All oral treatment regimes of drug-resistant TB have now become established TB pharmacotherapy, in line with WHO call for accelerated uptake of these all oral regimes [15]. Employing WHO data (https://www.who.int/teams/global-tuberculosis-programme/data), Fig. 4 shows the number of MDR-TB patients commenced on antibiotic treatment during the period 2010–2022. In a recent update, Gupta and colleagues showed that there has been consistent global growth in the use of shorter regimens in DR-TB treatment, with BPaLM reaching 126,792 patients, BPaL reaching 43,716 patients and the 9–11-month all-oral bedaquiline-based regimen reaching 13,119 patients by 2026 [16]. By 2026, it has been estimated that the longer all-oral regimen is projected to be used by 19,262 patients, and individualised treatment regimens by 15,344 patients [16].

Correlation between notified MDR/RR-TB cases and patients started on MDR-TB treatment for the period 2010 and 2022.

This shift in antibiotic formulations from iv to orals has been largely driven by the discovery of newer effective oral antibiotics that have been shown to be safer the iv antibiotics [17, 18]. The lengthy duration of treating drug-resistant TB with ivs increases the toxicological burden associated with this administrative route, as examplified by iv kanamycin and capreomycin [19, 20]. Additionally, clinical trial data using all oral treatment combinations have yielded positive outcomes [21,22,23]. An open-label, phase 2–3, multicenter, randomized, controlled, noninferiority trial was conducted in Belarus, South Africa, and Uzbekistan to evaluate the efficacy and safety of three 24-week, all-oral regimens (bedaquiline, pretomanid, linezolid, and moxifloxacin), for the treatment of rifampin-resistant tuberculosis. Results showed that this all-oral regimen was non-inferior to the accepted standard-care treatment and it had a better safety profile [23, 24].

Parenteral administration of antibiotics in the treatment of DR-TB has also included the intramuscular (im) route, especially for kanamycin and capreomycin. This route employs deep im injection, with alternating injection sites [25]. This route of antibiotic administration has been problematic due to the injections being painful, especially for those with limited muscle mass, becoming intolerant to im injection due to pain at the injection site [26]. For this reason, im antibiotic administration has been cited as one of the worst aspects of DR-TB treatment [27].

The switch from using iv and im antibiotics to exclusively oral antibiotics creates new challenges, particularly with treatment adherence and compliance. Employment of iv antibiotics involve allied healthcare professionals assisting with their administration to the patient, whereas with oral antibiotics, administering of these orals is largely goverened by the patient themselves. Therefore, antibiotic treatment adherence may be a bigger problem with solely oral regimes than with those regimes involving an iv antibiotic and an issue that requires careful reflection. A recent systematic review by Pradipta and colleagues of 14 studies, including 10 active TB and four latent TB studies showed that directly observed treatment (DOT) by trained community workers, short messaging service combined with education, counselling, monthly TB vouchers, drug box reminders and combinations of those were effective [6]. Previously, in a high DR-TB burden setting in Khayelitsha, Cape Town, South Africa, Mohr and colleagues describe their development of a patient-centric approach to DR-TB treatment that was integrated into existing TB and HIV primary care programmes [28]. Their model involved structured and standardised adherence support sessions that were developed into a DR-TB counselling toolkit, focussing on DR-TB treatment literacy, adherence strategies to encourage retention in care and provision of support throughout the patient’s long treatment journey [28].

The WHO describes the monitoring schedule for patients receiving the 9-month all oral MDR/RR-TB regimen, which includes the component “Treatment literacy and adherence counselling”, with inputs from this component at baseline, and at 0–2 months, at every healthcare worker interaction and then, as necessary for the following seven months [4]. However, there is no further discussion on what interventions or monitoring should entail with “Treatment literacy and adherence counselling”. Literacy plays an important role in the understanding of tuberculosis [29]. Developing resources for TB patients to support treatment literacy of the new WHO short 6-and 9 month all oral treatment regimes would be prudent, in order to help patients better understand their antibiotic medications, as well as dosing and treatment durations, in an attempt to maximise treatment adherence.

The patient information leaflet (PIL) is an important source of information for the patient, which accompanies presciption medicine and which is intended to help the patient understand key aspects of the medication for their treatment. PILs, which accompany medication, including antibiotics, have been shown to have a positive impact on medication adherence [31]. In this study by Al Jeraisy and colleagues in Saudi Arabia involving 1138 adult individuals, the practice of patients reading the PILs positively impacted their medication adherence (64.9%), whilst 8.8% of respondents indicated that reading the PIL negatively impacted on their adherence, due to concerns surrounding the medicines’ side effects and complications. Further data from India showed that PILs significantly improved patients knowledge about their medication and improved compliance at home [32]. Unfortunately there are no reports of audits checking whether or not every medicine is accompanied by a PIL within the packaging. In Western countries, the supply of the PIL is mandatory, accompanying each precription medication. Where repeat medication is supplied on a daily basis by a healthcare provider, the DR-TB patient should have initial access to the PIL for each medicine taken and be asked regularly if they would like an update on any information that the PIL describes.

To our knowledge, the current study is the first to conduct an assessment of the readability of PILs of antibiotics employed in the treatment of drug-resistant TB, according to the WHO guidelines [4]. In this study, we employed quantitaive measurement of words, sentences and syllables, as defined by readability formulae, including Flesch Reading Ease, Flesch Kincaid Grade Level, Gunning Fog and SMOG scores (Supplementary Table 1). Readability has now become a commonly employed tool to help healthcare professionals prepare patient-facing materials and resources, supported by a growing evidence-base of published literature, where currently there are approximately 500 publications cited in PubMed per year, devoted to its study and application within clinical medicine, particularly its value with patient-facing information and material resources. To date, an advanced PubMed search of the title terms “readability” and “antibiotic” returns one sole publication from our group, [33] describing its value amongst patients with cystic fibrosis, thereby demonstrating the novelty and opportunity of the application of such an approach to promote antibiotic usage awareness and treatment literacy amongst TB patients, receiving short all oral antibiotic regimes [33].

The design of our study involved the analyses of readability of PILs of the 10-listed oral antibiotics, defined in the WHO BPaL, BPaLM and BPaLC antibiotic regimens [4]. PILs information was sourced from three groups, namely (i) high TB incidence countries, including Rwanda (TB rate per 100,000 population (2022) (Data source: WHO available at https://worldhealthorg.shinyapps.io/tb_profiles/?_inputs_&entity_type=%22country%22&iso2=%22RW%22&lan=%22EN%22 [56/100,000), Malaysia (113/100,000) and South Africa (468/100,000), (ii) low incidence countries, including UK (7.6/100,000), Ireland (4.5/100,000) and Malta (13/100,000), as well as (iii) TB drug information web resources. All PILs from (i) and (ii) were sourced from websites of the medicines regulator of each respective country. Our first observation was that PILs information was difficult to source online from the majority of medicine regulators globally. More regulators listed the Summary of Product Characteristics (SPC) of these antibiotics, however these are not designed to be patient-facing, but rather healthcare professional-facing.

From examination and comparison of the readability and text metrics results of this study, the overall readability and text metric scores from all sources combined did not meet the readability reference targets of ≥ 60, for the Flesch Reading Ease score and ≤ 8, for the Flesch Kincaid Grade Level (Fig. 2A–C). Recommendations for suitable readability levels can vary between institutions, with the American Medical Association recommending that all patient-facing material be written at a sixth grade level (11 years old) [14]. Conversely, the Centers for Disease Control and Prevention (CDC) recommends that patient-facing information does not surpass an eighth grade reading level (13 years old) [14].

Only 11/125 (8.8%) of TB antibiotc information sources met this target and 12/125 (9.6%) reaching the target level for the Flesch Kincaid Grade Level. This indicates TB antibiotic information is not considered to be written adequately for the public and are thus too difficult for the general public to read. When the information sources within these three categories were compared to each other, the most readable of all the information sourced, was that from reliable internet web resources, including the US government’s National Library of Medicine, MedlinePlus, as well as the electronic medicines compendium (EMC) and Drugs.com. PILs from high TB incidence countries consistently had the lowest readability scores, when compared to low incidence countries and web resources (Flesch Reading Ease; p = 0.0056 and p < 0.0001, respectively) (Fig. 3A). There was no statistical differences (p > 0.05) in readability or text metrics scores between low incidence countries and web resources. Poor readability scores were associated with higher words per sentence and higher syllables per word text metrics.

It is concerning to note that the poorest readability scores were PILs from high incidence countries. PILs are essentially designed to inform the patient with important information regarding their medication, to allow patients the choice and enable them to make knowledgeable and responsible decisions with regard to their medications [34]. Therefore, it is important that PILs are easily accessible by inclusion in community-dispensed medicines and which are easily read and their value promoted to patients and service users, by the respiratory team and pharmacist treating the TB patient. The issues of poor readability of TB antibiotic PILs in the context of treating drug-resistant tuberculosis, as identified in the current study, is in itself a microcosm of a multitude of interwoven societal problems. We have reflected on these issues and have subsequently aligned those relevant UN Sustainable Development Goals to the issues of poor readability of TB antibiotic PILs, as shown in Fig. 5.

Alignment of identified and relevant UN Sustainable Development Goals (SDGs) associated with poor readability of TB antibiotic treatment information

The study presented here has several limitations. Firstly, the PILs collected and analysed were limited to the English language only, thereby making it of most value to the study of TB treatment and adherence in English-speaking countries. All non-English patient information sources were excluded from this study. This was due to the online readability tool (Readable), employed in this study, being best suited for scoring texts using the English alphabet, as it is not able to assess readability of texts written with alternative characters, such as Arabic, Chinese and Japanese. Another limitation was the lack of availability of PILs from the majority of countries, particularly high incidence countries, which would have reflected more robust representation of readability of PILs from high incidence countries. Where English is not the first language and where countries have a high rate of illiteracy, governments, NGOs and public health agencies should consider an alternative to the written PIL and adopt alternative media, such as video, animation or podcast, to allow high quality antibiotic information to be disemminated, as an alternative to the traditional PIL, thereby ensuring the same quality of public health messaging to maximise antibiotic treatment adherence. Additionally, countries should ensure that patients have independent and easy access to a source of high quality information on TB antibiotics, in an understandible and comprehensible format, matching the literacy and health literacy baseline values of that country, so that lack of knowledge about antibiotics is not allowed to translate into poor antibiotic adherence and onwards to poor clinical outcomes.

In conclusion, readability of PILs of the 10 antibiotics listed in WHO short, all-oral treatment regimens is poor, not reaching readability reference standards. Such poor readability could be reflected in poor understandibility, leading to non-compliances in patient-centred TB treatment regimens, cumulating in poor disease outcomes. To date, readability of antibiotic PILs has not been scrutinised, nor has it been considered as an integral intervention of TB treatment and patient health literacy. Authors of antibiotic PILs and other TB antibiotic information should consider the adoption of readability calculators when preparing medication information for TB patients, to check the readability of their work, so that the final material is within recommended readability reference parameters, to support the health literacy and treatment adherence of their readers, as well as maximising the value of the Patient Information Leaflet in independent, reliable and trusted TB information dessimination to TB patients globally.