India accounted for 27% of the global TB burden in the year 2020. Drug-resistant TB (DR-TB) is emerging to be a serious public health threat. In India, among all bacteriologically confirmed cases, around 3.1% had DR-TB.1,2 The prevalence of DR-TB among pediatric population has increased to 9.6% in 2018 from 5.6% in the pre-2010s according to a study done at B.J. Wadia Hospital, Mumbai, in 2016.3
For patients who do not respond to therapy with second-line TB drugs, treatment options are limited. Salvage therapy refers to the design of a regimen combining new and previously used drugs in a final attempt before declaring treatment failure.4 Bedquilline (Bdq) and Delamanid (Dlm) are newer drugs to combat MDR/XDR-TB and have been used individually as well as in combination as part of salvage regimens.5 Under the National Tuberculosis Elimination Programme (NTEP) of India, Bdq is approved only for patients above 18 years, and Dlm only for children above 6.6,7 However, the World Health Organization (WHO) consolidated 2020 DR-TB treatment guideline recommended the use of Bdq in children above 6 years and Dlm in children above 3 years of age and calls for a Dlm-based regimen in longer DR-TB treatment regimens.8
Imipenem and meropenem have been used in the treatment of MDR/XDR-TB when an effective combination regimen with second-line drugs is not possible. Although the treatment success rates with carbapenems are promising, the 2 or 3 daily injections usually requires patients to be hospitalized and are cumbersome.9,10 Attempts at implementing an ambulatory home-based Imipenem therapy through a port-a-cath have been made in the recent past and appear to be promising although several practical hurdles may have to be tackled.11
We present the findings of our study on feasibility of a “salvage regimen” using home-based carbapenem therapy through peripherally inserted central catheter (PICC) as part of a longer (18–20 months) optimized background regimen (OBR) including Dlm/Bdq/both in pediatric MDRFQ/SLI/XDR-TB patients.
MATERIALS AND METHODS
This study is a retrospective descriptive analysis of individual patient data. NTEP medical records of all pediatric MDRFQ/SLI/XDR-TB patients enrolled at the Pediatric DR-TB Clinic, BJ Wadia Hospital for Children, Mumbai who received salvage therapy between April 2018 and December 2020 in view of treatment failure to the standard MDR-TB regimen.
Standardized case definitions of rifampicin resistant TB (RR TB), multidrug resistance (MDR), extensive drug resistance (XDR), as per NTEP were used for categorizing DR-TB.12,13
Following case definitions were used for categorizing outcomes:
- a. Culture conversion: Patient is considered to have culture converted when 2 consecutive cultures taken at least 30 days apart are found to be negative.
- b. Lost to follow up: A TB patient whose treatment was interrupted for 1 consecutive month or more.
- c. Died: A patient who has died during the course of anti-TB treatment.
- d. Still on treatment: A patient who has not yet completed his treatment but has culture converted.
Criteria for Initiation
Patients identified to have treatment failure on standard MDR-TB regimens were identified. These patients underwent thorough clinical evaluation, necessary laboratory investigations including a complete hemogram, liver function tests, kidney function tests, thyroid function tests, audiometry, electrocardiogram, and microbiological testing with quality assured drug susceptibility testing (DST) using WHO endorsed rapid diagnostics. Resistance to SLI/FQ was tested in all MDR patients, and if found resistant, sensitivity to high-dose moxifloxacin, linezolid, clofazimine, ethionamide, and paraaminosalicylic acid was tested. Parents were counseled regarding the challenges involved in home-based salvage therapy and associated complications and only willing, motivated parents were then initiated on the regimen.
Composition of Salvage Regimen
A fresh DST was obtained before initiation of salvage regimen. An OBR was formulated based on personalized DST reports as per the WHO recommendations for individualized longer MDR/XDR-TB regimens. Dlm was added to OBR in children with pulmonary MDR/XDR-TB in children >6 years of age if an otherwise optimum regimen as per WHO cannot be constituted or was added on an individual basis after expert clinical opinion. Total duration of Dlm was limited to 24 weeks. Bdq was added in 3 children of 15 who were 12 years or older after review and approval by the central TB division experts on a case-to-case basis. Meropenem was used as the carbapenem in all patients in addition to above. Clearance from the hospital administration as well as informed written consent from both parents were obtained if children were initiated on salvage therapy with concomitant Bdq and Dlm. Such patients were closely monitored for possible side effects. Inclusion of other drugs was based on the DST results, past use, tolerability, and availability of the drugs. In 8 patients who were unable to tolerate linezolid and 3 unable to tolerate cycloserine, appropriate alternate drug was added. In children with resistance to high-dose moxifloxacin, the drug was still continued as part of regimen. However, in cases of clofazimine or linezolid resistance, these drugs were discontinued and other appropriate drugs were used to complete the regimen.
Administration of Meropenem
The Groshong peripherally inserted central catheter (PICC) with MI Kit (4 Fr, Bard) was inserted at our tertiary care center in the pediatric DR-TB ward on an in-patient basis. After radiograph or echocardiographic guided confirmation of position, the first dose of meropenem was administered. Meropenem was administered thrice daily at a dosage of 40/mg/kg/day over 1 hour using microdrip sets, via the PICC. Amoxicillin-Clavulanate was coadministered along with Meropenem thrice daily at a dose of 40 mg/kg/day orally. During the first week of stay, the patient was monitored for signs of complications such as leakage, block, or infections. During the week either the parents were trained to administer the drug via the PICC with complete aseptic precautions or a nurse/physician was identified close to the patient’s place of residence who could provide home-based therapy. Subsequent doses were administered by the parent/home nurse at home and back-up care givers were also identified. Total duration of the parenteral therapy was limited to 6 months; however, the duration was extended in exceptional cases as per the clinical, radiological and microbiological response of the patient.
Patient Follow up
Fortnightly visits were scheduled for dressing of the PICC site by a trained nurse. Adverse drug effects were duly monitored, noted, and recorded in the patient records. Patients followed-up in the DR-TB clinic fortnightly after discharge. In events of complications such as leakages, block, or infection, patient was admitted to hospital and the concerned PICC was duly removed and an alternate access obtained.
Outpatient and in-patient records of patients during the entire duration of their treatment was retrospectively analyzed. Variables such as demographic characteristics, clinical profile, comorbidities, type of pulmonary TB (PTB), presence of extrapulmonary TB, previous regimens received and duration of those, drug sensitivity patterns, current regimen composition and duration of treatment were studied. Clinical and microbiologic outcomes, time to conversion, need for surgical interventions, adverse drug reactions, initial hospital stay, hospital associated infections, need for hospitalization and PICC associated complications were noted.
All 15 patients initiated on salvage therapy with meropenem/clavulanate and newer drugs in an OBR for MDRFQ/SLI/XDR pulmonary TB during the study interval were included. Demographic details are depicted in Table 1. The mean age of the patient population was 12.53 ± 2.47 years. Of the total, 13 patients were female. At the time of initiation of therapy, all children were sputum positive. Thirteen patients had fibrocavitatory disease while 2 patients had miliary pattern of lung involvement. Radiologically, 6 children of 15 had predominantly unilateral involvement while the other 9 had bilateral involvement. Two patients had evidence of coexisting extrapulmonary TB. One patient had lymph nodal and mediastinal disease while the other had tubercular meningitis.
TABLE 1. -
Demographic Characteristics of 15 Drug-resistant TB Cases
|Age (in years)
|Type of disease
| Sensorineural hearing loss
| Left ventricular dysfunction
| Peripheral neuropathy
| Psychiatric dysfunction
Seven patients had XDR-TB while 8 had MDRFQ/SLI TB (Table 2). Resistance to high-dose moxifloxacin was detected in 4 patients. Resistance to all SLI including kanamycin, capreomycin and amikacin was detected in 8 patients. Furthermore, resistance to ethionamide, linezolid, and paraaminosalicylic acid were found in 12, 4 and 3 patients respectively. Three patients had history of prior treatment with first line antitubercular drugs.
TABLE 2. -
Drug Resistance Profile of TB Patients
||Individual drug resistance
|| High-dose moxifloxacin
|| All SLI—kanamycin, capreomycin, and amikacin
MDRFQ/SLI TB indicates multidrug resistant tuberculosis with additional resistance to fluoroquinolones or second-line injectables; PAS, paraaminosalicylic acid; XDRTB, extensively drug resistant tuberculosis.
The median duration after diagnosis at which these patients were initiated on salvage therapy was 9 months (IQR [interquartile range]: 5–20 months). One patient received in-patient care for the entire duration of salvage therapy caused by comorbid illness. Among the other 14 patients, the median duration of initial hospital stay for PICC insertion, post procedure care and care giver education was 26.5 days (IQR: 20–54 days). The median duration of meropenem administration as part of salvage therapy was 180 days (IQR: 120–210 days).
Among the patients, only 3 experienced drug-related side effects, in the form of dyselectrolytemia. All 3 patients had hypokalemia and hypomagnesemia, which required IV correction and subsequent oral supplementation. Eight patients had other complications caused by other antitubercular drugs added as part of OBR which included hypothyroidism (6 patients), sensorineural hearing loss (4 patients), anemia (2 patients), left ventricular dysfunction (2 patients) peripheral neuropathy, and psychiatric symptoms (1 patient each).
Catheter-related complications were reported by 5 patients. There were 3 instances of reported catheter block, 1 instance of catheter leak, and 1 patient developed venous thrombosis prompting change of catheter. None of the patients reported other local complications, infections, or systemic septicemia. Only 2 patients required a second hospital admission during the duration of salvage therapy for complications related to the PICC.
At the time of completion of study, all patients had attained sputum culture conversion. The median time from onset of salvage therapy to sputum culture conversion was 6 months (range: 2 months to 8 months). One patient underwent pneumonectomy for localized disease control during the treatment period at the completion of the study, 12 of 15 patients remained on treatment but remained culture negative, while 2 patients were lost to follow up, and 1 patient died because of complications of extra pulmonary disease.
Our study is unique in certain respects and has some key notable findings. Although a recent study done in Mumbai, India, in 2020 studied the outcomes and challenges of administering imipenem to adult MDRFQ/SLI/XDR-TB patients through a port-a-cath by trained nurse practitioners at home,11 this is the first time this has been attempted in the pediatric population by means of a PICC line with the caregivers trained to administer injections. Other notable features in our study also included using meropenem instead of imipenem due to the better safety profile, and the concomitant use of Dlm or Bdq as part of a potent antitubercular regimen.
The striking female:male ratio (13:2) seen in our study probably reflects the disproportionate prevalence of pulmonary TB among girls as shown in previous studies done in these areas.14 Similar to previous studies,11 our study too showed a high frequency of ethionamide resistance among the participants.
The most common drug-related serious adverse event was dyselectrolytemia. Despite electrolyte imbalances, importantly there were no instances of occurrence of arrhythmia or other life-threatening complications. Although our study reports a higher rate of catheter-related complications as compared to the study using port-a-caths, the hospitalization rates were found to be lower.11 This may be attributed to the high frequency of PICC line handling and inherent socioeconomic conditions at households hindering proper aseptic precautions. Our study notably showed a 100% rate of sputum culture conversion. Similar studies have documented only sputum culture conversion rates of up to 72%.11,15
Our study serves to prove that treatment of pediatric MDRFQ/SLI/XDR-TB using meropenem via home-based intravenous therapy is feasible even in resource constrained areas. It also shows that the newer antitubercular drugs, Dlm and Bdq may be promising therapeutic options even in the pediatric population especially for those with limited drug alternatives available. Compassionate use programs have affirmed favorable outcomes as well as good tolerability with these drugs in pediatric population above 6 years across countries16 Fast-tracking approval for these newer safer effective oral drugs among the younger population would enable provision of an all-oral effective and safer regimen in children as recommended by WHO. However, in situations where an effective regimen cannot be designed using effective oral drugs, implementation of home-based long-term meropenem therapy may be a promising, novel idea for tackling the menace of advanced M/XDR-TB in India.
Home-based ambulatory therapy with carbapenems using PICC in pediatric MDRFQ/SLI/XDR-TB patients with treatment failure is a feasible option. Meropenem when used with newer drugs—Dlm and Bdq along with an OBR showed minimal adverse events, with good rates of sputum conversion. Exploring the feasibility of such therapy on a wider scale is the need of the hour and may prove to be instrumental in improving outcomes of advanced MDR/XDR-TB in children.
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