The National Health Insurance program (JKN)
was introduced in Indonesia on January 1st 2014, to enhance healthcare access
for citizens, to guarantee Universal Health Coverage (UHC) for everyone and
protect them from financial risks while providing necessary healthcare services
(1). The JKN system provides public healthcare cost coverage for the
whole community, which is funded by the Sosial Health Insurance Administation (BPJS)
(2). BPJS ensures sufficient funding
for all participants healthcare expenses through strategic health purchasing (2, 3). With the criteria being
medication that is needed according to the epidemiology of diseases in
Indonesia and proven to be cost-effective (2, 3, 4, 5). Medication is an essential component of the healthcare
system as it accounts for a significant portion of healthcare funding,
specifically 40%. (6, 7). The government plans to provide
top-quality healthcare services by introducing all-encompassing healthcare
policies, including pharmaceutical policies (8).
JKN implementation led to a significant reduction of up to 79.6%
in drug costs, and three essential drug categories (antineoplastics,
antibiotics, and hyperglycaemia drugs) observed a price drop of 3.9%, 3.2%, and
2.6% for both generic and brand-name medications (3). The cost of producing drugs is unpredictable and has been
increasing each year due to the expense of materials and production (2). Antibiotics are crucial in
treating infectious diseases such as bacterial infections and pneumonia. Pneumonia
is a concern in several countries, especially Indonesia where infectious
diseases are among the top 10 main causes of death (1, 2), Antibiotics are widely used in
Indonesia, where a high number of hospitalized patients (988 out of 100,000)
suffer from pneumonia. Additionally, pneumonia has a high mortality rate among
adults in Indonesia, reaching 11.3% and ranking among the highest in Southeast
Asia (). The prevalence
rate of pneumonia diagnosed by health workers has increased by 2% from 1.8% in
2013, according to the Indonesian Basic Health Research (Riskesdas) 2018 data () and pneumonia was one of the top ten most expensive conditions seen
during inpatient hospitalizations. In 2013, pneumonia had an aggregate cost of
nearly $9.5 billion for 960,000 hospital stays ().
Declarations
Acknowledgment
We would like to thank the hospital, the Faculty of Pharmacy Universitas Pancasila, and BRIN to provide us the samples and laboratory facility.
Conflict of Interest
The authors declare no conflicting interest.
Data Availability
The unpublished data is available upon request to the corresponding author.
Ethics Statement
The study design was approved by the ethics committee of Faculty of Public Health, Universitas Indonesia, with approval letter number of Ket-102/UN2.F10.D11/PPM.00.02/2022.
The use of low-quality antibiotics has been practiced in some
countries but is still underrepresented, particularly in middle-income
countries (LMICs) (11). This study aims to determine the quality of two antibiotic drugs
based on highest utilization (DU 90%) in pneumonia patients at two hospitals A
and B. Hospital A is a public hospital and hospital B is a private hospital.
This hospital is a referral hospital for BPJS patients. Branded drugs,
typically more expensive, will also be considered as a comparator, whether the
price reduction through the JKN program does not result in a reduction in the
product's quality. Based on previous research, the brand is more cost-effective
and shortens hospital stays (13). The parameters for testing the tablet and injection formulations
will be based on the Indonesian Pharmacopoeia VI edition (FI VI). The assessment
of microba potency is based on parameters set by the Clinical Laboratory
Standard Institute (CLSI) (14).
Material and Methods
Study Setting
This study was conducted in pharmacies
located in hospital A and B Jakarta, Indonesia with two Drug Utilization (DU)
90% the two most use. In each hospital These antibiotics were from hospital A
ceftriaxone and levofloxacin 500 mg parenteral use, from hospital B ceftriaxone
and azithromycin 500 mg peroral use. Azithromycin was in the form of tablet
(one stripe contains 3 tablets). Ceftriaxone was in the form of vials.
Levofloxacin was in the form of infuse bottle, the three different types of
antibiotics, will be compared with branded antibiotics namely were
azithromycin, levofloxacin, ceftriaxone. Antibiotics are selected based on the
highest use in each hospital for treatment pneumonia patients.
Materials
The materials used were phosphate buffer pH
6.0 (Merck KGaA,
Darmstadt, Germany), hydrochloric acid 0.1 N (Merck KGaA, Darmstadt, Germany), Streptococcus pneumonia ATCC gram 10015 as test bacteria Gram-positive, and Klebsiella
pneumonia from human
as test bacteria Gram-negative (14). Samples were obtained from hospital A for parenteral antibiotics
ceftriaxone and azithromycin 500 mg tablets as well as from hospital B for injectable
ceftriaxone and levofloxacin 500 mg parenterally. As a comparison, branded
antibiotics are used with as reference standard (BPFI) was used for
each antibiotic. The tests were conducted at the Faculty of Pharmacy, Pancasila
University (FFUP) and the National Research and Innovation Agency (BRIN).
Quality Testing for Antibiotic Tablets and Injections
The sample quality involved dissolution testing, determination of content,
and examination of dosage uniformity, encompassing examination of weight
uniformity employing 20 tablets (15). The content determination method specified in the relevant
antibiotic monographs was used for testing content uniformity (15). The results of the weight uniformity test are used to calculate
the relative standard deviation (RSD) of the drug content in the preparation.
The dissolution test was carried out according to the procedure specified in the relevant
monograph of each formulation (15).
Potency-test Antibiotics
The test intended to compare antibacterial
activity was performed using the Disc-Cylinder Method. In the testing, for each
sterile petri dish, the medium was poured Mueller Hinton Agar (MHA) with sheep
blood (5% v/v), inoculum colony suspension 5 mL bacterumi Streptococcus
pneumonia and Klabsiella pneumonia, equivalent to 0,5 McFarland
standard, prepared using colonies from an overnight (18 to 20 hours) sheep
blood agar plate. Incubation 350
200C. the disc diffusion
method that uses a standard antibiotic solution and samples with a certain
concentration or dilution. This method involves adding 5 μL
of these solutions to each petri dish which then undergo incubation at a
temperature of 35-37ºC for a duration of 20-24 hours (14).
Antibiotics Disc Preparation
To prepare antibiotic disc we followed the
procedure suggested by Clinical Laboratory Standard Institute (CLSI) (14). Discs with 6 mm diameter were prepared by punching a sheet of
Whatman Number 3 filter paper using a perforator. To obtain 30 μg
of ceftriaxone, 1000 mg of injectable ceftriaxone was dissolved in 166.7 ml of
distilled water and 5 μL of dissolved stock antibiotic was impregnated onto the 6 mm sized
disc. To obtain 15 μg of azithromycin, 500 mg of azithromycin tablet was dissolved in a
166.7 ml of 95% ethanol with a broth media and 5 μL of
dissolved stock antibiotic was impregnated onto the 6 mm sized disc. To obtain
5 μg of levofloxacin 500 mg of infus ceftriaxone was dissolved in 166.7
ml of ½ volume of water, then 0,1 mol/L NaOH dropwise to dissolve onto the 6 mm
sized disc (14).
Antimicrobial Susceptibility Testing
The antimicrobial susceptibility testing
was performed following the Kirby-Bauer disc diffusion method as described in
the CLSI. Briefly, the reference strains (S.pneumonia and K.pneumonia)
were sub-cultured onto blood agar and incubated at 37˚C overnight. Using a
sterile wire loop, 3–5 pure colonies were emulsified in 5 mL of normal saline
until the turbidity matches 0.5 McFarland standard. Using a sterile dry cotton
swab, bacterial suspensions were uniformly inoculated onto the entire surface
of Muller Hinton agar (MHA). Antibiotic disks were placed on the surface of MHA
and incubated aerobically at 37˚C for 16–18 hours. The diameter of the zone of
inhibition was measured using a ruler; isolates were classified as potent
(pass) or not potent (fail) based on the CLSI cut-point (14). All experiments were conducted in triplicates and the means were
recorded to determine the potency of antibiotics.
Data Analysis
Data analysis was conducted descriptive,
including compared with FI-VI requirements for uniformity of tablet weights,
tablet dissolution and content of drug. Antibiotic inhibitory zone test using CLSI of
inhibition Azithromycin: It is considered as ‘pass’ if the diameter of the zone
of inhibition falls within or greater than the susceptibility range of 13-28
mm. Ceftriaxone: It is considered as ‘pass’ if the diameter of the zone of
inhibition falls within or greater than the susceptibility range of 19-24 mm.
Levofloxacin: It is considered as ‘pass’
if the diameter of the zone of inhibition falls within or greater than the
susceptibility range of 16-21 mm (14).
Ethical Clearance Approval
Through letter number Ket-102/UN2. F10.
D11/PPM.00.02/2022. the Faculty of Public Health, Universitas Indonesia, Health
Research Ethics Committee has granted permission (ethical clearance) for this
study.
Result
Quality of Antibiotics
Table 1 presents the results of analyzing
three antibiotics, specifically ceftriaxone and levofloxacin in injection
form, and azithromycin in tablet form. The research shows that the lowest percentage of
active ingredients is present in the generic drug azithromycin 500 mg
tablet from hospital B 90.05%, ceftriaxone from hospital A 91.74%, and levofloxacin from
hospital B 105.34%. However, all the active ingredient percentages confirm to the
minimum standard established by FI-VI which is 90.0%.
Table 1. Quality and potency of some antibiotic preparations.
Antibiotics
Content [RSD]
Dissolution
S. pneumonia
K. pneumonia
Injection ceftriaxone
INN DU 90% Hospital A
91.74
NA
90.00%
105.48%
INN DU 90% Hospital B
92.3
NA
90.07%
73.05%
Branded drug
101.55
NA
97.66%
102.01%
Tablet azithromycin
INN DU 90% Hospital A
90.05 [0.93]
94.41
70.38%
98.62%
Branded drug
91.13[0.92]
98.95
75.31%
109.49%
Infusion levofloxacin
INN DU 90% Hospital B
105.34
NA
91.77%
105.48%
Branded drug
107.41
NA
100.07%
110.31%
Description: NA: Not available, DU 90%:
Drug Utilization 90%, INN: International Nonpropietary Name, RSD: Relative Standard
Deviation.
Potency of Antibiotics
Table 2 shows the average zone of
antibiotic inhibition. In tests with S. pneumonia the results all
antibiotics were included in the sensitive range with azithromycin from
hospital A and branded azithromycin inhibition diameter ≥ 18 mm, levofloxacin from hospital B and branded levofloxacin
inhibition diameter ≥ 17 mm and
ceftriaxone all samples from hospital A, B and branded inhibition diameter ≥ 24 mm. Sensitivity is a condition in which microorganisms are
highly susceptible to antibiotics. Intermediate is a condition where there is a
change from a sensitive state to a resistant state, but not complete
resistance. Resistance is a condition in which microbes have become sensitised
or resistant to antibiotics (14).
Table 2. Inhibitory diameter of several antibiotic preparations.
Bacteria
Antibiotics
Mean ZI (mm±SD)
Zone diameter (mm)
S.pneumonia
Azithromycin Hospital Aa
28.97±0.09
S = ≥ 18
I = 14-17
R = ≤ 13
Azithromycin brandeda
36.26±0.22
Levofloxacin Hospital Bb
28.79±0.03
S = ≥ 17
I = 14-16
R = ≤ 13
Levofloxacin brandedb
31.40±0.16
Ceftriaxone Hospital A
39.11±0.09
S = ≥ 24
Ceftriaxone Hospital B
39.14±0.12
Ceftriaxone Branded
42.44±0.06
K.pneumonia
Azithromycin Hospital Aa
14.27±0.09
S = ≥ 13
R = ≤ 12
Azithromycin brandeda
15.85±0.05
Levofloxacin Hospital Bb
29.50±0.03
S = ≥ 21
I = 17-20
R = ≤ 16
Levofloxacin brandedb
30.64±0.03
Ceftriaxone Hospital A
12.76±0.04
S = ≥ 23
I = 20-22
R = ≤ 19
Ceftriaxone Hospital B
8.84±0.08
Ceftriaxone Branded
12.34±0.02
Description: S = Sensitive; I =
Intermediate; R = Resistance; a = tablet form; b = infuse
form.
Discussion
The
antibiotic tablets and injections from branded and INN obtained from hospitals
A and B met the FI-VI requirements for active drug ingredient content, weight
uniformity, and dissolution (Table 1). The azithromycin
500 mg tablets INN, even with the lowest active component level of 90.05%, nevertheless
satisfied the standards. Considering the RSD of 0.93, the azithromycin level in
the sample remained higher than the minimal requirement set by FI-VI, which is
applicable to all types of samples under study. The quality test
findings for tablet and parenteral antibiotic formulations met the expected
standards. Nevertheless, branded medications exhibited a propensity for
containing elevated concentrations of active pharmaceutical components. It is
crucial to acknowledge that these branded samples are manufactured by
pharmaceutical corporations and are pricier compared to products acquired from
hospitals. For example, the content of the branded antibiotic ceftriaxone
(101.55) is higher than samples taken from hospitals A (91.74) and B (92.3).
However, this is still within FI-VI requirements.
Research
conducted in various low- and middle-income countries in Asia and Africa has
revealed that counterfeit and substandard medicines are frequently discovered
in inexpensive medicines obtained from informal outlets currently there is
still lack of research in LMICs (16). These outlets include licensed
drug shops that are not legally authorized to sell ethical medicines. The drug
studied in this research was an officially licensed medication obtained from a
hospital. However, the price was considered to be cheap and well below the
regular price, even in the formal pharmaceutical industry, where it was
considered to be below the cost of production when it won an e-catalogue
auction (2). As an example the most expensive
injection was obtained from hospital B with IDR 11,663 per-vial, and from
hospital A with IDR 4,141 per-vial. The price difference was IDR 305,000
per-vial when compared to branded drug ceftriaxone. This price difference was
influenced by different profit margins between hospitals.
These
quality metrics are crucial for the maintenance of a pharmaceutical industry's
production license. Nevertheless, the quality of the final pharmaceutical
products may not precisely indicate the quality of the active medicinal
substances employed. The product's pricing can exert an influence on this. To
save costs, cheaper products often use lower quality ingredients, particularly
in the active medicinal ingredients and primary packaging (13, 17). In this
study, the INN disparity was lower than the generic brands.
The drugs available in e-catalog auctions are
typically simple formulations with low technological complexity. The availability of these
medications at affordable pricing is a result of fierce market rivalry. These
goods consist of active pharmaceutical components that have expired patents and
are accessible in the form of tablets, caplets, capsules, or other simple
preparations. The rivalry for such drugs is fierce, as all pharmaceutical
companies in Indonesia, including lesser-known small-scale organizations,
possess the capability to manufacture them. The pharmaceuticals can be
manufactured utilizing easily accessible raw ingredients sourced from several
locations, including India and China (17).
Chinese
insiders in the raw material pharmaceutical industry admit that quality
standards in their country, including those for exported products, are not
particularly strict. The quality of raw material pharmaceutical products
received by clients depends on demand and the bargaining power of the
pharmaceutical industry clients in question (13). The quality of the active
pharmaceutical ingredients used can affect both the effectiveness and safety of
the formulation. Antibiotic formulations can be evaluated for effectiveness by
analyzing their antibacterial activity and for safety by assessing their
impurity levels.
The study
assessed the effectiveness of broad-spectrum antibiotics in tablet and
injection form against both Gram-positive and Gram-negative bacteria. Hospital
B's cefriaxone antibiotic showed 73.05% potency against K. pneumoniae,
which was 28.96 percentage points lower than the branded sample, but is still
accepted. In the antibiotic sample ceftriaxone from Hospital A, however, the
potency against K. pneumoniae was 105.48%, a relative difference in
potency of 3.28% higher than the branded preparations. Hospital A's
azithromycin tablet had a potency of 98.62%, which is 10.87 percentage points
lower than the branded preparation. Similarly, hospital B's levofloxacin had a
potency of 105.48%, which is 4.83 percentage points lower than the branded
preparation.
The
efficacy of ceftriaxone injection preparations against S. pneumoniae
bacteria was 90% at hospital A and 90.07% at hospital B. The relative
difference in potency between the brand name ceftriaxone products was 8.51%
(7.66/90 x 100%) for hospital A and 8.42% (7.59/90.07 x 100%) for hospital B.
The potency of azithromycin 500 mg tablets from hospital A against S.
pneumoniae bacteria was 70.38%, 4.93 percentage points lower than the brand
name product, resulting in a relative difference in potency of 7.00%. The
hospital B's parenteral levofloxacin was found to have a potency of 91.77%
against S. pneumoniae bacteria, which is 8.3 percentage points lower than the
branded preparation. The relative difference in potency was calculated to be
9.04% (8.3/91.77 x 100%).
The
efficiency of antibiotics can vary significantly between oral and parenteral
forms, with variances occasionally reaching up to two decimal places.
Administering generic and branded versions of antibiotics to patients can lead
to measurable differences in effectiveness, despite statistical analysis
indicating no significant variations in inhibitory zones using Chi Square (p>0.05).
A study conducted on typhoid patients at a private hospital in Depok
demonstrated this. Patients who received the award-winning ceftriaxone
injection preparation as part of JKN had a longer average length of stay (LoS)
of 5.33 days compared to the independent group who were treated with branded
ceftriaxone from a well-established manufacturer (LoS: 4.96 days). Similarly,
patients who were part of JKN and received the e-catalog winning brand of
cefotaxime required an average length of stay (LoS) of 5.32 days, which was
longer than the independent group receiving branded cefotaxime from a renowned
manufacturer (LoS 5.04 days) (13).
The
difference in average LoS, which ranges from 0.28 to 0.37 days, may seem small.
However, with only 100 patients, the impact on bed utilization cannot be ignored:
28-37 person-days, or 28-37 times the room fee per patient in rupiah. If the
study shows that using e-Catalogue medicine is more effective, it is because
the cost of branded injectable antibiotics supplied to independent patients is
30 times higher than the cost of comparable e-catalogue drugs used by JKN
patients (13).
Table 2
shows the diameter of antibiotic inhibition against S. pneumonia and K.
pneumonia bacteria. All samples were sensitive except for ceftriaxone on K.
pneumonia, with an inhibition diameter of ≤ 19 (14). This is consistent with previous
research, the prevalence of K. pneumonia infection varies by country:
13% in the United States, 5% in Pakistan, 64.2% in Nigeria, 33.9% in India,
17.4% in Denmark, and 14.1% in Singapore (18). ESBL-producing
Klebsiella pneumonia infections accounted for 52% of Enterobacteriaceae
infections at Saiful Anwar Hospital Malang in Indonesia (19). The majority of Klebsiella
pneumonia isolates were obtained from respiratory specimens. This is
because Klebsiella pneumonia is a common bacterium that can cause respiratory
tract infections, such as pneumonia, sinusitis, or otitis (20). Klebsiella pneumoniae is
one of the nine bacteria of concern for antibiotic resistance, Klebsiella sp.
is an important extended spectrum β-lactamase (ESBL) producing pathogen associated
with the increasing incidence of antibiotic resistance, in the context of the
increase in the incidence of antibiotic resistance in hospitals (21).
Therefore,
given that only a limited number of pharmaceutical companies are capable of
producing parenteral formulations - about 20 out of 220 pharmaceutical
factories in Indonesia - market competition for formulations with a relatively
high technological content is likely to be less intense than market competition
for capsule/tablet/capsule formulations. Therefore, the price of the
e-catalogue for the injectable drugs ceftriaxone or cefotaxime will not be too
low and should provide a reasonable profit margin, even though it is far below
the regular price of similar drugs. If a drug product is sold at a price lower
than the cost of manufacturing, it is possible that the product's efficacy is
also lower than that of similar products sold at regular or reasonable prices.
This is especially true if there is a difference in efficacy, as indicated by
the difference in length of stay (LoS). Therefore, it is important to consider
both the price and efficacy when evaluating the quality of a drug product.
Moreover, research has found that there is a large discrepancy between the
average antibiotic potency of e-catalogue winning products which are generally
the cheapest and similar branded products which are generally much more
expensive (22).
Monitoring
is necessary due to the possibility of lower antibacterial activity and
significant disparities in more affordable antibiotic preparations.
Cost-effective preparations are often preferred in primary healthcare
facilities (puskesmas and clinics receiving capitation payments) and referral
healthcare facilities (hospitals compensated based on Ina-CBGs rates) in
anticipation of the upcoming JKN payment system. This has resulted in their
widespread use across the nation (13, 23).
Research
conducted in various countries has shown that a high level of antimicrobial
usage (AMU) is a risk factor for antimicrobial resistance (AMR) (22). Frequently,
the medicines that are commonly utilized are closely linked to difficulties of
antimicrobial resistance (AMR). Furthermore, the substandard drug formulation,
specifically insufficient amounts of active drug components, poses an
additional risk for antimicrobial resistance. (22,24–26).
Low
quantities of active medication components can reduce the effectiveness of
antibiotics, increasing the risk of antimicrobial resistance (AMR), treatment
failure, and unpleasant side effects (24). Other factors, such as
insufficient bioavailability/bioequivalence (BA/BE) and poor antimicrobial
activity, can also contribute to AMR, treatment failure, and unpleasant side
effects (25). These health-related costs will
result in significant socioeconomic losses, including reduced community
productivity (27).
Conclusion
All antibiotic tablets and injections tested met the requirements of the Indonesian Pharmacopoeia 6th Edition active ingredient content, uniformity of dosage weight and dissolution. However, it is important to consider several factors when determining antibacterial activity. Cheaper antibiotic samples generally have weaker antibacterial activity, as indicated by lower antibiotic potency, against both Gram-positive and Gram-negative bacteria. The inhibitory potency of the cheapest antibiotic samples originated from hospitals are the lowest. Branded drug preparations, the most expensive antibiotic samples, have the highest antibiotic potential. The antimicrobial activity showed all government-subsidized ceftriaxone samples resistant to K.pneumonia.
Several pharmaceutical companies have long complained that the price of medicines that win the e-catalogue tender is too low, in some cases even below the cost of production. However, it should not be a concern that only pharmaceutical products with regulation of Indonesian food and drug (BPOM) distribution licenses are eligible for the price tender, as they are of good quality. This study aims to determine the quality and potency of three antibiotic drugs based on their highest utilization (DU 90%) in pneumonia patients at two hospitals, A (ceftriaxone, azithromycin tablet) and B (ceftriaxone, levofloxacin infusion) compared to brand name. The quality of the samples was evaluated following the Indonesian Pharmacopoeia 6th Edition (FI-VI). Antibiotic potency was assessed using the Plate-Cylinder Method with K. pneumonia from human and S. pneumonia ATCC 10015 as the test bacteria evaluated following CLSI. All samples meet the criteria of FI-VI antibiotic content, weight uniformity, dissolution. Antibiotic potency all samples test S.pneumonia and K.pneumonia were sensitive but ceftriaxone test with K.pneumonia was resistance. All antibiotic tablets and injections studied met the requirements of the Indonesian Pharmacopoeia Edition 6 for active medicinal ingredient content, dosage weight uniformity, and dissolution. All drugs from hospitals (INN) have lower antibiotic potency than branded drugs. This highlight the importance of conducting microbiological testing on antibiotic preparations.
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