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    Infect Chemother. 2023 Mar;55(1):80-89. English.
    Published online Feb 23, 2023.
    https://doi.org/10.3947/ic.2022.0084
    Copyright © 2023 by The Korean Society of Infectious Diseases, Korean Society for Antimicrobial Therapy, and The Korean Society for AIDS
    Original Article

    Evaluation of the Use of Antimicrobial Therapy for Treating Diabetic Foot Infections in an Indonesia Referral Hospital: A Retrospective Cohort Study

    Memy Aviatin,1 Rani Sauriasari,1,* Em Yunir,2,* and Hindun Wilda Risni1
      • 1Faculty of Pharmacy, Universitas Indonesia, Depok, Indonesia.
      • 2Division of Endocrinology, Department of Internal Medicine Dr. Cipto Mangunkusumo National Referral Hospital, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.
    • Corresponding Author: Rani Sauriasari, BPharm, MMedSci, PhD. Faculty of Pharmacy, Universitas Indonesia, Building A, 3rd Floor, Kampus Baru UI Depok, 16424, West Java Province, Indonesia. Tel: +62-1-727-0031, Fax: +62-1-786-3433, Email: rani@farmasi.ui.ac.id
      Corresponding Author: Em Yunir, MD, PhD. Division of Endocrinology, Metabolism, and Diabetes, Department of Internal Medicine, Dr. Cipto Mangunkusumo National General Hospital, Faculty of Medicine Universitas Indonesia, Jakarta 10430, Indonesia. Tel: +62-21-390-7703, Email: e.yunir@ui.ac.id

      *These authors are contributed equally to this work.
    Received June 11, 2022; Accepted December 26, 2022.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    Background

    Diabetic foot infection (DFI) is a common complication of hyperglycemia and is related to prolongation of hospitalization, mortality, high hospitalization costs and decreased quality of life. Antibiotic therapy is one of the most critical factors in the eradication of infection. This study aims to determine the appropriateness of antibiotic use based on the local and international clinical guidelines and its short-term effect on patients’ clinical improvement.

    Materials and Methods

    This retrospective cohort study was conducted using secondary data from DFI inpatients from 1 January 2018 to 31 May 2020, from Dr. Cipto Mangunkusumo Hospital (RSCM), the National Referral Hospital of Indonesia. The Gyssens algorithm was used to help assess the appropriateness of antibiotics. All subjects were type 2 Diabetes Mellitus (T2DM) adult patients diagnosed with DFI. The primary outcome was a clinical improvement of infection after 7 - 14 days of antibiotic use. The clinical improvement of infection was defined by a minimum of three of these criteria: reduced or no purulent secretions, no fever, the area around the wound did not feel warm, no or reduced local oedema, no local pain, reduced redness or erythema, and decreased leukocytes count.

    Results

    A total of 113 (63.5%) eligible subjects from a total of 178 were recruited. Among the patients, 51.4% had a duration of T2DM for ≥10 years, 60.2% had uncontrolled hyperglycemia, 94.7% had a history of complications, 22.1% had a history of amputation, and 72.6% had ulcer grade ≥3. Based on the Gyssens algorithm, 54.0% of the subjects were given antibiotics appropriately, while the other 46.0% were not. The proportion of improved patients in the appropriate antibiotics group was higher but not statistically significant than those in the inappropriate group (60.7% vs. 42.3%, P = 0.079). However, the results of the multivariate analysis demonstrated that the appropriate use of antibiotics would increase clinical improvement by 2.6 times, compared to inappropriate use after controlling for the covariates (adjusted odds ratio: 2.616, 95% confidence interval: 1.117 - 6.126, P = 0.027).

    Conclusion

    Only half of the patients with DFI received appropriate antibiotics, although an appropriate antibiotics usage was independently associated with better short-term clinical improvement in DFI. This suggests that we should effort to improve appropriateness in antibiotics usage in DFI.

    Graphical Abstract

    Keywords
    Antibiotics; Clinical improvement; Diabetic foot; Infection

    Introduction

    Diabetes mellitus (DM) has become a global problem, with its incidence and prevalence increasing every year [1]. In Indonesia, primary health research data (Riskesdas) 2018 indicated an 11.0% increase in the prevalence of DM, with the highest prevalence in urban areas [2]. Hyperglycemia in uncontrolled and long-term DM will increase the risk of diabetic foot infection (DFI) that often worsen and require hospitalization while also increasing morbidity, mortality, disability and health costs, and reducing patients’ quality of life [3–5].

    Comprehensive DFI management should be carried out as soon as possible. Essential components of its management include metabolic and vascular control, wound care and infection control, and pressure control. The main principles of the successful treatment of DFI are accurate early detection of the signs and clinical manifestations and the correct selection of antibiotic therapy [6]. The main objective when giving antibiotics for DFI is to eradicate and prevent the worsening of the infection, not to heal wounds or prevent infection . For appropriate use, antibiotic is not recommended if there are no clinical manifestations of infection. Although studies have yet to identify the most effective and superior antibiotics therapy for DFI management due to limited research on the subject [7, 8], guidelines have recommended antibiotic options for certain conditions [6, 9]. The selection of antibiotics recommended by guidelines should be based on the antimicrobial susceptibility test results of the causative pathogen and the severity of the illness [6, 10].

    A review that conducted pooled estimation in Indonesia based on the Gyssens method showed that only 33.5% of prescriptions in hospitals were appropriate [11]. Inappropriate use of antibiotics would result in poor treatment outcomes and increased antibiotic resistance [12, 13]. The guideline of the Infectious Diseases Society of America - The International Working Group on the Diabetic Foot (IDSA-IWGDF) recommends that clinicians treat a person with DFI with an antibiotic agent that has been shown to be effective in clinical trials and is appropriate for the individual patient [6]. In Indonesia, published studies about infection control with appropriate antibiotics in DFI patients are still limited. Considering the limited data on the appropriate antibiotic therapy and its clinical impact among DFI patients in Indonesia, we investigated the current status of the appropriate antibiotic use and its association with short-term clinical improvement in a national Indonesian referral hospital.

    Materials and Methods

    1. Study design and subjects

    This is a retrospective cohort study conducted between June and September 2020 at the Dr. Cipto Mangunkusumo Hospital, the National Referral Hospital of Indonesia (RSCM), Jakarta.

    Between January 2018 and May 2020, 379 adult (>18 years old) patients with diabetes and lower extremity ulcers were identified. Of these, 178 were hospitalized and received antibiotics therapy for DFI for more than seven days. After excluding patients who had incomplete medical records of clinical outcomes and antibiotics, limb amputations within 72 hours of antibiotics therapy, and type 1 DM, 113 were finally included in this study (Fig. 1).

    Figure 1
    Study flow.
    DM, diabetes mellitus.

    2. Ethics statement

    It was approved by the Health Research Ethics Committee, Faculty of Medicine, Universitas Indonesia with KET-97/UN2.F1/ETIK/PPM.00.02/2020 dated January 20, 2020. The Ethics Committee waived the requirement for informed consent since there was no direct interventions to the patients and we collected retrospective data from the medical records.

    3. Outcomes and data collection

    Short-term assessment of clinical improvement was performed after the subject had been given antibiotic therapy for 7 - 14 days. The basis for clinical improvement was a doctor’s written statement that confirmed a minimum of three criteria out of these following criteria: reduced or no purulent secretions, no fever (body temperature of 36.0 - 37.2°C), the area around the wound did not feel warm, no or reduced local oedema, no local pain, reduced redness or erythema, and decreased leukocytes count [6, 14, 15, 16, 17]. The antibiotic appropriateness was assessed using the Gyssens flowchart [17].

    Other variables were obtained mostly from physicians’ written statements in the medical records. Age, sex, type 2 diabetes mellitus (T2DM) duration, hemoglobin A1c (HbA1c), smoking history, amputation, and mortality were obtained from clinicians’ assessments and documented in medical records. Underlying medical conditions, such as hypertension, kidney impairment, dyslipidemia, sepsis, anemia, hypoalbuminemia, Peripheral Arterial Disease (PAD), and neuropathy were assessed by physicians from the initial laboratory and radiologic data.

    4. Gyssens algorithm

    Gyssens algorithm is commonly used as a tool to assess the appropriateness of antibiotics use, particularly in Indonesia [10, 17, 18]. This algorithm evaluates antibiotics in terms of indication appropriateness; the presence of alternative, more effective, safer, more affordable, narrower spectrum of antibiotics; and the appropriateness of duration, dose, route and administration time [17]. The appropriateness was assessed based on the local and international guidelines, especially IDSA-IWGDF Guidelines and the 2017 RSCM Antibiotic Use Guidelines (the local guideline used in the research location) for the diagnosis and treatment of DFI [6, 9, 19]. We also considered the culture results (including susceptibility and resistance pattern) which was commonly available 5 days after sampling. We considered it inappropriate if there is a change in antibiotics before 3 days use without any reported culture results or other clinical reasons, since the local guidelines recommend minimum 3 days duration for evaluation based on clinical condition, laboratory, and/or imaging. We evaluated the use of each antibiotics and determined whether it was appropriate (category 0) or not (category I–V). A patient with at least one inappropriate antibiotics use based on the Gyssens algorithm results was included in the ‘inappropriate group’.

    5. Pathogen isolation and antibiotic susceptibility test

    All samples were obtained from the ulcer’s base. An antiseptic procedure was performed by rinsing the ulcer with saline before swabbing. The pathogen identification was done using a standardized microbiology assessment method that took place in RSCM laboratory (International Organization for Standardization 15189). Based on the guideline, the susceptibility test was performed using an automatic method and/or disc diffusion with the results categorized based on Clinical Laboratory Standards Institute (CLSI) [10]. One patient could undergo multiple culture tests and one can have more than one pathogen within one culture.

    6. Data analysis

    Based on the sample calculation formula of hypothesis testing (level sig. 5.0%, power 80.0%, two side test) with an anticipated dropout number of 25%, the minimum sample required was 45 subjects for each group [20]. The data analysis was performed using Statistic Program for Social Science (SPSS) (version 22, SPSS Inc., Chicago, IL, USA). The patients’ characteristics were tested by univariate analysis and the chi-square test was used to test the relationship between the appropriateness of antibiotics and other variables, and clinical improvement. Multivariate logistic regression analysis was performed to control the independent variables and other variables influencing clinical improvement. The variables included in the multivariate analysis were those with a P-value <0.25 in the bivariate analysis and if the variable theoretically or in the guidelines had a significant association with clinical improvement [21].

    RESULTS

    From 178 patients with DFI, only 113 patients met the inclusion and exclusion criteria. The number of male patients (52.2%) was slightly higher than females (47.8%). The average age was 57 years old. The majority (94.7%) of the subjects had a history of complications, including hypertension (75.2%), kidney impairment (57.5%), dyslipidemia (46.9%) and sepsis (8.8%). Fifty-four percent of the subjects were passive smokers. Half of the subjects had a duration of T2DM for more than 10 years, accompanied by uncontrolled blood glycemic levels marked by a high HBA1c level of ≥7.0% in 72.9% of subjects and a high blood glucose level baseline of ≥200 mg/dl in 60.2% of subjects. The nutritional characteristics of the subjects were anemia (85.0%), hypoalbuminemia (97.3%) and overweight (61.1%). Debridement was performed on all subjects during early admission, followed by wound care and observation periodically. The average foot ulcer duration was 20 days with Wagner ulcers grade ≥3 dominant. The number of patients that experienced amputation and died within 7 - 14 days of antibiotics administration was 10.6% and 1.8% respectively. Analysis of the Gyssens algorithm was performed for each antibiotics. Only 54.0% of patients were given appropriate antibiotics, meanwhile, 46.0% were not appropriate. Amputation and death within 7 - 14 days occured in some patients (Table 1).

    Table 1
    Socio-demographic and clinical characteristics in DFI subjects

    There were 233 regimens, with rates of single and combination antibiotic use were 95.3% and 4.7% respectively. The three most commonly used antibiotics were ampicillin-sulbactam, meropenem and levofloxacin. Antibiotic dosage form, frequency of use, and its Gyssens analysis are presented in Supplementary Table 1. The distribution of discrepancies in the use of antibiotics was as follows: 1.7% were in category IVA (presence of a more effective alternative because the antibiotics were not suitable with guidelines), 0.9% in category IIIA (duration too long; antibiotics were given longer despite clinical improvement and therefore need to deescalate), 14.9% in category IIIB (duration too short; the duration was only 2 days), 8.3% in category IIA (incorrect dose; the dose did not align with guidelines) and 9.6% in category IIB (inappropriate interval because kidney function was not considered) (Supplementary Table 2).

    Based on IDSA-IWGDF, our subjects with DFI were mostly severe infection. As much as 61.9% of subjects performed one or more culture tests during 7 - 14 days of treatment. From a total of 107 culture tests, causative pathogens included 75.7% mono-pathogens and 24.3% poly-pathogens. The three most frequent Gram-negative pathogens in moderate and severe infection were Pseudomonas aeruginosa (17.7% and 22.5%), Klebsiella pneumonia (17.7% and 19.7%) and Escherichia coli (12.9% and 16.9%). Meanwhile, the most frequent Gram-positive pathogens were Staphylococcus aureus (12.9% and 4.2%), Enterococcus faecalis (6.5% and 7.0%) and methicillin-resistant Staphylococcus epidermidis (MRSE) (4.8% and 7.0%) (Table 2). The pathogens’ pattern and sensitivity can be seen in Supplementary Table 3 and Table 4.

    Table 2
    Pathogen isolated in DFI subjects based on severity

    Patients’ characteristics and outcomes based on antibiotic appropriateness were shown in Table 3. The primary outcome of this study was a short-term clinical improvement in 7 - 14 days of antibiotics administration. We found that 60.7% of subjects in the appropriate antibiotics group experienced clinical improvement, compared to 42.3% in the inappropriate group (P = 0.079). Within 7 - 14 days, there were 13.1% and 7.7% of patients amputated in the appropriate and inappropriate groups, respectively (P = 0.531). In the same duration, one patient was dead in each group.

    Based on the bivariate analysis, the appropriate use of antibiotics was not significantly associated with clinical improvement (relative risk [RR] = 1.434, 95% confidence interval [CI]: 0.984 - 2.089; odds ratio [OR] = 2.102, 95% CI: 0.990 - 4.463; P = 0.079). However, the multivariate logistic regression analysis revealed that the appropriate use of antibiotics (adjusted odds ratio [aOR]: 2.616; 95% CI: 1.117 – 6.126) and the Wagner degree of DFI (aOR 2.709; 95% CI: 1.031 – 7.119) were the independent predictors of improvement in clinical outcome. Other variables that may influence the clinical improvement were PAD, neuropathy and dyslipidemia (Table 4).

    Table 3
    Clinical characteristic and outcomes between groups

    Table 4
    Multivariate analysis of prognostic factors associated with clinical improvement

    DISCUSSION

    Our main finding is that the appropriate use of antibiotics led to a higher proportion of improved patients compared to inappropriate use. After controlling for covariates, the appropriate use of antibiotics was found to significantly improve the clinical condition of the DFI subjects by 2.6 times compared to the inappropriate use. This finding is important since antibiotic therapy prescribed for DFI is often inappropriate [3, 22–24]. Our result is supported by a study in China showing that the administration of antibiotics according to the data of local antibiotics resistance patterns can improve clinical improvement in DFI cases [25]. The updated IWGDF-IDSA has been recommending that the selection of antibiotics should be based on the results of published randomized controlled trials (RCTs), individualized, and given in appropriate duration [6].

    This study was conducted in a large and national reference hospital. Therefore, the results obtained are helpful as reference material for national policy makers and for RSCM as the main referral hospital in Indonesia. In addition, the results encourage health professionals to regularly evaluate the use of antibiotics in DFI patients. Since it has been shown that clinical improvement is affected by the rational use of antibiotics and this study identified a relatively high number of inappropriate uses, health professionals should be reassured in implementing a good antibiotic stewardship program.

    Inappropriate antibiotic therapy for DFI results in delayed wound healing, progression of wound infection, development of underlying osteomyelitis, amputation, and sometimes fatality. A rise in antibiotics-resistant bacteria is another consequence [6, 14, 26–28]. A study in Ethiopia in 2020 showed that the use of antibiotics that did not follow guidelines led to a 2.5 times greater chance of amputation compared to the use of antibiotics that was in line with guidelines [26]. This finding supports research conducted in the United Kingdom in 2016, which showed a fall in the average level of leg amputations from 70% to 30% after the administration of appropriate antibiotics [27]. Our study showed the proportion of amputated patients was not significantly different between appropriate and inappropriate groups (P = 0.531). However, amputation is a long-term outcome, and not merely due to inappropriate empirical antibiotics. Appropriate empirical antibiotics is only a part of integrated care for people at high risk of amputation. More comprehensive study with bigger sample size and longer follow-up period are needed in further research to see the factors contributed in reducing leg amputations.

    In this research, the most frequent pathogen isolated was P. aeruginosa, which is among the most common pathogens of DFI in Asian countries [29], followed by K. pneumoniae. The most common antibiotics in this study were ampicillin-sulbactam and meropenem. Ampicillin-sulbactam was the most frequently used as it is a beta-lactam antibiotic and beta-lactamase inhibitor that covers Gram-negative, Gram-positive as well as anaerobic bacteria. It is recommended in the guidelines as an empirical antibiotics in mild to severe conditions [6]. Furthermore, IWGDF recommends certain antibiotic options, including meropenem to treat P. aeruginosa empirically. P. aeruginosa is well known to possess high intrinsic and acquired antibiotic resistance. Cases of P. aeruginosa resistance to carbapenem have been increasing [30]; however, we found that the average sensitivity of this pathogen to meropenem in the study location was 51.8% and the average resistance was 18.5%. The causative Gram-positive pathogens in severe DFI cases were S. aureus (8.2%) and E. faecalis (7.0%) with average sensitivity to ampicillin-sulbactam were 90.9% and 55.6% respectively. Enterococcus spp. is a normal flora in human guts which could be disturbed by wide-spectrum and long-duration antibiotics [31]. This may cause the normal gut flora to be replaced by multi-drug resistant pathogens, such as vancomycin-resistant Enterococcus spp. (VRE), carbapenem-resistant Enterobacteriaceae (CRE) and extended-spectrum beta-lactamases-producing Enterobacteriaceae (ESBL-E) [32].

    We found that 52 patients were not given antibiotics appropriately, compared to the other 61 patients. Based on all the assessments, every regimen was as indicated, and only one patient was deemed to require a more effective antibiotics. This result should not be surprising due to the guideline recommendations that refer to various clinical trial results showing no significant difference in clinical improvement for various antibiotics [8, 33]. The most abundant drop in the Gyssens flow was in category IIIb (duration too short), followed by the next category of incorrect dosage and interval. Inappropriate dose was linked to the absence of dosage adjustments for certain patients with renal impairment. Dose adjustment is necessary when anticipating a change in protein binding, volume of distribution, and renal and non-renal clearance [34]. A normal dose in patients with renal impairment may potentially cause toxicity, which in turn will worsen the clinical outcome, resulting in high mortality, morbidity and cost. There were 2 patients with too long durations of antibiotics. Aside from potential resistance, a study in Maryland showed a 3% increase in the risk of adverse drug events with each additional 10 days of prolongation of antibiotics therapy. The importance of wise administration of antibiotics in terms of accuracy of indication, selection of antibiotic type, duration, route, frequency and timing of antibiotic administration can improve patient safety [35]. Because this study did not observe adverse drug events, further study may be needed.

    The limitation of this study concerns the use of the Gyssens criteria which did not only mean that enrolled patients received the antibiotics against possible microbial etiologies but also received a longer duration of antibiotics that is not associated with clinical improvement. The validity of a retrospective cohort study design is also highly dependent on the completeness of the data in the medical records. In addition, the discussion was limited to aspects of infection control with the use of antibiotics in DFI but did not consider in detail other control aspects that have the potential to affect clinical improvement. We observed a short-term clinical improvement for 7 - 14 days of antibiotic use, which is not adequate to describe the optimal course of antibiotics. Further research is needed by considering the long-term clinical outcomes, including >14 days of clinical improvement, amputation and mortality, given the longer duration of antibiotics and occurrence of osteomyelitis and repeated surgery in more severe cases.

    In this study, only 54.0% of the patients with DFI received appropriate antibiotics, although an appropriate antibiotic usage was the independent favorable prognostic factor in DFI. This suggests that we should effort to improve appropriateness in antibiotics usage in DFI.

    SUPPLEMENTARY MATERIALS

    Supplementary Table 1

    Gyssens analysis based on antibiotics

    Click here to view.(48K, xls)

    Supplementary Table 2

    Analysis of antibiotics appropriateness using Gyssens algorithm

    Click here to view.(42K, xls)

    Supplementary Table 3

    Sensitivity pattern

    Click here to view.(46K, xls)

    Supplementary Table 4

    Resistance pattern

    Click here to view.(46K, xls)

    Notes

    Funding:This study was supported by Penelitian Dasar Unggulan Perguruan Tinggi (PDUPT) Grant, Ministry of Research and Higher Education, Republic of Indonesia, Indonesia No. NKB-93/UN2.RST/HKP.05.00/2020, addendum No. NKB-2692/UN2.RST/HKP.05.00/2020.

    Conflict of Interest:No conflict of interest.

    Author Contributions:

    • Conceptualization: MA, RS, EY.

    • Data curation: MA, HWR.

    • Formal analysis: MA, HWR.

    • Funding acquisition: RS.

    • Investigation: MA, HWR.

    • Methodology: MA, RS.

    • Project administration: MA, RS.

    • Resources: RS.

    • Software: MA.

    • Supervision: RS, EY.

    • Validation: RS, EY Visualization.

    ACKNOWLEDGMENTS

    The authors thank the Director of Dr. Cipto Mangunkusumo Hospital Jakarta, the Internal Medicine Department team, and the staff of the Medical Records Department for assisting in retrieving patients' medical records.

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    MeSH Terms
    Adult
    Amputation
    Anti-Bacterial Agents
    Cohort Studies*
    Diabetes Mellitus, Type 2
    Diabetic Foot*
    Erythema
    Fever
    Hospitalization
    Humans
    Hyperglycemia
    Indonesia*
    Inpatients
    Leukocytes
    Mortality
    Multivariate Analysis
    Odds Ratio
    Quality of Life
    Referral and Consultation*
    Retrospective Studies*
    Ulcer
    Wounds and Injuries
    Metrics
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