Displaying all 10 publications

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  1. Mohd Sazlly Lim S, Shamsudin N
    Malays Fam Physician, 2014;9(2):55-7.
    PMID: 25883766 MyJurnal
    A 5-month-old Malay boy presented with purpuric papules and plaques on the face and extremities accompanied by fever, coryzal symptoms and bilateral lower limb oedema. There were also bullous linear purpuric lesions on the right upper limb. Blood and culture tests were normal. Histopathological tests showed leucocytoclastic vasculitis, confirming the diagnosis of acute haemorrhagic oedema of infancy. The patient achieved complete recovery after 2 weeks with no recurrence.
  2. Mohd Sazlly Lim S, Sime FB, Roberts JA
    Int J Antimicrob Agents, 2019 Jun;53(6):726-745.
    PMID: 30831234 DOI: 10.1016/j.ijantimicag.2019.02.016
    Acinetobacter baumannii remains a difficult-to-treat pathogen that poses a significant challenge to clinicians and costs to the healthcare system. There is a lack of clinical efficacy data to aid in the selection of optimal treatment for multidrug-resistant (MDR) A. baumannii infections. This paper aimed to review recent literature on the treatment of MDR A. baumannii infections and novel agents in the pipeline and to discuss the clinical data supporting their use. Colistin has been widely studied as monotherapy or as part of combination therapy, but its use is limited due to nephrotoxicity. The clinical benefit of combination therapy, whether empirical or targeted, has yet to be demonstrated owing to a lack of definitive evidence from randomised controlled trials (RCTs). Most available clinical studies are retrospective and lack control groups, which offers low-grade evidence. Novel agents such as cefiderocol, plazomicin, eravacycline and sulbactam/ETX2514 combination are promising options for the treatment of different infectious pathologies caused by MDR A. baumannii, but these have yet to be evaluated in RCTs. A better understanding of the pharmacokinetics/pharmacodynamics of the 'old' antibiotics is required to optimise their dosing regimens in order to maximise bacterial killing, minimise toxicities and improve clinical outcomes.
  3. Mohd Sazlly Lim S, Heffernan AJ, Roberts JA, Sime FB
    Microb Drug Resist, 2021 Apr;27(4):546-552.
    PMID: 32898467 DOI: 10.1089/mdr.2020.0197
    Background and Objective: Combination therapy may be a treatment option against carbapenem-resistant Acinetobacter baumannii (CR-AB) infections. In this study, we explored the utility of fosfomycin in combination with meropenem (FOS/MEM) against CR-AB isolates. Materials and Methods: Screening of synergistic activity of FOS/MEM was performed using the checkerboard assay. A pharmacokinetic/pharmacodynamic analysis was performed for various FOS/MEM regimens using Monte Carlo simulations. Results: The minimum inhibitory concentration (MIC) required to inhibit the growth of 50% of the isolates (MIC50) and MIC required to inhibit the growth of 90% of the isolates (MIC90) of FOS and MEM were reduced fourfold and twofold, respectively. The combination was synergistic against 14/50 isolates. No antagonism was observed. Sixteen out of fifty isolates had MEM MICs of ≤8 mg/L when subjected to combination therapy, compared to none with monotherapy. Forty-one out of 50 isolates had FOS MICs of ≤128 mg/L when subjected to combination therapy, compared to 17/50 isolates with monotherapy. The cumulative fraction response for MEM and FOS improved from 0% to 40% and 40% to 80%, with combination therapy, respectively. Conclusions: Addition of MEM improved the in vitro activity of FOS against the CR-AB isolates. FOS/MEM could be a plausible option to treat CR-AB for a small fraction of isolates.
  4. Heffernan AJ, Mohd Sazlly Lim S, Lipman J, Roberts JA
    Anaesth Crit Care Pain Med, 2021 12;40(6):100970.
    PMID: 34728411 DOI: 10.1016/j.accpm.2021.100970
    Critically ill patients admitted to intensive care unit (ICU) with severe infections, or those who develop nosocomial infections, have poor outcomes with substantial morbidity and mortality. Such patients commonly have suboptimal antibiotic exposures at routinely used antibiotic doses related to an increased volume of distribution and altered clearance due to their underlying altered physiology. Furthermore, the use of extracorporeal devices such as renal replacement therapy and extracorporeal membrane oxygenation in these group of patients also has the potential to alter in vivo drug concentrations. Moreover, ICU patients are likely to be infected with less-susceptible pathogens. Therefore, one potential contributing cause to the poor outcomes observed in critically ill patients may be related to subtherapeutic antibiotic exposures. Newer concepts include the clinician considering optimised dosing based on a blood antibiotic exposure defined by pharmacokinetic modelling and therapeutic drug monitoring, combined with a knowledge of the antibiotic penetration into the site of infection, thereby achieving optimal bacterial killing. Such optimised dosing is likely to improve patient outcomes. The aim of this review is to highlight key aspects of antibiotic pharmacokinetics and pharmacodynamics (PK/PD) in critically ill patients and provide a PK/PD approach to tailor antibiotic dosing to the individual patient.
  5. Mohd Sazlly Lim S, Heffernan AJ, Roberts JA, Sime FB
    Antimicrob Agents Chemother, 2023 May 01;65(5).
    PMID: 33685901 DOI: 10.1128/AAC.02472-20
    Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are now considered potential treatments for CR-AB. This study aimed to explore the utility of fosfomycin-sulbactam combination (FOS/SUL) therapy against CR-AB isolates.Synergism of FOS/SUL against 50 clinical CR-AB isolates were screened using the checkerboard method. Thereafter, time-kill studies against two CR-AB isolates were performed. The time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Monte Carlo simulations were then performed to estimate the probability of stasis, 1-log kill and 2-log kill after 24-hours with combination therapy.The FOS/SUL combination demonstrated a synergistic effect against 74% of isolates. No antagonism was observed. The MIC50 and MIC90 of FOS/SUL were decreased four- to eight-fold, compared to the monotherapy MIC50 and MIC90 In the time-kill studies, the combination displayed bactericidal activity against both isolates and synergistic activity against one isolate, at the highest clinically achievable concentrations. Our PK/PD model was able to describe the interaction between fosfomycin and sulbactam in vitro Bacterial kill was mainly driven by sulbactam, with fosfomycin augmentation. FOS/SUL regimens that included sulbactam 4 g every 8 hours, demonstrated a probability of target attainment of 1-log10 kill at 24 h of ∼69-76%, as compared to ∼15-30% with monotherapy regimens at the highest doses.The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that FOS/SUL may potentially be effective against some CR-AB infections.
  6. Mohd Sazlly Lim S, Wong PL, Sulaiman H, Atiya N, Hisham Shunmugam R, Liew SM
    J Hosp Infect, 2019 May;102(1):8-16.
    PMID: 30653999 DOI: 10.1016/j.jhin.2019.01.012
    BACKGROUND: β-Lactamase resistance among certain Gram-negative bacteria has been associated with increased mortality, length of hospitalization, and hospital costs.

    AIM: To identify and critically appraise existing clinical prediction models of extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-EKP) infection or colonization.

    METHODS: Electronic databases, reference lists, and citations were searched from inception to April 2018. Papers were included in any language describing the development or validation, or both, of models and scores to predict the risk of ESBL-EKP infection or colonization.

    FINDINGS: In all, 1795 references were screened, of which four articles were included in the review. The included studies were carried out in different geographical locations with differing study designs, and inclusion and exclusion criteria. Most if not all studies lacked external validation and blinding of reviewers during the evaluation of the predictor variables and outcome. All studies excluded missing data and most studies did not report the number of patients excluded due to missing data. Fifteen predictors of infection or colonization with ESBL-EKP were identified. Commonly included predictors were previous antibiotic use, previous hospitalization, transfer from another healthcare facility, and previous procedures (urinary catheterization and invasive procedures).

    CONCLUSION: Due to limitations and variations in the study design, clinicians would have to take these differences into consideration when deciding on how to use these models in clinical practice. Due to lack of external validation, the generalizability of these models remains a question. Therefore, further external validation in local settings is needed to confirm the usefulness of these models in supporting decision-making.

  7. Mohd Sazlly Lim S, Sinnollareddy M, Sime FB
    J Clin Med, 2020 Sep 06;9(9).
    PMID: 32899911 DOI: 10.3390/jcm9092878
    Diabetic patients have an increased propensity to Candida sp. infections due to disease-related immunosuppression and various other physiological alterations. The incidence of candidiasis has increased in number over the years and is linked to significant morbidity and mortality in critically ill and immunosuppressed patients. Treatment of infection in diabetic patients may be complicated due to the various disease-related changes to the pharmacokinetics and pharmacodynamics (PK/PD) of a drug, including antifungal agents. Application of PK/PD principles may be a sensible option to optimise antifungal dosing regimens in this group of patients. Further studies on PK/PD of antifungals in patients with diabetes mellitus are needed as current data is limited or unavailable.
  8. Mohd Sazlly Lim S, Zainal Abidin A, Liew SM, Roberts JA, Sime FB
    J Infect, 2019 12;79(6):593-600.
    PMID: 31580871 DOI: 10.1016/j.jinf.2019.09.012
    OBJECTIVE: The objective of this works was to assess the global prevalence of multidrug-resistance among A. baumannii causing hospital-acquired (HAP) and ventilator-associated pneumonia (VAP), and describe its associated mortality.

    METHODS: We performed a systematic search of four databases for relevant studies. Meta-analysis was done based on United Nations geoscheme regions, individual countries and study period. We used a random-effects model to calculate pooled prevalence and mortality estimates with 95% confidence intervals (CIs), weighted by study size.

    RESULTS: Among 6445 reports screened, we identified 126 relevant studies, comprising data from 29 countries. The overall prevalence of multidrug-resistance among A. baumannii causing HAP and VAP pooled from 114 studies was 79.9% (95% CI 73.9-85.4%). Central America (100%) and Latin America and the Caribbean (100%) had the highest prevalence, whereas Eastern Asia had the lowest (64.6%; 95% CI, 50.2-77.6%). The overall mortality estimate pooled from 27 studies was 42.6% (95% CI, 37.2-48.1%).

    CONCLUSIONS: We observed large amounts of variation in the prevalence of multidrug-resistance among A. baumannii causing HAP and VAP and its mortality rate among regions and lack of data from many countries. Data from this review can be used in the development of customized strategies for infection control and antimicrobial stewardship.

  9. Mohd Sazlly Lim S, Naicker S, Ayfan AK, Zowawi H, Roberts JA, Sime FB
    Int J Antimicrob Agents, 2020 Oct;56(4):106115.
    PMID: 32721600 DOI: 10.1016/j.ijantimicag.2020.106115
    Due to limited therapeutic options, combination therapy has been used empirically to treat carbapenem-resistant Acinetobacter baumannii (CRAB). Polymyxin-based combinations have been widely studied and used in the clinical setting. However, the use of polymyxins is often limited due to nephrotoxicity and neurotoxicity. This study aimed to evaluate the activity of non-polymyxin-based combinations relative to polymyxin-based combinations and to identify potential synergistic and bactericidal two-drug non-polymyxin-based combinations against CRAB. In vitro activity of 14 two-drug combinations against 50 A. baumannii isolates was evaluated using the checkerboard method. Subsequently, the two best-performing non-polymyxin-based combinations from the checkerboard assay were explored in static time-kill experiments. Concentrations of antibiotics corresponding to the fractional inhibitory concentrations (FIC) and the highest serum concentration achievable clinically were tested. The most synergistic combinations were fosfomycin/sulbactam (synergistic against 37/50 isolates; 74%), followed by meropenem/sulbactam (synergistic against 28/50 isolates; 56%). No antagonism was observed for any combination. Both fosfomycin/sulbactam and meropenem/sulbactam combinations exhibited bactericidal and synergistic activity against both isolates at the highest clinically achievable concentrations in the time-kill experiments. The meropenem/sulbactam combination displayed synergistic and bactericidal activity against one of two strains at concentrations equal to the FIC. Non-polymyxin-based combinations such as fosfomycin/sulbactam and meropenem/sulbactam may have a role in the treatment of CRAB. Further in vivo and clinical studies are required to scrutinise these activities further.
  10. Mohd Sazlly Lim S, Heffernan AJ, Zowawi HM, Roberts JA, Sime FB
    Eur J Clin Microbiol Infect Dis, 2021 Sep;40(9):1943-1952.
    PMID: 33884516 DOI: 10.1007/s10096-021-04252-z
    Due to limited treatment options for carbapenem-resistant Acinetobacter baumannii (CR-AB) infections, antibiotic combinations are commonly used. In this study, we explored the potential efficacy of meropenem-sulbactam combination (MEM/SUL) against CR-AB. The checkerboard method was used to screen for synergistic activity of MEM/SUL against 50 clinical CR-AB isolates. Subsequently, time-kill studies against two CR-AB isolates were performed. Time-kill data were described using a semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) model. Subsequently, Monte Carlo simulations were performed to estimate the probability of 2-log kill, 1-log kill or stasis at 24-h following combination therapy. The MEM/SUL demonstrated synergy against 28/50 isolates. No antagonism was observed. The MIC50 and MIC90 of MEM/SUL were decreased fourfold, compared to the monotherapy MIC. In the time-kill studies, the combination displayed synergistic killing against both isolates at the highest clinically achievable concentrations. At concentrations equal to the fractional inhibitory concentration, synergism was observed against one isolate. The PK/PD model adequately delineated the data and the interaction between meropenem and sulbactam. The effect of the combination was driven by sulbactam, with meropenem acting as a potentiator. The simulations of various dosing regimens revealed no activity for the monotherapies. At best, the MEM/SUL regimen of 2 g/4 g every 8 h demonstrated a probability of target attainment of 2-log10 kill at 24 h of 34%. The reduction in the MIC values and the achievement of a moderate PTA of a 2-log10 reduction in bacterial burden demonstrated that MEM/SUL may potentially be effective against some CR-AB infections.
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