Antibiotic Use Evaluation in ICU/HCU of Muhammadiyah University General Hospital Malang using DDD and Gyssens Methods Evaluasi

Infection is a condition caused by the propagation of harmful microorganisms with or without clinical symptoms. Improper use of antibiotics can lead to antibiotic resistance. The Ministry of Health of the Republic of Indonesia recommended a quantitative evaluation of the use of antibiotics using the Defined Daily Dose (DDD) method and a qualitative evaluation using the Gyssens method. This study evaluated antibiotics usage using DDD and Gyssens methods in ICU/HCU of the Muhammadiyah University General Hospital Malang. Employing retrospective observational method, data were collected from patient medical records hospitalized during January-December 2020. Results of the DDD quantitative analysis showed that the most widely used antibiotic was Ceftriaxone with a 35.79 DDD/100 patient-days. The Gyssenss qualitative analysis showed that the category VI (incomplete patient's medical record data) was 3%, category IVa (antibiotic use is more effective) (2%), category IIIb (duration of antibiotic use is too short) (3%), category IIb (antibiotic use is not at the right interval) (3%).


INTRODUCTION
Infection is a condition caused by the propagation of adverse microorganisms that cause the emergence of clinical symptoms or without clinical symptoms (1,2).Infections are caused by pathogenic microorganisms, such as bacteria, viruses, parasites, or fungi (3).Infectious diseases have high morbidity and mortality and are among the top 10 diseases that cause death in Indonesia.Infection is caused by bacteria that are able to pass through the mucosal barrier or skin and penetrate the body tissues (2).
According to WHO data in 2019, there were nine types of infections with the highest incidence that threaten public health, i.e. cholera, plague, yellow fever, meningitis, hemorrhagic fever, influenza, HIV/AIDS, African trypanosomiasis, and leishmaniasis.Their high incidence associated with complicated epidemic patterns, ability to develop new strains, and the tendency to spread rapidly to new locations (3)(4)(5)(6)(7).
One of the drugs used to overcome these problems is antimicrobial agent, namely antibiotic or antibacterial, antiviral, antiprotozoal, and antifungal (2).Antibiotics are mostly effective for mild to severe infections (8).The high prevalence of infectious diseases is followed by the increased use of antibiotics in hospital wards, including the Intensive Care Unit (ICU) and the High Care Unit (HCU).Antibiotics use must follow some guidelines to ensure efficay and to prevent antibiotic resistance.Failure to apply the antibiotic use guidelines may cause the occurence of antibiotic resistance and may increase, cost of services, length of treatment, undesirable side effects, and the risks for pain and even death (3).
An effort is needed to control the problem of antibiotic resistance.These control efforts can be done by evaluating the use of antibiotics quantitatively using the Defined Daily Dose (DDD) method and qualitatively using the Gyssens method (9,10).The DDD method aims to determine and assess the quantity of antibiotic use.Meanwhile, the Gyssens method evaluates the use of antibiotics more specifically by grouping patients in 6 categories based on appropriateness of indication, efficacy, toxicity, spectrum, dose, interval dose, duration of antibiotics use, and time of drug administration to price (10)(11)(12).
This study evaluated the use of antibiotics in the ICU/HCU of Muhammadiyah University General Hospital Malang (UMM General Hospital) by quantitative analysis using the DDD method and qualitative analysis using the Gyssens method.The results of the evaluation will serve as basis to improve antibiotics use, in particular to reduce inappropriate use of antibiotics at the ICU/HCU of Muhammadiyah University General Hospital Malang.

METHODS
The study was observational and conducted in April 2021.Data collection was retrospective, extracted from medical records of patients who hospitalized in the ICU/HCU of the UMM General Hospital in the period of January 1 -August 31, 2020.The inclusion criteria was adult patients (≥ 18 years old) of the ICU/HCU who received antibiotics.Data collected were gender, age, diagnosis, indications for antibiotic use, and length of hospitalization.Evaluation of the use of antibiotics employed the DDD method, by calculating the DDD value/100 patient days with the following calculation formula --(9,13) : DDD/100 patient days is calculated by dividing the total DDD usage by the total Length of Stay (LOS) previously divided per 100 patient-days.DDD values were calculated all antibiotic uasage, whether as prophylactic and/or therapeutic purposes.Qualitative evaluation of antibiotic using the Gyssens method was carried out by collecting data (indication, length/duration of administration, dose, frequency, route of administration) then analyzing them following the Gyssens flow, as described previously (10,11,14).

Table 1. Patient demographic characteristics
The LOS was calculated from hospital admision to discharge - (15).In this study, the range of LOS patients was mostly 1-5 days (29 patients, 73%) and the shortest LOS was 2 days.Antibiotics were classified into two categories whether as prophylactic or as therapeutic (definitive therapy).Prophylactic antibiotics were given to 5 (8%) patients, and most patients received empirical antibiotics (92%) which meant that the organism(s) causing the disease not yet known or microbiologically data not available yet.There were no patients with antibiotics as definitive therapy, which microbiological supporting data available and organism causing the disease was established (Table 2).).Only a small percentage of patients underwent surgical measure (Table 3).

Results of Qualitative Analysis of Antibiotic Use Using Gyssens Method
Data showed that of 40 patient of ICU/HCU, in total 65 antibiotics were prescribed (Table 5).There were some patients who received antibiotic therapy more than one.
The results of qualitative evaluation using the Gyssens method in the ICU/HCU Room obtained 89% of antibiotic use in patients was appropriate and relevant or rational (Category 0).A total of 2 patients were found with incomplete medical records (Category VI) (3%).Incomplete medical record data such as there were patients without working diagnosis (clinical enforcement of anamnesis and physical examination) or there were missing medical record pages that could not be evaluated (9,14).

DISCUSSION
The patients in this study were mostly females and age range over 65 yo.The patient profile is the same as the profile of sepsis sufferers in the ICU RSUP Prof. Dr. R. D. Kandou Manado with a greater proportion of females (54%) --( 13).This was in contrast with the results of other studies that showed more male patients than female.The prevalence of severe sepsis is lower in females than in males, but the higher risk of death for patients with severe sepsis in the ICU was in female patients (12,16).
The high proportion of elderly patients in this study may be associated with that elderly was more prone to infection due to decreased endurance and physiological function of the body, sub-optimal nutrition, possessing more than one comorbidites and social environmental factors which less supportive (17).The diagnosis of sepsis in the elderly is rather difficult because the elderly provides or showed unclear responses and clinical symptoms of sepsis, and sometimes accompanied by delirium.The difficulty of establish the diagnosis of sepsis in the elderly can cause the management of sepsis to be delayed which in turn affects the final result of the treatment (18,19).
The LOS of patients in this study was mostly in the range of 1 -5 days with the shortest LOS of 2 days.This is in accordance with the results of another study which showed that 57 patients (74%) were treated in the ICU for less than 7 days (20).LOS of patients depends on patient characteristics, clinical circumstances, medical actions, patient management, and administrative problems at the hospital - (15).
The study showed that the indication of antibiotic use in the ICU/HCU Room was mostly for empirical treatment (60, 92%).The purpose of administering antibiotics for empirical therapy is the eradication or inhibition of the growth of bacteria suspected to be the cause of the infection, before the results of microbiological examination are obtained, and the indication of its administration is the observation of clinical syndromes leading to the involvement of certain bacteria that are most often the cause of the infection (21).
In this study, 51 patients (91.07%) received non-surgical measures and 9 patients (16%) were diagnosed with sepsis.Sepsis is a condition in which patients experience organ failure caused by a decrease in body regulation in response to infection, this condition will worsen into severe sepsis and sepsis shock which can cause death (4).
The second most diagnosed were patients with ESRD (8 cases, 14%).Our study showed higher percentage patients compared with other study which reported patients with septic shock (7.7%) were also chronic dialysis patients (22).
Our study showed that the highest value DDD/100 patientdays was ceftriaxone at 35.79, and that the greater the value of DDD/100 patient-days, the greater the level of antibiotic use.Such results were similr with studies in Lampung and Bantul (23,24) Based on the guidelines for antibiotic use, ceftriaxone is indicated in these cases so that the use of Ceftriaxone is also high (2).Ceftriaxone administration in combination with doxycycline macrolide is the first line in cases of sepsis.Therefore, the high use of ceftriaxone was apparently associated with the high incidence sepsis in the ICU (27,28).
Our study using Gyssens method showed that in the ICU/HCU, 89% of antibiotic use in patients was appropriate or rational.Patients which should have been prescribed with alternative antibiotics with better efficacy were of 2%, which probably require updating the existing local guidelines for antibiotic use according to the lattest evidence based published data.In this study, inappropriate duration of antibiotics treatment was 3%.Too long or unnecessary administration of antibiotics may be due to delayed results of microbiological test/culture which usually took up to 5 days whereas the reguation of Ministry of Health RI (2,9) stated that empirical antibiotics are given for 48 -72 hours.Inappropriate antibiotic administration at intervals was found in the ICU/HCU Room at 3%.In the administration of Ceftriaxone antibiotics 2 x 1g iv was administered every 12 -24 hours (4,8,23,29), but in this study it was found that Ceftriaxone antibiotics were administered for less than 12 hours.
It can be concluded that quantitatively the most widely used antibiotic is ceftriaxone with a DDD value of 100 patient-days 35.79.Qualitatively, most antibiotics (89%) were appropriate for their use, although there was still a small percentage (2-3%) of incomplete patient data, more appropriate antibiotic options, duration of antibiotic therapy too short and intervals inappropriate.

5 .
Results of qualitative evaluation using gyssens method in ICU/HCU room (Cont.)Note: * Patients with single or multiple antibiotics.

Table 2 . Length of Stay (LOS) and indications for antibiotic use
Antibiotic Use Study in ICU/HCU...

Table 2 . Length of Stay (LOS) and indications for antibiotic use (Cont.)
Note: *Number of Patients: there were patients who get more than one antibiotic Clinical diagnosis of patients with antibiotics were mostly sepsis (9, 16%), end stage renal disease (8.14%), and Cerebro Vascular Accident(7, 13%

Table 3 . Diagnosis of patients with antibiotic therapy
Note: *patients with single or multiple diagnosisQuantitative Evaluation of Antibiotics Use Using DDD MethodThe calculation of DDD values in the ICU/HCU Room was using total LOS patients for 190 days with total antibiotic use of 98.22 DDD/100 patient-days.Ceftriaxone is an antibiotic with the greatest DDD value of 35.79 DDD/100 patient-days which means that every 100 days of hospitalization there are 35 -36 patients who get Ceftriaxone antibiotics in accordance with WHO standards of 2 grams.The next highest DDD value was Gentamycin as 22.68 DDD/100 patient-days and Levofloxacin as 16.05 DDD/100 patient-days (Table4).

Table 4 . Quantitative data of antibiotic (DDD/Patient-days) in ICU/HCU
Note: *Total DDD = **Total DDD/100 Patient-days = ***Total LOS obtained from the total length of treatment of all samples in the ICU Room

Tabel 5. Results of qualitative evaluation using gyssens method in ICU/HCU room
Antibiotic Use Study in ICU/HCU...