University of Groningen
Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic treatments
Purba, Abdul
DOI:
10.33612/diss.128518764
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Publication date: 2020
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Purba, A. (2020). Pharmacoeconomics of prophylactic, empirical, and diagnostic-based antibiotic
treatments: Focus on surgical site infection and hospitalized community-acquired pneumonia. University of Groningen. https://doi.org/10.33612/diss.128518764
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CHAPTER 1
General introduction
14
INTRODUCTION
Surgical site infection (SSI) and hospitalized community-acquired pneumonia (CAP) reflect two infectious conditions caused by bacterial infections. The focal infections underlying SSI and hospitalized CAP can develop into further advanced complications with manifestations of systemic infection symptoms such as sepsis, with pathogens spreading into the blood circulation and organs. Specific situations require antibiotics for prophylactic and/or empirical treatments. Potentially, sometimes antibiotics are being used improperly and ineffectively, leading to further impacts such as antimicrobial resistance (AMR) with a related burden in terms of morbidity, mortality, and cost, especially in developing countries.1,2 Diagnostic-based antibiotic treatments
are the potential solution to reduce such unguided antibiotic treatments. Ergo, there is a need for careful analysis of infections, its treatment and AMR, both in the developed world like The Netherlands as well as in the developing world like in Indonesia. This thesis aims to address this issue in both settings, with a focus on pharmacoeconomic aspects.
Among limited-resource countries, Indonesia has a documented low application of pharmacoeconomics in infectious disease treatments.3,4 Such assessment is needed to provide
adequate evidence and contribute to Indonesian national government policy strategies, with the pharmacoeconomics approach being used to evaluate the treatment and diagnostic bundles within a restricted budget setting. In addition to pharmacoeconomics assessments of infection treatments, medical microbiology evaluations are essential in order to develop strategies to prevent increased antibiotic resistance by identifying the specific characteristics of the underlying pathogens causing the infections. In this thesis, we illustrate this approach with data, figures analyses for SSI and hospitalized CAP.
The surgical site is a potential port of entry for exogenous organisms: these pose an immediate threat to the body, and infections cause prolonged wound healing.5,6 SSI is the most common
focal infection related to surgery and an important target for infectious disease prevention.6,7
In low and middle-income countries, SSI rates in 100 surgical patients doubled from 5.6 to 11.8 between 1995 and 2008.8 Antiseptic and prophylactic antibiotics used properly in the preoperative
phase should be considered to prevent SSI. Parenteral and oral antibiotic prophylaxis based on the patterns of bacteria and antibiotic susceptibility has been recommended recently to reduce SSI rates efficiently.5 The most crucial goal in the preoperative preparation period is to reduce
the bacterial load surrounding the incision area.9,10 Various modalities have been implemented,
ranging from the prevention of SSI using a prophylactic antibiotic before surgical incision and in the postoperative period.10–12 The World Health Organization (WHO) has released guidelines on
preventing SSI by assessing prophylactic antibiotics in three consecutive periods: preoperative, intraoperative and postoperative. Broad utilization of prophylactic antibiotics, however, comes with the potential danger of improper use and leads to repercussions such as readmission and additional cost. Economic analysis of prophylactic antibiotic use can help in guiding adequate SSI prevention. Given its resource-limited setting, Indonesia has employed the limited bundle for SSI prevention adopting four out of the 21 WHO measures (Figure 1.1).10,13 As yet, there has been no
integrated efficacy and cost assessment of antibiotic prophylaxis for SSI prevention in Indonesia.
Figure 1.1 The measures for preoperative, intraoperative, and postoperative care to prevent surgical
site infections.10
Note: *These four measures have been considered in Indonesia for SSI prevention.13
Hospitalized CAP is a non-surgical-related infectious disease, contributing high morbidity in terms of more hospitalizations for ICU admissions, requiring mechanical ventilators and further sepsis complication.14–16 Elevated hospitalization costs for ICU patients with CAP were strongly associated
with the use of a mechanical ventilator, the presence of severe sepsis and sepsis shock.17 According
to information from the Centers for Disease Control and Prevention (CDC) in Indonesia, lower respiratory tract infections (LRTIs) reflected the most common cause of death among infectious disease cases.18 Among LRTIs in Indonesia, CAP has been reported with an incidence rate of 4%
in 2018.19,20 CAP can pose challenges in treatment and primary healthcare providers, especially in
a limited-resource setting such as Indonesia, frequently refer moderate and severe CAP cases to hospitals that have more comprehensive facilities. Hospitalization is often required for cases with underlying bacterial infections and to need at least one empirical antibiotic.21–25
16
Table 1.1 Microorganisms causing hospitalized community-acquired pneumonia in Indonesia, based
on a local survey between 1989 and 2001 in Surabaya, Medan, and Makasar26
Microorganisms n % Klebsiella pneumoniae 85 21.5% Streptococcus pneumoniae 51 12.9% Staphylococcus aureus 39 9.8% Streptococcus β haemolyticus 35 8.8% Staphylococcus epidermidis 27 6.8% Streptococcus viridans 25 6.3% Streptococcus pyogenes 21 5.3% Enterobacter aerogenous 19 4.8% Proteus vulgaris 18 4.5% Pseudomonas aeruginosa 15 3.8% Candida albican 12 3.0%
Streptococcus gamma haemolyticus 7 1.8%
Klebsiella oxytoca 7 1.8% Escherichia coli 7 1.8% Staphylococcus albus 7 1.8% Klebsiella ozainae 6 1.5% Proteus mirabillis 6 1.5% Enterobacter agglomerans 3 0.8% Peptostreptococcus spp. 2 0.5% Streptococcus faecalis 2 0.5% Candida parapsilosis 2 0.5%
Note: Adapted from Indonesian Society of Respirology, Guideline for diagnosis and management of community-acquired
pneumonia in Indonesia [Perhimpunan Dokter Paru Indonesia. Pneumonia Komuniti: pedoman diagnosis dan penatalaksanaan di Indonesia]. 2003. Available from https://www.klikpdpi.com/
With the increasing problem of AMR, guidelines for antibiotic use are needed. Underlying such guidelines should be updated antimicrobial resistance data and data on treatment efficacy, for example, supporting new national guidelines on the empirical use of antibiotics can be put forward. Table 1.1 shows the underlying pathogens causing hospitalized CAP in three big cities in Indonesia. The current Indonesian guidelines on hospitalized CAP treatment have been developed in 2003, following the American Thoracic Society (ATS) guidelines.23,25 These
guidelines, however, were based on studies conducted in 1991-2001 in high-income countries where Streptococcus pneumoniae and some Gram-positive bacteria were the most dominant pathogens causing CAP.27 The guidelines, therefore, recommend selecting antibiotics that are
particularly effective to Gram-positive bacteria.23 In contrast, among the pathogens causing
CAP in Indonesia, Gram-negative bacteria are considered to be the most common underlying
pathogen.28,29 Indiscriminate use of antimicrobials as a result of unrepresentative guidelines, not
guided by local/national microbiological evidence, generally results in the increasing emergence of antimicrobial resistance, both in individual patients and at the community level.
SCOPE OF THE THESIS
The main focus of this thesis is to assess pharmacoeconomic aspects in the management of bacterial infections; applied to illustrative cases, namely, SSI and hospitalized CAP. Chapter 2 presents a discussion of the burden of two conditions concerning sepsis related to various focal infections. This chapter also puts forward a proposed national unit price taking into account the cost of focal infections with sepsis with universal health coverage now being introduced in Indonesia. Focusing on the use of prophylactic antibiotics for SSI prevention, Chapter 3 reviews the methodologies used in published economic evaluations on prophylactic antibiotics in SSI prevention. The review also includes a comprehensive discussion of the local epidemiology of pathogen-causing SSIs. In addition, Chapter 4 discusses the impact of surgical site infections on readmissions and costs in an academic hospital in the Netherlands. This potentially provides a prospective model for developing a health policy on implementation strategies to tackle SSI cases in Indonesia as the Dutch model may be conceived as being successful. For example, the European Centre for Disease Prevention and Control’s point prevalence surveys in 2016 and 2017 documented that the Netherlands successfully decreased SSI incidence from 2.2 to 1.0 per 100 surgeries.30,31 Focusing on the use of empirical antibiotics versus diagnostic-based antibiotic
treatment, Chapter 5 outlines the clinical epidemiology of multidrug-resistant infections among hospitalized adults with CAP in an Indonesian tertiary referral hospital. Chapter 6 analyzes the cost-effectiveness of culture-based versus empirical antibiotic treatment for hospitalized adults with CAP in Indonesia, based on a real-world patient database study. Finally, Chapter 7 discusses the main findings presented in the previous chapters and makes several recommendations, particularly for institutions or policymakers who are currently facing uncertainty about bundling SSI and hospitalized CAP sepsis in healthcare management due to the excessive cost in a limited-resource setting. As an Annex to Chapter 7 additional clinical evidence on laboratory biomarkers as independent factors to sepsis mortality is presented in Chapter 8.
18
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