Guidelines on Implementing Antimicrobial Stewardship Programs in Korea

These guidelines were developed as a part of the 2021 Academic R&D Service Project of the Korea Disease Control and Prevention Agency in response to requests from healthcare professionals in clinical practice for guidance on developing antimicrobial stewardship programs (ASPs). These guidelines were developed by means of a systematic literature review and a summary of recent literature, in which evidence-based intervention methods were used to address key questions about the appropriate use of antimicrobial agents and ASP expansion. These guidelines also provide evidence of the effectiveness of ASPs and describe intervention methods applicable in Korea.

Guidelines on Implementing Antimicrobial Stewardship Programs in Korea

These guidelines were developed as a part of the 2021 Academic R&D Service Project of the Korea Disease Control and Prevention Agency in response to requests from healthcare professionals in clinical practice for guidance on developing antimicrobial stewardship programs (ASPs). These guidelines were developed by means of a systematic literature review and a summary of recent literature, in which evidence-based intervention methods were used to address key questions about the appropriate use of antimicrobial agents and ASP expansion. These guidelines also provide evidence of the effectiveness of ASPs and describe intervention methods applicable in Korea.

Self-Assessment Questionnaire for Efficient and Safe Evaluation of Patients with Mild COVID-19

As the outbreak of coronavirus disease 2019 continues and the number of confirmed cases requiring isolation increases, there is a need for a safe and efficient system to assess patients' condition. We developed and evaluated a self-assessment questionnaire consisting of 23 symptoms with linear-scale scores from 0 to 10. Patients were asked to indicate their worst score for each symptom daily, and medical personnel assessed clinical improvement or deterioration based on the changes in scores. Focused communication on severity of specific symptoms was the primary advantage for the clinicians, and a thorough check for their symptoms was helpful for patients.

Development of Antibiotic Classification for Measuring Antibiotic Usage in Korean Hospitals Using a Modified Delphi Method

In 2019, a project designed to develop a system for measuring and comparing antibiotic usage in hospitals was launched in Korea. As part of this project, we developed a means to classify antibiotic usage in Korean hospitals using a modified Delphi method. In results, the following categories of antibiotic classification were accepted for use in Korean hospitals: 1) broad-spectrum antibacterial agents predominantly used for hospital-onset infections in adults, 2) broad-spectrum antibacterial agents predominantly used for community-acquired infections in adults, 3) antibacterial agents predominantly used for resistant gram-positive infections in adults, 4) narrow-spectrum beta-lactam agents in adults, 5) antibacterial agents predominantly used for extensive antibiotic resistant gram-negative bacteria in adults, and 6) total antibacterial agents.

Guideline for Antibiotic Use in Adults with Community-acquired Pneumonia

Community-acquired pneumonia is common and important infectious disease in adults. This work represents an update to 2009 treatment guideline for community-acquired pneumonia in Korea. The present clinical practice guideline provides revised recommendations on the appropriate diagnosis, treatment, and prevention of community-acquired pneumonia in adults aged 19 years or older, taking into account the current situation regarding community-acquired pneumonia in Korea. This guideline may help reduce the difference in the level of treatment between medical institutions and medical staff, and enable efficient treatment. It may also reduce antibiotic resistance by preventing antibiotic misuse against acute lower respiratory tract infection in Korea.

Rapidly Fatal Emphysematous Osteomyelitis with Multiple Septic Emboli and Liver Abscess Caused by Klebsiella pneumoniae

Emphysematous osteomyelitis, characterized by intraosseous gas, is a rare but potentially fatal condition that requires prompt diagnosis and aggressive therapy. Causative organisms are members of the bacterial family Enterobacteriaceae or anaerobes in most cases and significant comorbidities such as diabetes mellitus and malignancy, may predispose an individual to the development of emphysematous osteomyelitis. We report a case of extensive emphysematous osteomyelitis via hematogenous spread from Klebsiella pneumoniae liver abscess, complicated by gas-containing abscesses in adjacent soft tissues and epidural space, and multiple systemic septic emboli in a diabetic patient.

Guideline for Antibiotic Use in Adults with Community-acquired Pneumonia

Community-acquired pneumonia is common and important infectious disease in adults. This work represents an update to 2009 treatment guideline for community-acquired pneumonia in Korea. The present clinical practice guideline provides revised recommendations on the appropriate diagnosis, treatment, and prevention of community-acquired pneumonia in adults aged 19 years or older, taking into account the current situation regarding community-acquired pneumonia in Korea. This guideline may help reduce the difference in the level of treatment between medical institutions and medical staff, and enable efficient treatment. It may also reduce antibiotic resistance by preventing antibiotic misuse against acute lower respiratory tract infection in Korea.

Rapidly Fatal Emphysematous Osteomyelitis with Multiple Septic Emboli and Liver Abscess Caused by Klebsiella pneumoniae

Emphysematous osteomyelitis, characterized by intraosseous gas, is a rare but potentially fatal condition that requires prompt diagnosis and aggressive therapy. Causative organisms are members of the bacterial family Enterobacteriaceae or anaerobes in most cases and significant comorbidities such as diabetes mellitus and malignancy, may predispose an individual to the development of emphysematous osteomyelitis. We report a case of extensive emphysematous osteomyelitis via hematogenous spread from Klebsiella pneumoniae liver abscess, complicated by gas-containing abscesses in adjacent soft tissues and epidural space, and multiple systemic septic emboli in a diabetic patient.

Population Pharmacokinetic Analysis of Piperacillin/Tazobactam in Korean Patients with Acute Infections

BACKGROUND: For more effective and safer usage of antibiotics, the dosing strategy should be individualized based on the patients’ characteristics, including race. The aim of this study was to investigate the population pharmacokinetic (PK) profiles of piperacillin and tazobactam in Korean patients with acute infections. MATERIALS AND METHODS: At least four consecutive 2/0.25 g or 4/0.5 g doses of piperacillin/tazobactam (TZP) were intravenously infused over 1 h every 8 h for patients with creatinine clearance (CL(cr)) ≤50 ml/min or CL(cr) >50 mL/min, respectively. Blood samples from 33 patients at a steady-state were taken pre-dose and at 0 min, 30 min, and 4-6 h after the fourth infusion. The population PK analysis was conducted using a non-linear mixed-effects method. A likelihood ratio test was used to select significant covariates, with significance levels of P <0.05 for selection and P <0.01 for elimination. RESULTS: Both piperacillin PK and tazobactam PK were well described by a two-compartment model with first-order elimination. Creatinine clearance and body weight, as covariates on clearance (CL) and volume of central compartment (V1), were selected among the covariates possibly affecting PK parameters of both drugs. CL was defined as CL = 2.9 + 4.03 × CL(cr)/47 for piperacillin and CL = 1.76 + 4.81 × CL(cr)/47 for tazobactam. V1 was defined as V1 = 19.5 × weight/60 for piperacillin and V1 = 22.6 × weight/60 for tazobactam. CONCLUSION: The PK profiles of TZP at a steady-state in Korean patients with acute infections were well described by a two-compartment model with first-order elimination. Both piperacillin and tazobactam clearances were significantly influenced by creatinine clearance.

Interpretation of Epithelial Lining Fluid Concentrations of Antibiotics against Methicillin Resistant Staphylococcus aureus

Although antibiotics whose epithelial lining fluid (ELF) concentrations are reported high tend to be preferred in treatment of pneumonia, measurement of ELF concentrations of antibiotics could be misled by contamination from lysis of ELF cells and technical errors of bronchoalveolar lavage (BAL). In this review, ELF concentrations of anti-methicillin resistant Staphylococcus aureus (MRSA) antibiotics were interpreted considering above confounding factors. An equation used to explain antibiotic diffusion into CSF (cerebrospinal fluid) was adopted: ELF/free serum concentration ratio = 0.96 + 0.091 x ln (partition coefficient / molecular weight1/2). Seven anti-MRSA antibiotics with reported ELF concentrations were fitted to this equation to see if their ELF concentrations were explainable by the penetration capacity only. Then, outliers were modeled under the assumption of varying contamination from lysed ELF cells (test range 0-10% of ELF volume). ELF concentrations of oritavancin, telavancin, tigecycline, and vancomycin were well described by the diffusion equation, with or without additional impact from cell lysis. For modestly high ELF/free serum concentration ratio of linezolid, technical errors of BAL should be excluded. Although teicoplanin and iclaprim showed high ELF/free serum ratios also, their protein binding levels need to be cleared for proper interpretation. At the moment, it appears very premature to use ELF concentrations of anti-MRSA antibiotics as a relevant guide for treatment of lung infections by MRSA.

Correlations between Microbiological Outcomes and Clinical Responses in Patients with Severe Pneumonia

BACKGROUND: In treatment of pneumonia, microorganisms sometimes persist, appear or reappear despite good clinical responses. On the other hand, recent increasing antibiotic resistance emphases the goal of rapid eradication of pathogen in severe infection. This study was planned to evaluate the correlations between microbiological outcomes and clinical responses in severe pneumonia. MATERIALS AND METHODS: Data was gathered from 3 clinical trials regarding severe pneumonia. Microbiological outcomes, determined by serial culture of respiratory tract samples,were compared with clinical outcomes. RESULTS: In total, 146 bacterial strains from 76 patients were analyzed. While clinical success was generally related to total or partial eradication of isolated organisms, Acinetobacter, Enterobacter, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia were often not eradicated and yet were observed in 56% of cases considered clinically successful at the end of antibiotic treatment. Most of the non-eradicated strains (71%) already had or developed resistance against the antibiotics used for treatment. Ten patients relapsed during the follow-up period; 7 of these relapses were associated with 10 non-eradicated organisms. CONCLUSIONS: These data raise concern about the pathogenicity of bacteria that persist in the respiratory tract even though good clinical outcomes of pneumonia are achieved, especially when Acinetobacter, Enterobacter, P. aeruginosa, or S. maltophilia were involved. Thus, clinical relapse and development of drug resistance by non-eradicated organisms may be raised.

Synergy of Arbekacin-based Combinations Against Vancomycin Hetero-intermediate Staphylococcus aureus

This study was undertaken to evaluate the in vitro activities of arbekacin-based combination regimens against vancomycin hetero-intermediate Staphylococcus aureus (hetero-VISA). Combinations of arbekacin with vancomycin, rifampin, ampicillin-sulbactam, teicoplanin, or quinipristin-dalfopristin against seven hetero-VISA strains and two methicillin-resistant S. aureus strains were evaluated by the time-kill assay. The combinations of arbekacin with vancomycin, teicoplanin, or ampicillinsulbactam showed the synergistic interaction against hetero-VISA strains. Data suggest that these arbekacin-based combination regimens may be useful candidates for treatment options of hetero-VISA infections.

Phase Variation of Biofilm Formation in Staphylococcus aureus by IS 256 Insertion and Its Impact on the Capacity Adhering to Polyurethane Surface

While ica gene of Staphylococcus epidermidis is known to undergo phase variation by insertion of IS256, the phenomenon in Staphylococcus aureus has not been evaluated. Six biofilm-positive strains were tested for the presence of biofilm-nega-tive phase-variant strains by Congo red agar test. For potential phase-variant strains, pulsed-field gel electrophoresis was done to exclude the possibility of contamination. To investigate the mechanism of the biofilm-negative phase variation, PCR for each ica genes were done. Changes of ica genes detected by PCR were confirmed by southern hybridization, and their nucleotides were analyzed by DNA sequencing. Influence of ica genes and biofilm formation on capacity for adherence to biomedical material was evaluated by comparing the ability of adhering to polyurethane sur-face among a biofilm-negative phase-variant strain and its parent strain. A biofilm-negative phase-variant S. aureus strain was detected from 6 strains tested. icaC gene of the phase-variant strain was found to be inactivated by insertion of additional gene segment, IS256. The biofilm-negative phase-variant strain showed lower adher-ing capacity to polyurethane than its parent strain. This study shows that phase variation of ica gene occurs in S. aureus by insertion of IS256 also, and this biofilm-neg-ative phase variation reduces adhering capacity of the bacteria.

Efficacy of Vancomycin-beta-lactam Combinations Against Heterogeneously Vancomycin-Resistant Staphylococcus aureus (hetero-VRSA)

There have been conflicting data about the interactions between vancomycin and beta-lactam agents against Staphylococcus aureus strains with heterogeneous resistance to vancomycin. We evaluated the efficacy of these combinations against Mu 3 and heterogeneously vancomycin-resistant S. aureus (hetero-VRSA) strains which were isolated from Korean patients using a population analysis method. Antagonistic effects were observed when less than 1 g/mL of beta-lactam antibiotics was combined with vancomycin, whereas synergistic effects were noticed with more than 4 microgram/mL of beta-lactam antibiotics. The antagonistic effects at low concentrations of beta-lactams were most prominent at 2 microgram/mL of vancomycin, which were the vancomycin MICs of tested hetero-VRSA strains. This study showed the variable effects of vancomycin- beta-lactam combinations depending on the concentrations of beta-lactam antibiotics and this property could be used to develop screening methods for hetero-VRSA strains.