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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 24-28

The activity-based cost of drug-susceptibility test of Mycobacterium tuberculosis through Kit SIRE Nitratase® Plastlabor


1 Mycobacteria Research Laboratory, Department of Internal Medicine, Faculty of Medicine, Federal University of Minas Gerais, Minas Gerais, Brazil
2 Tuberculosis Research Center, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
3 International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil
4 Júlia Kubitschek Hospital, Hospital Federation of the State of Minas Gerais, Minas Gerais, Brazil
5 Department of Social Pharmacy, Faculty of Pharmacy, Federal University of Minas Gerais, Minas Gerais, Brazil

Date of Submission16-Jan-2020
Date of Decision13-Feb-2020
Date of Acceptance27-Jan-2020
Date of Web Publication6-Mar-2020

Correspondence Address:
Silvana Spíndola de Miranda
Avenida Professor Alfredo Balena, 190 – Santa Efigênia. Belo Horizonte, 30130-100 Minas Gerais
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijmy.ijmy_8_20

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  Abstract 


Background: Drug-resistant tuberculosis (TB) is an ongoing health threat, and the greatest challenge to adequate control of TB in many countries lies in the lack of proper laboratory drug-susceptibility test. The aim of this study was to evaluate the activity-based costs (ABC) of Kit SIRE Nitratase® (Kit SIRE) and compare its values with the conventional drug-susceptibility test. Methods: The ABC was calculated for three different approaches: Kit SIRE (clinical samples and cultures), proportion methods in Lowenstein Jensen (PM-LJ), and the Bactec™ MGIT™ 960 system based on Mycobacterial Research Laboratory's routine. Results: The ABC of Kit SIRE from cultures was US$ 148.54, while from clinical samples was US$ 136.12. In the case of conventional tests, the ABC of Bactec™ MGIT™ 960 was US$ 227.63 and of the PM-LJ was US$ 132.64. The Kit SIRE has a lower ABC when clinical samples are used instead of cultures. Compared to conventional tests, the ABC is similar to the PM-LJ and lower the Bactec™ MGIT™ 960. Conclusion: The Kit SIRE should be used as a screening method in clinical specimens and in culture for laboratories that do not have Bactec™ MGIT™ 960. Therefore, it can be incorporated into the routine of laboratories in countries with low resources and a high burden of TB and drug-resistant TB.

Keywords: Cost, multidrug-resistant tuberculosis, nitrate reductase, technology, tuberculosis


How to cite this article:
de Almeida IN, da Silva SC, Junior HA, Figueredo LJ, Soares VM, Carvalho Wd, Kritski A, da Costa Fiori MC, de Miranda SS. The activity-based cost of drug-susceptibility test of Mycobacterium tuberculosis through Kit SIRE Nitratase® Plastlabor. Int J Mycobacteriol 2020;9:24-8

How to cite this URL:
de Almeida IN, da Silva SC, Junior HA, Figueredo LJ, Soares VM, Carvalho Wd, Kritski A, da Costa Fiori MC, de Miranda SS. The activity-based cost of drug-susceptibility test of Mycobacterium tuberculosis through Kit SIRE Nitratase® Plastlabor. Int J Mycobacteriol [serial online] 2020 [cited 2020 Mar 30];9:24-8. Available from: http://www.ijmyco.org/text.asp?2020/9/1/24/280153




  Introduction Top


Drug-resistant tuberculosis (TB) is an ongoing health threat. It is estimated that in 2018, 186772 people worldwide developed TB that was multidrug-resistant TB or rifampicin-resistant (TB MDR/RR-TB) and in Brazil in the year 1119 MDR/RR-TB were notified.[1] Moreover, in a recent meta-analysis of 50 studies, which included 12,030 MDR-TB participants, the pooled treatment success reached only 61% had treatment success.[2]

The management of MDR-TB is characterized by delayed diagnoses, uncertainty regarding the extent of bacillary drug resistance, imprecise standardized drug regimens and dosages, excessive therapy time, and a high frequency of adverse events. This all translates into a poor prognosis for many of the affected patients. In addition, the treatment of isoniazid-resistant TB with first-line drugs results in suboptimal outcomes, which supports the need for better regimens. Standardized empirical treatment of new cases may well contribute substantially to the MDR-TB epidemic, particularly in settings where the prevalence of isoniazid resistance is high.[3],[4]

In 2015, the World Health Assembly endorsed the end TB strategy proposed by the World Health Organization (WHO). This strategy has set ambitious targets to be met by the year 2035 and recommends that governments provide universal access to drug-susceptibility testing (DST).[5] However, the greatest challenge to adequate control of DR-TB in many countries lies in the lack of proper laboratory facilities to perform DST.[6]

The indirect proportion method in the Lowenstein Jensen medium (PM-LJ) is the most widely used DST method; however, it takes 8–12 weeks to yield the results in good circumstances and up to 6 months in field conditions.[7] The use of the BACTEC™ MGIT™ 960 system (MGIT), Becton, Dickinson and Company©, Franklin Lakes, NJ USA has improved the time to obtain DST results to approximately 25–45 days, but this liquid culture system is, in most cases, unavailable where the need is greatest.[6],[7]

There are studies evaluating the performance of DST, with promising results; however, studies on the costs of implementation in routine conditions are scarce,[8] and these DST cost studies mainly cover PM-LJ and MGIT.[8],[9],[10]

There are several costing methods that can be applied to health technology economic evaluation studies, among them activity-based costing (ABC) stands out for being a suitable method for evaluating the activities performed by multiple processes, appropriate for complex organizations, such hospitals and clinical laboratories.[11],[12]

This cost parameter can improve managerial decisions when determines the costs of services/products provide greater precision in product costs, offers support in the negotiation of contracts and provides support in the increase in revenue, and helping customers to understand the cost reductions as consequence of the use of their products and services. Hence, ABC is a cost methodology to pinpoint the advantage of being able to observe a significant quantity of tests, thus making it possible to identify a standard cost and conduct a detailed inventory of the cost items.[11],[13],[14]

Alternative methods for DST have been developed, including colorimetric indicators for the early detection of bacterial growth.[15] In 2009, the WHO recommended the use of the in-house nitrate reductase assay (NRA) for the rapid screening of patients suspected to have contracted MDR-TB.[15] The in-house NRA technique has already been evaluated in clinical samples and has proven to be a good alternative for the rapid diagnosis of resistant TB.[16]

In order to choose an algorithm for the screening and diagnosis of TB and MDR-TB in accordance with WHO recommendations (which is appropriate at both national and local levels), an assessment of the accuracy of the algorithm and the cost of the tests should be carried out under field conditions.[17]

In the last years, the commercial liquid culture systems as MGIT have been endorsed by the WHO as standards methods for the detection of MDR–TB, and hence, these methods present some limitations such as technical complexity and high cost (MGIT).[15]

In Brazil, an innovative approach was taken using technology transfer from academia to industry (PlastLabor©) to create a commercial test based on the NRA for DST of Mycobacterium tuberculosis (M. tuberculosis) strains for the first-line drugs – streptomycin (S), isoniazid (I), rifampin (R), and ethambutol (E). As a result of this approach, Kit SIRE Nitratase® (Kit SIRE), Plastlabor©, Rio de Janeiro, RJ, Brazil was developed with a high level of accuracy when considered MGIT as standard method – 95% (S), 97.5% (I), 100% (R), and 80% (E),[18] and these values are so close to the MGIT accuracy – 96.4% (S), 98.2% (I), 99.5% (R), and 95.3% (E), and in general PM-LJ's accuracy has a good correlation with MGIT.[19],[20]

This kit, therefore, is an attractive option for the screening of M. tuberculosis strain resistance in high-burden countries and those without resources. Kit SIRE was updated in 2017, wherein, following the Brazilian Guidelines, a tube containing para-nitro benzoic acid (PNB) was incorporated to evaluate contamination or the prior identification of nontuberculous mycobacteria (NTM) directly in clinical samples.[21]

This study evaluates the activity-based costs (ABC) of Kit SIRE for the rapid screening of MDR TB by cultures and clinical samples in a general hospital as well as a tertiary referral hospital in the Brazilian public health system.


  Subjects and Methods Top


Study sites and diagnostic routine

This research consisted of a hypothetical cohort study modeled using population parameters based on the routine of the Research Laboratory in Mycobacteria/School of Medicine of Universidade Federal de Minas Gerais (UFMG). The study considered the drug-susceptibility tests performed on samples and cultures from the UFMG's Clinical Hospital and from Hospital Júlia Kubitschek (HJK), a public and tertiary referral hospital for the treatment of TB and MDR-TB in the state of Minas Gerais, Brazil.

Research Laboratory in Mycobacteria/Universidade Federal de Minas Gerais

This site is a level 3 biosafety laboratory (B3) that evaluates the clinical samples from presumed TB participants who receive medical care at UFMG Hospital, public and general teaching hospital that conducts educational, research, and medical care activities. From October 2014 to December 2017, all positive cultures of M. tuberculosis from UFMG Hospital and HJK were sent to the laboratory for a Genotype MTBDR® plus molecular test and a Kit SIRE evaluation. Monthly are performed on average 15 DST (Kit SIRE) in the laboratory and the routine flow of this laboratory is described in the flowchart of [Figure 1].
Figure 1: Mycobacterial Research Laboratory Routine Flowchart: CH/UFMG: Clinical Hospital of University Federal of Minas Gerais; HJK: Hospital Julia Kubstichek

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Kit SIRE Nitratase®

The commercial Kit SIRE was used according to the protocol previously described by Angeby et al.; the critical concentrations of isoniazid, rifampicin, streptomycin, and ethambutol in the LJ medium were 0.2 μg/mL, 40 μg/mL, 4 μg/mL, and 2 μg/mL, respectively. The LJ medium was prepared according to the manufacturer's specifications (DIFCO; Becton Dickinson Diagnostic Systems) with the addition of potassium nitrate (final concentration of 1 mg/mL). Tubes without drugs were used as growth control.[22] The company was accredited and validated by the Brazilian National Agency of Sanitary Surveillance (Agência Nacional de Vigilância Sanitária).[18]

Inoculum turbidity was adjusted to McFarland tube no. 1 and diluted 1:10; 0.2 mL of the 1:10 dilution was used to inoculate three drug-free tubes; and 0.2 mL of the undiluted suspension (McFarland tube no. 1) was inoculated into tubes-containing drugs. The inoculum was originated from the first isolate. The tubes were incubated at 37°C for 7 days. The reading included the preparation of a color-developing reagent mixture consisting of one part 50% (vol/vol) concentrated HCL, two parts 0.2% (wt/vol) sulfanilamide, and two parts 0.1% (wt/vol) n-1-naphthylethylenediamine dihydrochloride. These reagents were mixed separately immediately before being added to the tubes to detect growth.

The Kit SIRE was also performed on the samples of respiratory origin with positive bacilloscopy, according to the method described by Rosales et al., and for clinical isolates, according to the methodology described by Miranda et al.[16],[18]

Cost analysis

The cost of Kit SIRE was calculated by ABC. The ABC is suitable for complex organizations, such as hospitals, where products use consumes resources in a very heterogeneous manner.[11] The ABC is calculated considering activity as the denominator for the calculation of the unit cost per activity. This method avoids fluctuations in the calculation of the activity's unit cost based on the variation of the real processed quantity.[11],[12],[23]

The cost components considered to calculate the costs of Kit SIRE, such as infrastructure, equipment, inputs, personal protective equipment, human resources, and the maintenance of B3[14] were verified at both sites to calculate the mean cost and ABC, as well as the cost of human resources and the maintenance sectors.

The ABC was calculated in two different scenarios: (1) Kit SIRE from cultures, which correspond to 15 tests/month and (2) Kit SIRE from clinical samples, corresponding to 12 tests/month, according to Laboratory routine [Figure 1].

It is important to emphasize that in the cost calculation of the kits from cultures, the respective cost of the culture in LJ was added to the values, as they are essential procedures for the realization of the Kit SIRE.[14]

The ABC was also calculated for conventional methods: (1) the PM-LJ and (2) MGIT, with the aim of comparing the costs of Kit SIRE with the costs of these two methods, as these are the most commonly used for M. tuberculosis phenotypic DST in Brazil as well as globally.

All the costs were expressed in US$ using a conversion rate of US$ 1.00 = R$ 2.029 by the factor Purchasing Power Parity in 2019.[24]

This study was approved by the Research Ethics Committee of the Fundação Hospitalar do Estado de Minas Gerais (logged under technical report number 018B/20, UFMG Ethics Committee protocol numbers CAAE: 11821913.6.000.5257 and CAAE: 0223.2412.7.1001.5149, and Clinical Hospital/UFMG protocol number 139/12).


  Results Top


The ABC of Kit SIRE from cultures was US$ 148.54, whereas the value from clinical samples was US$ 136.12. The ABC of the MGIT was US$ 227.63, while that of the PM-LJ was US$ 132.64.

The impact of the cost components in the ABC of the Kit SIRE from cultures and clinical samples is shown in [Table 1], which highlights the supplies as the component with the greatest impact, followed by the aggregate methods (culture and sample collection), human resources, and equipment. Infrastructure had no interfered with this parameter.
Table 1: Cost components and activity-based cost of Kit SIRE Nitratase®

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The ABC for cultures was US$ 20.23 (added in final ABC of Kit SIRE from cultures; MGIT and of PM-LJ), while the ABC for sample collections was US$ 2.06 (added in final ABC of Kit SIRE from clinical samples).

The average time taken to release the results of the three DST methods evaluated in this study is shown in [Table 2].
Table 2: Average release time of drug-susceptibility tests

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  Discussion Top


The ABC of Kit SIRE in cultures was higher than in clinical samples, owing to the value of the supplies used in previous stages such as culture testing for the isolation of mycobacteria.

The incorporation of Kit SIRE presents a great advantage in relation to the PM-LJ used in our study and other in-house drug susceptibility tests, as it uses a product manufactured on an industrial scale. This ensures rigorous operating procedures that are controlled by quality management programs. In contrast, noncommercial methods are prone to errors due to local variations in standardization.[15]

Through the ABC method, the values found in this study allow managers to show the exact costs of tests,[25],[26] which in turn enables one to decide whether or not to incorporate these tests in routine laboratories, such as the Laboratory/UFMG and other UHS mycobacteria laboratories.

The routine use of the Kit SIRE commercial test for clinical samples is highly important in decreasing the time taken to release results, as the maximum time is 3 weeks. When the test is performed using the clinical isolate, the time ranges from 6 to 10 weeks, as it adds time needed for the growth of M. tuberculosis (on average 4–8 weeks) to that of the release of the Kit SIRE result (2 weeks).[16],[18]

Currently, in most laboratories in Brazil, when MGIT is incorporated into the diagnostic routine, drug-resistance testing is not performed directly on the clinical sample but only on the positive culture. The average time for the growth of M. tuberculosis in culture using MGIT is 2 weeks. The test result also takes an average of 2 weeks. Therefore, the total turnaround time for DST using MGIT is 4 weeks.[4],[26]

When DST is performed by conventional in-house methods, such as the PM-LJ, the turnaround time for a clinical sample DST is on average 4–8 weeks. When DST is performed in the clinical isolate, adding the time for mycobacterial growth, the DST turnaround time is approximately 10–12 weeks.[4],[6]

When DST is made directly from the clinical sample, it should be emphasized that a disadvantage is the possibility of contamination and the presence of NTM. However, the incorporation of PNB may be useful in detecting the M. tuberculosis complex.[21]

Although the cost is higher, conducting the Kit SIRE in culture, positive for M. tuberculosis and negative smear microscopy, has the advantage of being less laborious than PM-LJ.[4],[6],[18] and also of having the shortest turnaround time, as described above. It is important to highlight that input was the cost component that most impacted the ABC of Kit SIRE in cultures and in clinical samples, as described in other studies that evaluated others diagnostic test′s costs.[9],[14]

The data of this study present the importance of using ABC for the economic evaluation of diagnostic tests due to the fact that the ABC is a horizontal method capable of reaching an analysis that is not restricted to profit. This vision is based on planning, execution, and assistance in making strategic decisions, as well as on changes in processes, the elimination of waste, and the preparation of estimates based on activities performed, thereby increasing the efficiency of public services.[11],[14],[25]

The incorporation of Kit SIRE in laboratory routines in Brazil as well as in other countries that have a high TB burden and low resources can be economically sustainable, especially when considering its lower values when compared with MGIT (US$ 141.63). Even in places where MGIT is used in Brazil, there are difficulties in the acquisition of supplies, which promote the use of PM-LJ.

One limitation of this study is that a cost-effectiveness analysis was not performed, as well as the minimization cost study since the test accuracy values are very close.[27] Therefore, it is necessary to study the clinical and economic impact of the incorporation of Kit SIRE within the diagnostic and therapeutic cascade of drug-sensitive and drug-resistant TB in different regions of the country. In this way, the UHS' National Commission for the Incorporation of Technologies can evaluate the incorporation of this DST in the UHS laboratory routine.

We concluded that Kit SIRE should be used as a screening method in clinical specimens and in culture for laboratories that do not have MGIT. Therefore, it can be incorporated into the routine of laboratories in countries with low resources and a high burden of TB and drug-resistant TB.


  Conclusions Top


The Kit SIRE should be used as a screening method in clinical specimens and in culture for laboratories that do not have MGIT. Therefore, it can be incorporated into the routine of laboratories in countries with low resources and a high burden of TB and drug-resistant TB.

Financial support and sponsorship

Fundação de Amparo à Pesquisa do Estado de Minas Gerais Process Number: CDS - APQ-03266-13, the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) (Process number: CNPq 310174/2017-7 446796/2014), and Fundação para a Ciência e a Tecnologia, Portugal, for their financial support, as well as the Graduate Department of the UFMG Medical School, REDE-TB, CNPq/INCT 465318/2014–2, for laboratory supplies and pos-doc scholarship.

Conflicts of interest

There are no conflicts of interest.



 
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