Clinical utility of procalcitonin in implementation of procalcitonin-guided antibiotic stewardship in the South-East Asia and India: evidence and consensus-based recommendations.

INTRODUCTION: The South-East Asian (SEA) region and India are highly susceptible to antibiotic resistance, which is caused due to lack of antimicrobial stewardship (AMS) knowledge, uncontrolled use of antibiotics, and poor infection control. Nonadherence to national/local guidelines, developed to combat antimicrobial resistance, is a major concern. A virtual advisory board was conducted to understand the current AMS standards and challenges in its implementation in these regions. AREAS COVERED: Procalcitonin (PCT)-guided antibiotic use was discussed in various clinical conditions across initiation, management, and discontinuation stages. Most experts strongly recommended using PCT-driven antibiotic therapy among patients with lower respiratory tract infections, sepsis, and COVID-19. However, additional research is required to understand the optimal use of PCT in patients with organ transplantation and cancer patients with febrile neutropenia. Implementation of the solutions discussed in this review can help improve PCT utilization in guiding AMS in these regions and reducing challenges. EXPERT OPINION: Experts strongly support the inclusion of PCT in AMS. They believe that PCT in combination with other clinical data to guide antibiotic therapy may result in more personalized and precise targeted antibiotic treatment. The future of PCT in antibiotic treatment is promising and may result in effective utilization of this biomarker.

Correlation P2Y12 Genetic Polymorphism As Risk Factor of Clopidogrel Resistance in Indonesian Stroke Patients.

Background: Stroke is one of the highest causes of disability and mortality in several countries worldwide. Secondary prevention is important in the management of stroke. Clopidogrel is widely used in Asia as secondary prevention for ischemic stroke, even though several studies in Western show limited data related to clopidogrel resistance in Asia. This study aims to determine the correlation between P2Y12 genetic polymorphism and clopidogrel resistance in Indonesia. Methods: This study was conducted on one-year duration, the subjects were chosen through the consecutive sampling method, all subjects were examined for genetics and resistance to clopidogrel. The data were analyzed through statistical analysis, a bivariate analysis was conducted to determine the correlation between several variables and the resistance variable. This study employed resistance diagnostic methods with VerifyNow. Polymorphism of receptor P2Y12 was tested with the Polymerase Chain Reaction method (PCR) and analysis of restriction fragment length polymorphism (RFLP). The genes tested in this study were G52T and C34T. Results: The number of participants in this study was 112. Examination of gene P2Y12 showed that the majority was homozygote, wild-type C34T allele (67%), and G52T (66.1%). There was no significant correlation between clopidogrel resistance and gene G52T and C34T of P2Y12 (p > 0.05). Hb levels significantly correlated with P2Y12 G52T (p = 0.024). Meanwhile, Fatty Liver significantly correlated with P2Y12 C34T (p = 0.037). Conclusion: Indonesia showed a low clopidogrel resistance rate and a very low C34T and G52T allele P2Y12 gene mutation, meaning that Indonesia had low mutations in the P2Y12. This is the cause of clopidogrel resistance in this study only 15%. Therefore, in a region with less clopidogrel resistance, examination of the P2Y12 gene would not give significant results.

Low BALF CD4 T cells count is associated with extubation failure and mortality in critically ill covid-19 pneumonia.

BACKGROUND: Critically ill COVID-19 pneumonia is one of the main causes of extubation failure and mortality. Understanding clinical characteristics, laboratory profiles and bronchoalveolar lavage fluid (BALF) immunopathology may help improve outcomes in critically ill COVID-19 pneumonia. We aimed to describe clinical characteristics, laboratory profiles and BALF immunopathology based on lung severity in critically ill COVID-19 pneumonia patients. MATERIALS AND METHODS: Forty critically ill severe pneumonia patients requiring invasive mechanical ventilation in Cipto Mangunkusumo General (National Tertiary Referral Hospital), Indonesia within November 2020-January 2021 were enrolled in this study. Early BALF collection was performed after patients' intubation. Clinical characteristics, laboratory profiles and BALF biomarkers (sTREM-1, alveolar macrophage amount and function, IL-6, IL-17, CD4 T-cells, Tregs, SP-A and Caspase-3) were observed and analysed. Outcomes were measured based on extubation failure (within 19 days) and 28-days mortality. Univariate and bivariate analyses were performed. RESULTS: Early bronchoscopy was performed in an average of 4 h (SD = 0.82) after patients' intubation. Twenty-three and twenty-two patients had extubation failure (within 19 days) and 28-days mortality, respectively. In the baseline clinical characteristics of critically ill COVID-19 patients, we found no significant differences in the extubation and mortality status groups. In the laboratory profiles of critically ill COVID-19 patients, we found no significant differences in the extubation status groups. In critically ill COVID-19 pneumonia patients, there was a significant high D-dimer levels in survived group (p = .027), a significant low BALF CD4 T-cells count in the right lung (p = .001) and a significant low BALF CD4 T-cells count (p = .010 and p = .018) in severely affected lung with extubation failure and mortality. CONCLUSIONS: BALF CD4 T-cells count evaluation of severely affected lung is associated with early extubation failure and mortality in critically ill COVID-19 pneumonia patients. KEY MESSAGEFew studies have been conducted during the peak COVID-19 period analysing combined bronchoalveolar lavage fluid (BALF) immunopathology biomarkers within four hours of intubation to assess extubation failure and mortality. In this study, we reported eight BALF immunopathology biomarkers (sTREM-1, alveolar macrophage, IL-6, IL-17, CD4 T-cells, Tregs, SP-A and Caspase-3).We found significantly low BALF CD4 T-cells count in the right lung, and low BALF CD4 T-cells count in severely affected lung of critically ill COVID-19 pneumonia patients in extubation failure and mortality.

Clopidogrel Resistance Among Ischemic Stroke Patients and Its Risk Factors in Indonesia.

OBJECTIVE: Clopidogrel is a common antiplatelet used as secondary prevention of ischemic stroke, known to have better efficacy than aspirin, with a equivalent safety profile. However, clopidogrel resistance is not uncommon but has not been widely studied in Asia. This study will further assess clopidogrel resistance and its risk factors. MATERIALS AND METHODS: A cross-sectional study was conducted at Rumah Sakit Universitas, Indonesia, and Rumah Sakit Cipto Mangunkusumo, Indonesia in 2020-2021. All patients had had at least one episode of ischemic stroke. Clopidogrel resistance was assessed using a VerifyNow assay. RESULTS: 57 subjects were enrolled in this study. We found 15.8% of subjects were clopidogrel resistant. Gender was significantly associated with clopidogrel resistance, with males having 80% lower clopidogrel resistance (OR 0.2 (95% CI 0.022 - 0.638); P=0.006). Meanwhile, smoking was not associated with clopidogrel responsiveness (P=0.051). We found no association between haemoglobin, blood glucose, HbA1c, cholesterol, liver enzymes, serum urea concentration or creatinine levels and clopidogrel resistance. CONCLUSION: Clopidogrel remains an effective treatment to prevent recurrent ischemic stroke in Indonesia. Further studies are needed to assess gene polymorphism and clopidogrel resistance, which may explain the findings of this study.

Rapid Antigen Detection Test for Severe Acute Respiratory Syndrome Coronavirus 2: How to Use It Properly?

Cases of coronavirus disease 2019 (COVID-19) in Indonesia are still increasing and even higher in the last few weeks. Contact tracing and surveillance are important to locate cases in the community, including asymptomatic individuals. Diagnosis of COVID-19 depends on the detection of viral RNA, viral antigen, or indirectly, viral antibodies. Molecular diagnosis, using real time, reverse transcriptase polymerase chain reaction (RT-PCR), is the common standard method; however, it is not widely available in Indonesia and requires a high standard laboratory. Rapid, point-of-care antibody testing has been widely used as an alternative; however, interpretation of the results is not simple and now it is no longer used by the Indonesian government as a screening test for people travelling between locations. Thus, the rapid antigen detection test (Ag-RDT) is used by the Indonesian government as a screening test for travellers. As a result, many people buy the kit online and perform self-Ag-RDT at home. This raises the question of how safe and accurate it is to perform self-Ag-RDT at home. Before a test is applied, it is suggested to research its sensitivity and specificity, as compared to gold standard, and its limitations. In this article, laboratory diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is discussed, with an emphasis on Ag-RDT and the recommendation to use it properly in daily practice.

A rare case of septic arthritis of the knee caused by Salmonella typhi with preexisting typhoid fever in a healthy, immunocompetent child - A case report.

INTRODUCTION: Septic arthritis is a rapid and progressive infection caused by invasion of bacteria into the synovial joint. Disease of the joint causedby Salmonella spp in healthy children is an unusual event, with an estimated incidence of 0.1 to 0.2% of septic arthritis cases among children. The incidence of knee septic arthritis caused by Salmonella typhi with preexisting typhoid fever is very rare. METHOD: We reported a case of 2-years old boy with a history of saddle-type fever 2 weeks prior to right knee pain. Typhoid fever was confirmed by immunoassay test. Knee septic arthritis was established from clinical findings, increased CRP level, ultrasonography, and joint aspiration. Culture of the aspirate subsequently grew Salmonella typhi. This case report had been reported in line with SCARE criteria. RESULT: Arthrotomy and debridement were immediately performed.Intravenous piperacillin tazobactam was given for 6 days and replaced by amoxicillin clavulanic acid after the culture and sensitivity test was available. Patient recovered completely 5 months post surgery and showed excellence result with normal range of knee joint motion. CONCLUSION: This case report suggests that any episode of joint swelling following preexisting typhoid fever should arise the physician's awareness toward the possibility of septic arthritis and warrant immediate as well as proper management.

Isolation and identification of Streptococcus pneumoniae serotype 6B from a patient with bacterial meningitis infection in Jakarta, Indonesia.

CNS infection is a life-threatening condition in developing countries and Streptococcus pneumoniae has been reported as the most common cause of bacterial meningitis; however, there is limited data on pneumococcal meningitis in Indonesia. This cross-sectional study aimed to isolate and identity S. pneumoniae strains from cerebrospinal fluid (CSF) specimens collected as part of routine testing from patients with clinically diagnosed central nervous system infection at a national referral hospital in Jakarta, Indonesia in 2017. S. pneumoniae isolation and identification were performed using conventional culture and molecular tools. Antibiotic susceptibility patterns were monitored through minimum inhibitory concentration testing. From 147 CSF specimens, one S. pneumoniae strain was identified from a patient with bacterial meningitis symptoms. The isolate was serotype 6B (ST5661) and susceptible to 18 antimicrobial agents tested, including penicillin, tetracycline, and the macrolide group. Our data provide insights into the epidemiology of invasive pneumococcal disease in Indonesia.

Clinical Practice Guidelines in Complicated Intra-Abdominal Infection 2018: An Indonesian Perspective.

BACKGROUND: The occurrence of complicated intra-abdominal infections (cIAI) remains high despite system improvement in accordance with Joint Commission International because of heterogeneity of management. However, published clinical practice guidelines (CPGs) were not feasible to be implemented because these guidelines were not specific to Indonesian characteristics. Thus, a national CPG should be developed to minimize heterogeneity in the management of cIAI in Indonesia. METHODS: We developed a CPG on cIAI through the adaptation of published CPGs. The process proceeded in steps recommended by ADAPTE. Published CPGs were critically appraised using Appraisal of Guidelines for Research and Evaluation (AGREE) II critical appraisal tools. For a specific updated CPG, the analysis was performed using Checklist for the Reporting of Updated Guidelines (CheckUp). Appropriate statements and recommendations in selected CPGs were adapted into our CPG with consideration of Indonesian characteristics. The recommendations were established by the hierarchy of evidence on Grading of Recommendations Assessment, Development and Evaluation (GRADE). The approval of the recommendation draft was performed using the Delphi method. RESULTS: Sixty-eight full-text guidelines were downloaded from several sites. Thirty-three CPGs were related to intra-abdominal infection and 18 others were specific on CPG on intra-abdominal infection and cIAI. On review of these 18 CPGs, 13 were strongly recommended, three were recommended, and two were not recommended. On review updated CPGs, five updated CPGs were found, all with the same score. Two of the strongly recommended updated CPGs had been published in 2016 and 2017, i.e. recommendations by the World Society of Emergency Surgery 2016 consensus conference and revised CPG of the Surgical Site Infection Society. There were a total of 84 statements and recommendations developed and approved by the task force through using the Delphi method. CONCLUSIONS: This guideline summarizes the definition, classification, pathophysiology, etiology, risk factors, assessments, and management of cIAI. Evidence-based recommendations have been developed with consideration of Indonesian-specific characteristics.

Emergence of Melioidosis in Indonesia and Today's Challenges.

A recent modeling study estimated that there could be as many as 20,000 human melioidosis cases per year in Indonesia, with around 10,000 potential deaths annually. Nonetheless, the true burden of melioidosis in Indonesia is still unknown. The Indonesia Melioidosis Network was formed during the first melioidosis workshop in 2017. Here, we reviewed 101 melioidosis cases (99 human and two animal cases) previously reported and described an additional 45 human melioidosis cases. All 146 culture-confirmed cases were found in Sumatra (n = 15), Java (n = 104), Kalimantan (n = 15), Sulawesi (n = 11) and Nusa Tenggara (n = 1). Misidentification of Burkholderia pseudomallei was not uncommon, and most cases were only recently identified. We also evaluated clinical manifestations and outcome of recent culture-confirmed cases between 2012 and 2017 (n = 42). Overall, 15 (36%) cases were children (age <15 years) and 27 (64%) were adults (age ≥15 years). The overall mortality was 43% (18/42). We conducted a survey and found that 57% (327/548) of healthcare workers had never heard of melioidosis. In conclusion, melioidosis is endemic throughout Indonesia and associated with high mortality. We propose that top priorities are increasing awareness of melioidosis amongst all healthcare workers, increasing the use of bacterial culture, and ensuring accurate identification of B. pseudomalleiand diagnosis of melioidosis.

In Vitro Antibacterial Interaction of Doripenem and Amikacin against Multidrug-Resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae Isolates.

Evaluation of the in vitro interaction of doripenem and amikacin against Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae was done by classifying them into four groups: doripenem and amikacin sensitive (DOR-S/AMK-S), doripenem sensitive and amikacin resistant (DOR-S/AMK-R), doripenem resistant and amikacin sensitive (DOR-R/AMK-S), and both doripenem and amikacin resistant (DOR-R/AMK-R). The MIC of each antibiotic and their combination was obtained using the Etest method. The fractional inhibitory concentration index was calculated to classify the results as synergistic, additive, indifferent, or antagonistic interaction. In the DOR-S/AMK-S class, 1 isolate of A. baumannii showed synergy and the other 5 showed additive results, 5 isolates of P. aeruginosa showed additive and 1 isolate showed indifferent result, and 2 isolates of K. pneumoniae showed additive and the other 4 showed indifferent results. In the DOR-S/AMK-R class, 3 isolates of A. baumannii showed additive and the other 3 showed indifferent results, 2 isolates of P. aeruginosa showed indifferent results, and 1 isolate of K. pneumoniae showed additive and the other 5 showed indifferent results. In the DOR-R/AMK-S class, 1 isolate of A. baumannii showed additive and the other 5 showed indifferent results, 1 isolate of P. aeruginosa showed additive and the other 5 showed indifferent results, and 4 isolates of K. pneumoniae showed additive and the other 2 showed indifferent results. In the DOR-R/AMK-R class, 6 isolates of A. baumannii showed indifferent results, 1 isolate of P. aeruginosa showed additive and the other 5 showed indifferent results, and 1 isolate of K. pneumoniae showed additive and the other 5 showed indifferent results. Synergy occurred in only 1 (1.5%) isolate. Additive interaction occurred in 24 (35.3%) isolates, and indifferent interaction occurred in 43 (63.2%) isolates. Doripenem sensitive combined with amikacin sensitive reduced MIC significantly in all bacterial isolates when compared to single MIC of each antibiotic.

Correlation Between Vitreous Advanced Glycation End Products, and D-dimer with Blood HbA1c Levels in Proliferative Diabetic Retinopathy.

BACKGROUND: proliferative diabetic retinopathy (DR) is an advanced form of DR that eventually could lead to blindness. Levels of vitreous advanced glycation end products (AGEs) and D-dimer may reflect the pathological changes in the retina, but only few studies have assessed their correlation with blood hemoglobin A1C (HbA1c) levels. This study aimed to find the association between blood HbA1c levels with vitreous AGEs and D-dimer levels in patients with proliferative DR. METHODS: an analytical cross-sectional study was performed in subjects with proliferative DR who underwent vitrectomy. Subjects were divided into 2 subgroups, i.e. uncontrolled (HbA1c >7%) and controlled (HbA1c <7%) groups. Vitreous AGEs and D-dimer levels were assessed; the levels were compared between uncontrolled and controlled hyperglycemic patients. Statistic correlation tests were also performed for evaluating blood HbA1c, vitreous AGEs, and D-dimer levels. RESULTS: a total of 47 patients were enrolled in this study and 32 (68.1%) of them were women. Median vitreous AGEs level was 11.0 (3.0 - 48.0) µg/mL; whereas median vitreous D-dimers level was 5,446.0 (44.0 - 37,394.0 ) ng/mL. The median vitreous AGEs levels was significantly higher in patients with uncontrolled vs. controlled hyperglycemia (14.0 vs. 4.0 mg/mL; p<0.001). There was a significant positive correlation with moderate strength between blood HbA1c level and vitreous AGEs level (r=0.524; r2=0.130; p=0.0001). Blood HbA1c level could be used to predict vitreous AGEs level by using the following calculation: vitreous AGEs = -1.442+ (1.740xblood HbA1c). Vitreous D-dimer levels were not significantly different between uncontrolled and controlled hyperglycemia (median 4607.5 vs. 5701.6 ng/mL; p = 0.458). There was a positive significant correlation between blood HbA1c and vitreous D-dimer levels (r = 0.342; p = 0.019); however the correlation was weak. Vitreous AGEs level had a positive significant correlation with vitreous D-dimer levels (r = 0.292; p = 0.046) and the correlation strength was also weak. CONCLUSION: median vitreous AGEs levels were significantly higher in proliferative DR patients with uncontrolled than those with controlled hyperglycemia. Blood HbA1c level can be used to assess vitreous AGEs level in patients with proliferative DR by using the following calculation: vitreous AGEs = -1.442+(1.740 x HbA1c). However, the blood HbA1c level can not be used to predict vitreous D-dimer level in patients with proliferative DR.

Screening of methicillin-resistant Staphylococcus aureus nasal colonization among elective surgery patients in referral hospital in Indonesia.

OBJECTIVE: Methicillin-resistant Staphylococcus aureus (MRSA) colonization is associated with serious surgical site infection in high-risk patients. High prevalence of MRSA colonization was reported in many settings, nonetheless local data is required. The purpose of this study is to identify the prevalence and risk factor of MRSA nasal carriage in adult patients in National Referral Hospital in Indonesia before underwent elective surgical procedure. RESULTS: From 384 patients, 16.9% patients of them had undergone orthopaedic surgery, 51.3% had received antibiotics within the previous 3-month and 41.1% patients had history of hospitalization within the previous 1 year. Total of 21.6% patients were on invasive devices for at least 48 h before the operation; 24.2% had an open wound; 19.3% patients were referred from other hospital/ward. Of these patients, solid tumor without metastasis was the most common factor identified by the Charlson index (38.3%). Nasal colonization of Gram-positive bacteria was detected in 76.8%; S. aureus in 15.6% of patients (n = 60). MRSA was identified in three isolates (0.8%) by both culture and polymerase chain reaction (PCR) tests. Due to low prevalence of MRSA nasal carriage, this finding supports the recommendation to not routinely apply mupirocin for nasal decolonization on patient planned for surgery in Indonesia.

Colistin: an antibiotic and its role in multiresistant Gram-negative infections.

Increasing number of infection cases caused by multiresistant Gram-negative bacteria or multidrug resistant organism (MDRO) has become a major problem worldwide since there have been a lot of resistance to many classes of antibiotics. Mutant isolates such as fluoroquinolone-resistant and -lactamase-resistant bacteria have been commonly found, particularly in intensive care unit (ICU). During the last two decades, there has been no study of developing antibiotics in search of discovering new type of antibiotics; meanwhile, the resistance of Gram-negative bacteria or MDRO to antibiotics is increasing. Colistin or polymyxin E is an old antibiotic, which has been used since 1959 for treating infection caused by Gram-negative MDRO. It was revealed that colistin has side effects of nephrotoxicity and neurotoxicity; therefore, the use of this antibiotic was stopped and it was replaced by other antibiotics which were effective and were considered safer at that time. There is an increasing number of infections with multi-resistant Gram-negative (MDRO) against the available antibiotics and the availability of alternative antibiotics has not been satisfying; therefore, microbiologists are searching back to the old option, which has been proven to be effective against multi-resistant Gram-negative bacteria, the old antibiotic that has been long forgotten, i.e. colistin, as an alternative treatment against Gram-negative MDRO. It is expected that colistin may have essential and reliable role as future antibiotics for treatment of multi-resistant Gram-negative infections and as an alternative of antibiotics that have been available so far.

Acute Kidney Injury (AKI) biomarker.

The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery. The Acute Kidney Injury Network (AKIN) defined Acute Kidney Injury (AKI) as "functional and structural disorder or signs of renal damage including any defect from blood and urine test, or tissue imaging that is less than 3 months". RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria is the most frequently used system. Ideal biomarker for AKI should be affordable, quick and measurable, precise and accurate, with prognostic ability to define severity of renal dysfunction, specific for renal, increase in the early stage dysfunction, with high sensitivity and specificity. Efforts to detect AKI in the earlier stage has resulted in some promising biomarkers such as KIM-1, NGAL, IL-18, Clusterin, etc. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, NAG, RBP, IL-18, NGAL, Netrin-1, KIM-1, Clusterin, Sodium Hydrogen Exchanger Isoform and Fetuin A are biomarkers for tubular reabsorption function.