adherence. Adding medication to the current regimen could be considered to improve patient’s adherence.5 Recently, more studies have analyzed the potential of additional antibacterial agents in enhancing the efficacy of MDT for leprosy cases. Ofloxacin, a fluoroquinolone with strong activity against M. leprae, has shown promise when added to standard MDT. One study highlighted the potential benefits of using ofloxacin in leprosy treatment, noting that it is well tolerated and achieves similar bacterial clearance, even when ofloxacin is only administered during the first month.6 A retrospective study further demonstrated that patients receiving MDT combined with ofloxacin showed good adherence, as no adherence failures was identified among subjects receiving ofloxacin. Additionally, the combination therapy was associated with a lower relapse rate and improved long-term outcomes, supporting its use as a promising option for treating severe leprosy cases.5
The evaluation of leprosy treatment is typically followed up using two key bacteriological indices: the Bacterial Index (BI), which measures the overall bacterial load in skin smears, and the Morphological Index (MI), which assesses the proportion of viable (solid) bacilli, which depicts treatment efficacy. A significant reduction in both indices over time reflects successful bacterial clearance and a reduced risk of disease transmission and relapse.7
Certainly, there are specific considerations that should be given while adding ofloxacin to standard MDT treatment, such as: initial high viable infection load that is indicated by a high MI from acid-fast staining of slit-skin smears, persistently positive MI after at least six months therapy of standard MDT,8 or relapse, diagnosed based on criteria by Linder et al.9
The most common adverse effect of ofloxacin is tendinopathy, and there may be hypersensitivity reactions, central nervous system adverse drug reactions, peripheral neuropathy, though uncommon.10
With above mentioned findings, this study aims to analyse the efficacy of MDT combined with ofloxacin in patients with lepromatous form of leprosy (BL and LL). By assessing the reduction in BI and MI during the course of treatment regimens, the study seeks to determine whether adding ofloxacin enhances MDT’s bacteriological outcomes, leading to faster bacterial clearance and improved patient outcomes. This is particularly important for patients with lepromatous form of leprosy, where the bacterial load is high and conventional MDT may take longer time than standard duration of multibacillary (MB) therapy to achieve bacteriological cure.
Between 2020 and 2024, all medical records of eligible patients with lepromatous form leprosy treated at the Dermatology and Venereology Clinic, Dr. Cipto Mangunkusumo National Hospital, Jakarta, Indonesia, were examined in this retrospective cohort study.
The cohort study evaluated treatment outcomes by comparing BI & MI parameters in the same patients before and after the initiation of ofloxacin 400 mg once daily as an adjunct therapy. Each patients were given 400 mg once daily as an adjunct therapy.
Patients were included if they (1) were diagnosed with leprosy according to WHO criteria; (2) classified as borderline lepromatous (BL) leprosy or lepromatous form of leprosy (LL) based on Ridley-Jopling criteria10; (3) were adults aged ≥18 years at the start of leprosy treatment; and (4) received ofloxacin in addition to the standard multidrug therapy (MDT) regimen under these circumstances: (a) a high initial viable infection load, evidenced by a high MI from acid-fast staining of slit-skin smears; (b) persistently positive MI, typically after ≥6 months of standard MDT; (c) re-positivity of MI; and (d) relapse, diagnosed based on criteria by Linder et al.8,9 To prevent selection biases, patients were excluded if they (1) had missing initial AFB examination data or (2) did not return for follow-up acid-fast bacilli (AFB) examination at least once after three months of additional ofloxacin ( Figure 1).
Patient data were extracted from electronic patients records by authors on October 2024. Patient information related to demographic, clinical presentation, disability status based on WHO disability grading (grade 0 for no disability, grade 1 for loss of sensation but no visible deformity or damage, and grade 2 for visible deformity of damage present), treatment course, microbiology investigations particularly the results from slit-skin smear examination, and also treatment outcome were gathered.
At our center, slit-skin smear examinations are routinely performed from six sites (both earlobes and four lesions) every three months in patients with positive initial MI or in cases requiring close monitoring. Smears are processed using Ziehl-Neelsen staining and evaluated for bacterial and morphological indices by a trained technician, under the supervision of a clinical microbiologist. The BI represents the total number of bacilli, measured semi-quantitatively using the Ridley-Jopling logarithmic scale, while the morphological index is the percentage of solid-staining bacilli.
After commencing ofloxacin therapy, patients underwent follow up to do acid-fast bacilli (AFB) examination at least once after three months of addition of adjunct therapy. At each visit, dermatology resident performed clinical examination, including assessment for new lesions, nerve involvement and other clinical findings. Slit-skin smears were collected from standard sites to determine the BI and MI according to established procedures.
The primary outcomes of this study are (1) change in Bacteriological Index (BI) as this measures the bacterial load in skin smears, and (2) change in Morphological Index (MI) for assesses the proportion of viable bacteria in the smears. The secondary outcome of this study is a proportion of patients achieving an MI of zero.
Statistical analyses were conducted using SPSS Statistics 26 (IBM Corp, Armonk, NY, USA). and visualized using GraphPad Prism 9.0 (GraphPad Software, Inc., San Diego, CA, USA). Spatial data was visualized using Google My Maps (Google LLC, Mountain View, CA, USA).
Subject characteristics were presented as frequency and percentage for categorical data, while numerical data were reported as mean and standard deviation. The non-parametric Friedman test was performed to compare MI and BI across AFB measurements, with post-hoc Dunn’s test applied to identify significant differences between time points and baseline value. BI across AFB measurements, with post-hoc Dunn’s test applied to identify significant differences between time points and baseline value.
Twenty-one patients met the eligibility criteria and were included in the analysis ( Table 1). The majority of the subjects were male (66.7%) and unemployed (42.9%). All patients resided in the Jakarta metropolitan area, with most domiciled in Jakarta province (57.2%) and the remainder in surrounding regions (Tangerang, Bogor, Depok, and Bekasi). According to the Ridley-Jopling classification, most patients (71.4%) had polar lepromatous (LL) leprosy, while the remaining patients had borderline lepromatous (BL) disease. Notably, one LL patient was diagnosed with histoid leprosy, and another had Lucio’s leprosy. In terms of disability, 11 patients (52.4%) had no disability, 3 patients (14.3%) had grade 1 disability, and 7 patients (33.3%) had grade 2 disability. Additionally, 6 patients (28.6%) had no history of reaction, while 14 patients (66.7%) experienced a type 2 reaction, 1 patient (4.8%) had a type 1 reaction, and 1 patient (4.8%) had Lucio’s phenomenon. Patients received WHO-MDT for a duration of 9 months (median; range 1–31 months) before starting combined therapy with ofloxacin.
A significant reduction in the morphological index (MI) was observed after the addition of ofloxacin to the standard MDT regimen ( Figure 2, left). The median MI decreased to 0 after six months of ofloxacin treatment. Significant differences were noted across visits (p < 0.001), with post-hoc comparisons showing significant differences between baseline and six months (p = 0.003), nine months (p = 0.014), and 12 months (p = 0.008), but not at three months (p = 0.060).
A consistent and significant reduction in the bacterial index (BI) was also observed following the addition of ofloxacin ( Figure 2, right). Significant differences were noted across visits (p = 0.007), with pairwise comparisons showing significant reductions in BI between baseline and three months (p = 0.039), six months (p = 0.003), nine months (p = 0.006), and 12 months (p = 0.004).
There was a consistent increase in the proportion of patients achieving an MI to 0 following the addition of ofloxacin, demonstrating the treatment’s effectiveness in reducing viable bacterial load over time ( Figure 3).
This study demonstrated a significant reduction in the morphological index (MI) following the addition of ofloxacin to the standard MDT regimen, and the median MI also decreased to 0 after six months of ofloxacin treatment. This finding aligns with the known bactericidal effects of ofloxacin, a floroquinolone antibiotic that directly kills the bacteria responsible for leprosy rather than merely inhibiting its growth.11 This characteristic accelerates bacterial clearance and contributes to faster clinical improvement and reduces transmission.
Ofloxacin has proven effective in both paucibacillary (PB) and multibacillary (MB) leprosy, especially when combined with potent bactericidal agents like rifampicin and minocycline.12 Though the treatment duration remains similar to standard MDT, ofloxacin-added regimens may offer enhanced efficacy, particularly in lepromatous cases.13
The cure rate in this study showed a consistent increase in patients achieving an MI of 0, demonstrating the effectiveness of ofloxacin in reducing viable bacterial load. This result is similar to other study evaluating OMDT in non-endemic area that showed a high cure rate and tolerability.5 Additionally, studies combining ofloxacin with rifampicin and minocycline reported 2-year cure ranging from 93.1% to 99%.14,15 A long-term follow-up trial also recorded relapse in only 1 of 58 patients over an average of 10.8 years.16
Another advantage of ofloxacin is its rapid action compared to some other drugs traditionally used in leprosy treatment. Studies have shown that it can quickly reduce the BI, which can be crucial in treating severe or resistant cases of leprosy.17 Our study observed significant MI reduction following its addition, with the median MI reaching 0 after six months. Statistical analysis confirmed significant differences across visits (p < 0.001), with post-hoc comparisons showing significant differences between baseline and six months (p = 0.003), nine months (p = 0.014), and 12 months (p = 0.008). Previous studies support this, showing daily ofloxacin in lepromatous patients were experiencing rapid MI decline and >99.99% bacterial killing by day 28.18 Another study found no resumption of bacterial growth even 18 months post-treatment.19 Compared to WHO MDT, MI reduction was more significant with ROM (rifampicin, ofloxacin and minocycline) regimen: 79.97% of WHO MDT and 94.83% of ROM.20 In addition to MI, our study also found significant reductions in the bacterial index (BI) across visits (p = 0.007), with pairwise differences noted at three (p = 0.039), six (p = 0.003), nine (p = 0.006), and 12 months (p = 0.004). These findings emphasize the importance of early ofloxacin addition in cases with high bacterial loads, enhancing bacterial clearance and reducing relapse risk.7
Early use of ofloxacin, especially under the right clinical criteria, may shorten treatment, boost adherence, and reduce discontinuation. In our cohort, WHO MDT had been administered for a median of nine months (range 1–31) before ofloxacin was introduced. However, waiting this long may not be necessary—patients with high MI and BI may benefit from earlier ofloxacin initiation.
Ofloxacin also contributes to resistance prevention when combined with other antibiotics such as rifampicin, clofazimine, and dapsone, as it offers broader coverage and improves outcomes while reducing resistance risk.21 Notably, studies have shown that ROM regimens are better tolerated than MDT-WHO, improving adherence.20
Its utility is especially crucial in MB leprosy with higher MI and bacterial load.22 Ofloxacin and minocycline have shown stronger bactericidal effects than dapsone and clofazimine in both animal models and clinical trial.23 This is vital in special cases like dapsone hypersensitivity syndrome (DHS).24 Effective bacterial clearance in such cases is crucial, given that high BI is a known risk factor for grade 2 disability.25
Finally, in cases of drug-resistant leprosy, ofloxacin has been used as an alternative when standard drugs fail.5 As leprosy cases become increasingly concentrated in specific regions, newer antibiotics like ofloxacin will play an increasing role in global leprosy control, preventing complications and disabilities.20
This is the first Indonesian study evaluating ofloxacin’s addition to WHO MDT in lepromatous leprosy. Its use is recommended in cases with: (1) a high initial MI; (2) persistently positive MI, typically after ≥6 months of MDT; (3) re-positivity of MI; and (4) relapse, diagnosed based on criteria by Linder et al.8 In Indonesia, ofloxacin is the only second-line drug for leprosy covered by the national health insurance, limited to referral hospital and for one week’s use. Patient must either self-fund or return weekly to continue therapy, highlighting the need for improved access and policy reform, especially for those in rural areas.
We acknowledge that this study has limitations. Firstly, being a being a retrospective study, it inherently carries the potential for biases that are simply part of this design. This also meant that some aspects, such as comprehensive patient follow-up data and a systematic evaluation of drug tolerance and adverse reactions, were challenging to capture adequately from existing records. Secondly, the absence of a concurrent control group receiving standard multi-drug therapy (MDT) without ofloxacin restricts direct comparative analysis of bacteriological and morphological indices. This design choice was influenced by ethical considerations at our national referral center, which primarily manages challenging cases. Thirdly, as a single-center study, the generalizability of our findings may be limited to other populations or healthcare settings. Despite these limitations, we believe that our findings could be a preliminary data for the future randomized control trial study with larger sample size to evaluate the efficacy of ofloxacin in lepromatous form of leprosy thoroughly.
The addition of ofloxacin to the standard WHO MDT regimen in lepromatous leprosy resulted in a significant and consistent reduction in the morphological index (MI) and bacterial index (BI), with the median MI reaching 0 after six months of treatment. These findings support the potent bactericidal activity of ofloxacin and its potential to accelerate bacterial clearance, enhance clinical outcomes, and reduce transmission and relapse risk.
The study protocol was reviewed and approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo Hospital (Komite Etik Penelitian Kesehatan Fakultas Kedokteran Universitas Indonesia – RSUPN Dr. Cipto Mangunkusumo).
The approval date was December 8, 2024, valid for one year from the date of approval. The protocol number assigned to this study is KET-1769/UN2.F1/ETIK/PPM.00.02/2024. As this research involved retrospective secondary data extracted from medical records, no direct patient contact was required. Consequently, the need for individual informed consent specific to this study was waived by the Ethics Committee. However, all patients at Dr. Cipto Mangunkusumo Hospital provide general consent for treatment and the use of their data for research purposes upon admission, with strict adherence to anonymity, and in accordance with all relevant regulations and ethical standards.
MHP: Conceptualisation, data curation, methodology, statistical analysis, visualisation, writing (original draft and revisions)
MSY: Data curation, methodology, statistical analysis, visualisation, writing (original draft and revisions)
SLM: Conceptualisation, data curation, methodology, writing (original draft and revisions)
EJN: Conceptualisation, data curation, methodology, writing (original draft and revisions)
MM: Conceptualisation, data curation, methodology, writing (original draft and revisions)
Figshare: Dataset OMDT.xlsx. https://doi.org/10.6084/m9.figshare.28331675.v1.26
The project contains the following underlying data:
Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).
To facilitate accessibility for future studies, we note the following open-source alternatives, such as JASP (JASP Team, Amsterdam, Netherlands) for statistical analyses and ggplot2 3.5.1 (Hadley Wickham, Auckland, New Zealand) or SciDAVis (SciDAVis Development Team) for data visualization.
Views | Downloads | |
---|---|---|
F1000Research | - | - |
PubMed Central
Data from PMC are received and updated monthly.
|
- | - |
Is the work clearly and accurately presented and does it cite the current literature?
Yes
Is the study design appropriate and is the work technically sound?
Yes
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Yes
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: The use of standard leprosy drugs in some cases is often resistant, characterized by unchanged bacterial index and morphology index values or only a slight decrease. This results in longer MDT drug use and reduced patient compliance with medication. With preliminary research on the use of ofloxacin, it can be used as a guideline for further research in the future.
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
No
Are sufficient details of methods and analysis provided to allow replication by others?
Yes
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
No
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: leprosy
Is the work clearly and accurately presented and does it cite the current literature?
Partly
Is the study design appropriate and is the work technically sound?
No
Are sufficient details of methods and analysis provided to allow replication by others?
No
If applicable, is the statistical analysis and its interpretation appropriate?
Yes
Are all the source data underlying the results available to ensure full reproducibility?
Yes
Are the conclusions drawn adequately supported by the results?
Partly
Competing Interests: No competing interests were disclosed.
Reviewer Expertise: leprosy
Alongside their report, reviewers assign a status to the article:
Invited Reviewers | |||
---|---|---|---|
1 | 2 | 3 | |
Version 3 (revision) 06 Aug 25 |
read | ||
Version 2 (revision) 28 Apr 25 |
read | ||
Version 1 03 Mar 25 |
read |
Provide sufficient details of any financial or non-financial competing interests to enable users to assess whether your comments might lead a reasonable person to question your impartiality. Consider the following examples, but note that this is not an exhaustive list:
Sign up for content alerts and receive a weekly or monthly email with all newly published articles
Already registered? Sign in
The email address should be the one you originally registered with F1000.
You registered with F1000 via Google, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Google account password, please click here.
You registered with F1000 via Facebook, so we cannot reset your password.
To sign in, please click here.
If you still need help with your Facebook account password, please click here.
If your email address is registered with us, we will email you instructions to reset your password.
If you think you should have received this email but it has not arrived, please check your spam filters and/or contact for further assistance.
Comments on this article Comments (0)