The objective of this study was to investigate the antimicrobial resistance patterns of 47 clinical isolates of Aeromonas aquariorum and to identify the presence of plasmids and the relevant antibiotic resistance genes (ARGs). Antibiotic susceptibilities were determined by the standard disc diffusion method. The presence of plasmids and ARGs was detected by gel electrophoresis and monoplex PCR. Resistance to amoxicillin/clavulanic acid (98%), amoxicillin (91%), gentamicin (13%), trimethoprim/sulfamethoxazole (11%) and kanamycin (6%) was observed, whilst no ciprofloxacin- or amikacin-resistant strains were detected. All isolates harboured plasmids with sizes ranging from ca. 2 kb to 10 kb. PCR revealed that A. aquariorum carried three β-lactam resistance genes (bla(TEM), bla(MOX) and bla(PSE)) and two sulphonamide resistance genes (sul1 and sul2). This study provides further understanding of the phenotypic and genotypic characteristics of multiresistant A. aquariorum clinical isolates.
The role of membrane permeabilisation and disruption in the mechanism of action of some polymyxin analogues against Gram-negative organisms is contentious. The effects of polymyxin B (PMB) and its analogue polymyxin B nonapeptide (PMBN) on Escherichia coli envelopes should correlate, but previous work by other workers suggests that PMBN has a different mode of action. This study has reassessed the biochemical techniques used previously and has shown that, in contrast to previous studies, PMBN (a well-characterised antibacterial synergist) readily releases periplasmic proteins and lipopolysaccharide from treated E. coli at subinhibitory concentrations in normal physiological buffer conditions. We conclude that, when tested with appropriate methodology, PMBN closely correlates with the early effects of PMB on the cell envelope of E. coli and this study shows that it is now consistent with the accepted interactions of membrane-active agents against Gram-negative cells.
Bloodstream infections (bacteraemia) account for approximately 25-30% of febrile episodes in patients with febrile neutropenia (FN). In developed countries, Gram-positive pathogens predominate. Mortality is higher in Gram-negative bacteraemia. A recent study involving 2142 patients with FN was reviewed, including 168 patients with Gram-negative bacteraemia (mortality 18%), 283 patients with Gram-positive bacteraemia (mortality 5%) and 48 patients with polymicrobial bacteraemia (mortality 13%). Among patients who received prophylactic antibiotics, Gram-positive bacteraemia was far more common than Gram-negative bacteraemia (75% vs. 25%), compared with approximately 50% of each in patients without prophylactic antibiotics. Patients with a Multinational Association for Supportive Care in Cancer (MASCC) score <15 had a 36% mortality compared with 3% if the MASCC score was >21. The MASCC score may help risk stratification of patients with FN and bacteraemia, although these data require confirmation. In two series of patients from developing countries (Lebanon and Malaysia), Gram-negative bacteraemia was more common and mortality was higher. In developing countries, Gram-negative bacteraemia may be more frequent due to less use of prophylactic antibiotics and central lines. Laboratory markers may have predictive and prognostic value for bacteraemia in patients at the onset of FN, including mannose-binding lectin, interleukin (IL)-6, IL-8 and procalcitonin, but further studies are required before they can be recommended. New therapies are required to lower the mortality in patients with FN with a high risk for bacteraemia.
Doripenem is approved in the Asia-Pacific (APAC) region for treating nosocomial pneumonia (NP) including ventilator-associated pneumonia (VAP), complicated intra-abdominal infections (cIAIs) and complicated urinary tract infections (cUTIs). Clinical usage of doripenem (500mg intravenously, infused over 1h or 4h every 8h for 5-14 days) in APAC was evaluated in a prospective, open-label, non-comparative, multicentre study of inpatients (≥18 years) with NP, VAP, cIAI or cUTI. A total of 216 [intention-to-treat (ITT)] patients received doripenem: 53 NP (24.5%); 77 VAP (35.6%); 67 cIAI (31.0%); and 19 cUTI (8.8%). Doripenem MIC90 values for Pseudomonas aeruginosa, Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae were 32, 32, 0.094 and 0.64μg/mL, respectively. Doripenem was used most commonly as monotherapy (86.6%) and as second-line therapy (62.0%). The clinical cure rate in clinically evaluable patients was 86.7% at the end of therapy (EOT) and 87.1% at test of cure (TOC) (7-14 days after EOT). In the ITT population, overall clinical cure rates were 66.2% at EOT and 56.5% at TOC. The median duration of hospital stay, intensive care unit (ICU) stay and mechanical ventilation was 20, 12 and 10 days, respectively. Of 146 discharged patients, 7 were re-admitted within 28 days of EOT; 1 VAP patient was re-admitted to the ICU. The all-cause mortality rate was 22.7% (49/216). The most common treatment-related adverse events were diarrhoea (1.4%) and vomiting (1.4%). Doripenem is a viable option for treating APAC patients with NP, VAP, cIAI or cUTI. [ClinicalTrials.gov: NCT 00986102].
Carbapenem-resistant Enterobacteriaceae infections have spread globally, leaving polymyxins, including colistin, as 'last-resort treatments'. Emerging colistin resistance raises the spectre of untreatable infections. Despite this threat, data remain limited for much of the world, including Southeast Asia where only 3 of 11 nations submitted data on carbapenem and colistin resistance for recent World Health Organization (WHO) reports. To improve our understanding of the challenge, we utilised broad strategies to search for and analyse data on carbapenem and colistin resistance among Escherichia coli and Klebsiella in Southeast Asia. We found 258 studies containing 526 unique reports and document carbapenem-resistant E. coli and Klebsiella in 8 and 9 of 11 nations, respectively. We estimated carbapenem resistance proportions through meta-analysis of extracted data for nations with ≥100 representative isolates. Estimated resistance among Klebsiella was high (>5%) in four nations (Indonesia, Philippines, Thailand and Vietnam), moderate (1-5%) in two nations (Malaysia and Singapore) and low (<1%) in two nations (Cambodia and Brunei). For E. coli, resistance was generally lower but was high in two of seven nations with ≥100 isolates (Indonesia and Myanmar). The most common carbapenemases were NDM metallo-β-lactamases and OXA β-lactamases. Despite sparse data, polymyxin resistance was documented in 8 of 11 nations, with mcr-1 being the predominant genotype. Widespread presence of carbapenem and polymyxin resistance, including their overlap in eight nations, represents a continuing risk and increases the threat of infections resistant to both classes. These findings, and remaining data gaps, highlight the urgent need for sufficiently-resourced robust antimicrobial resistance surveillance.
As the number of pathogenic microbial strains resistant to different antibiotics increases, amphipathic peptides with antimicrobial activity are promising agents for the therapy of infectious diseases. This work deals with the effect of an amphipathic antimicrobial peptide, melittin, expressed within recombinant plasmid vectors, on infection with urogenital pathogens Chlamydia trachomatis and Mycoplasma hominis in HeLa cell culture. Recombinant plasmid constructs with the melittin gene under the control of the tetracycline-responsive promoter of human cytomegalovirus were obtained. We showed inhibition of C. trachomatis and M. hominis infection after the introduction of recombinant plasmid vectors expressing the melittin gene into the infected cell culture.
A total of 9599 isolates of Gram-negative bacteria (GNB) causing urinary tract infections (UTIs) were collected from 60 centres in 13 countries in the Asia-Pacific region from 2010-2013. These isolates comprised Enterobacteriaceae species (mainly Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Klebsiella oxytoca, Enterobacter cloacae and Morganella morganii) and non-fermentative GNB species (predominantly Pseudomonas aeruginosa and Acinetobacter baumannii). In vitro susceptibilities were determined by the agar dilution method and susceptibility profiles were determined using the minimum inhibitory concentration (MIC) interpretive breakpoints recommended by the Clinical and Laboratory Standards Institute in 2015. Production of extended-spectrum β-lactamases (ESBLs) amongst E. coli, K. pneumoniae, P. mirabilis and K. oxytoca isolates was determined by the double-disk synergy test. China, Vietnam, India, Thailand and the Philippines had the highest rates of GNB species producing ESBLs and the highest rates of cephalosporin resistance. ESBL production and hospital-acquired infection (isolates obtained ≥48h after admission) significantly compromised the susceptibility of isolates of E. coli and K. pneumoniae to ciprofloxacin, levofloxacin and most β-lactams, with the exception of imipenem and ertapenem. However, >87% of ESBL-producing E. coli strains were susceptible to amikacin and piperacillin/tazobactam, indicating that these antibiotics might be appropriate alternatives for treating UTIs due to ESBL-producing E. coli. Fluoroquinolones were shown to be inappropriate as empirical therapy for UTIs. Antibiotic resistance is a serious problem in the Asia-Pacific region. Therefore, continuous monitoring of evolutionary trends in the susceptibility profiles of GNB causing UTIs in Asia is crucial.
This study was conducted to investigate the epidemiology and antimicrobial susceptibility patterns of Gram-negative bacilli (GNB) isolated from intra-abdominal infections (IAIs) in the Asia-Pacific region (APR) from 2010-2013. A total of 17 350 isolates were collected from 54 centres in 13 countries in the APR. The three most commonly isolated GNB were Escherichia coli (46.1%), Klebsiella pneumoniae (19.3%) and Pseudomonas aeruginosa (9.8%). Overall, the rates of extended-spectrum β-lactamase (ESBL)-producing E. coli and K. pneumoniae were 38.2% and 24.3%, respectively, and they were highest in China (66.6% and 38.7%, respectively), Thailand (49.8% and 36.5%, respectively) and Vietnam (47.9% and 30.4%, respectively). During 2010-2013, the rates of ESBL-producing E. coli and K. pneumoniae isolates causing community-associated (CA) IAIs (collected <48 h after admission) were 26.0% and 13.5%, respectively, and those causing hospital-associated (HA) IAIs were 48.0% and 30.6%, respectively. Amikacin, ertapenem and imipenem were the most effective agents against ESBL-producing isolates. Piperacillin/tazobactam displayed good in vitro activity (91.4%) against CA ESBL-producing E. coli. For other commonly isolated Enterobacteriaceae, fluoroquinolones, cefepime and carbapenems exhibited better in vitro activities than third-generation cephalosporins. Amikacin possessed high in vitro activity against all GNB isolates (>80%) causing IAIs, except for Acinetobacter calcoaceticus-baumannii (ACB) complex (30.9% for HA-IAI isolates). All of the antimicrobial agents tested exhibited <45% in vitro activity against ACB complex. Antimicrobial resistance is a persistent threat in the APR and continuous monitoring of evolutionary trends in the susceptibility patterns of GNB causing IAIs in this region is mandatory.
This study aimed to investigate the geographical trends of minimum inhibitory concentrations (MICs) for tigecycline and colistin in Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae isolates which were collected for the Antimicrobial Testing Leadership and Surveillance (ATLAS) programme from 2016-2021. MICs of the isolates were determined using the broth microdilution method. In the study period, there was an increase in MIC50 and MIC90 values in Asia for tigecycline MICs in A. baumannii isolates, and the geometric mean of MICs increased significantly from 0.51-0.96 (R2 value of 0.912). The isolates in Europe and Latin America also showed an increase in the geometric mean, but the percentage of MIC values ≤ 2 mg/L decreased from 99.7% to 86.7% in Asia. Among the Asian countries studied, China (90.9%), Thailand (94.3%), and Malaysia (95.5%) showed the lower percentages of tigecycline MIC values ≤0.5 mg/L for E. coli isolates. In terms of colistin susceptibility among A. baumannii isolates, there was no increase in MIC50/ MIC90 or the geometric mean from 2016-2021. Compared to other continents, A. baumannii isolates in Europe had the highest MIC50 (0.5 mg/L), MIC90 (2 mg/L), and geometric mean (0.55 mg/L). For E. coli, the percentage of colistin MIC values ≤2 mg/L was consistently >98% in the study areas from 2016-2021. Among K. pneumoniae isolates, Europe and Latin America had higher geometric means of MICs (0.41 and 0.4 mg/L, respectively) and lower percentages of colistin MICs ≤2 mg/L than those in the other continents.
To understand the global changes in non-susceptibility rates of Streptococcus pneumoniae to ceftriaxone, we conducted a study using the Antimicrobial Testing Leadership and Surveillance database. A total of 15,717 S. pneumoniae isolates were collected from 2016 to 2021. The minimum inhibitory concentrations (MICs) were determined using broth microdilution. The overall susceptibility rates of S. pneumoniae isolates to penicillin, ceftriaxone and ceftaroline were 63.4%, 94.0% and 99.6%, respectively. The geometric mean of MICs and MIC50/MIC90 values of ceftriaxone were higher in Asia than in other continents. China (33.9%), South Korea (33.8%) and Taiwan (27.6%) had the highest ceftriaxone non-susceptibility rates, followed by Turkey, India, Brazil, Malaysia, South Africa and Colombia, with rates between 10% and 20%. During the study period from 2020 to 2021, Asia had the highest MIC90 value (4 mg/L) for ceftriaxone in S. pneumoniae isolates, and the geometric mean of MICs increased from 0.25 mg/L in 2016-2017 to 0.39 mg/L in 2020-2021. Both Asia (from 83.4% to 75.1%) and Latin America (from 94.2% to 86.3%) showed a decreasing trend in ceftriaxone susceptibility rates from 2016 to 2021. In North America, Europe and Oceania, the susceptibility rate was higher than 95%, and there was no obvious change in the rate during the 6 y. Further analysis of the data from Asia revealed that individuals younger than 6 y of age had a lower susceptibility rate to ceftriaxone (71.6% vs. 81.7%, P < 0.05) than patients ≥6 y. The higher non-susceptibility rates of ceftriaxone in S. pneumoniae in Asia may lead to therapeutic challenges in community-acquired pneumonia.
In addition to being a human pathogen, Staphylococcus aureus causes an array of infections in economically important livestock animals, particularly pigs. In Asia, there have been few reports on livestock-associated meticillin-resistant S. aureus (LA-MRSA), mostly from developed countries, with very few data available from resource-limited countries, not because of low prevalence but probably due to a shortage of diagnostic facilities. Unlike the wide spread of sequence type 398 (ST398) LA-MRSA in European countries and North America, ST9 predominates in most Asian countries. The prevalence of LA-MRSA among pigs in Asian countries varied widely (0.9-42.5%). The prevalence may vary by geographic location, age of pigs and sampling methodologies. Among pig farmers, the prevalence of nasal MRSA colonisation varied from 5.5% in Malaysia to 15% in China and 19.2% in Taiwan. Although most LA-MRSA isolates in Asia are of the same ST, molecular characteristics are not all the same. Dominant isolates in China were characterised as spa type t899-SCCmec III and t899-SCCmec IVb or V for isolates in Hong Kong, and t899-untypeable SCCmec for Taiwan. Dominant isolates in Malaysia were spa type t4358-SCCmec V and t337-SCCmec IX for isolates in Thailand. In addition, MRSA ST221 was reported in Japan and MRSA ST398 was isolated from commercial pigs in South Korea. Attention should be paid because pigs could become an important reservoir for MRSA and spread them to humans, as observed in many countries. There is a potential risk from the livestock reservoir to community and hospitals.
Indiscriminate antimicrobial use (AMU) in aquaculture to treat and prevent diseases is common and can lead to the emergence of antimicrobial-resistant micro-organisms, potentially impacting public health and connected ecosystems. This study aimed to develop a typology to classify and characterise interventions to reduce AMU in aquaculture and identify points of action. Seventeen aquaculture and animal health professionals in Asian and African countries were interviewed to gather information on characteristics of interventions in different contexts to develop a typology. Seven types of interventions were defined: (i) legislation and regulations; (ii) industry rules and standards; (iii) voluntary instruments; (iv) commercial technology and alternatives to antimicrobials; (v) on-farm management; (vi) learning and awareness-raising; and (vii) activities with co-benefits. Types were based on intervention function, scope of implementation, implementer, compulsion, strength of the intervention, AMU/antimicrobial resistance (AMR) objective and stakeholder to influence. For each type, examples were described and discussed. The most common interventions to address AMU and AMR were legislative and regulatory frameworks and voluntary instruments, including National Action Plans. Interventions addressing AMU/AMR specifically were scarce. Other interventions focused on indirect effect pathways to AMU and AMR reduction aiming to improve good aquaculture practices, disease prevention and improved management. Monitoring and evaluation of these interventions were found to be rare, only present for interventions driven by development projects and international agencies. The presented typology of existing strategies and interventions addressing AMU/AMR in aquaculture systems can guide evaluation of AMR-sensitive interventions that promote responsible AMU, and informs the design and implementation of future interventions.
Antibiotic prescribing by primary care doctors has received renewed interest due to the continuing emergence of antibiotic resistance and the attendant cost to healthcare. We examined the antibiotic prescribing rate in relation to selected socio-demographic characteristics of the prescribers at the Seremban Health Clinic, a large public primary care clinic, designated for teaching, in the state of Negeri Sembilan, Malaysia. Data were obtained from: (1) retrospective review of prescriptions for the month of June 2002 and (2) a questionnaire survey of prescribers. A total of 10667 prescriptions were reviewed. The overall antibiotic prescribing rate was 15%; the rate (16%) was higher for the general Outpatient Department (OPD) than the 3% for the Maternal & Child Health Clinic (MCH). The antibiotic prescription rates for upper respiratory tract infection (URTI) were 26% and 16%, respectively, for the OPD and MCH. Half of all the antibiotic prescriptions were for URTI making prescribing for URTI an appropriate target for educational intervention. The URTI-specific antibiotic prescription rate did not correlate with the prescribers' intention to specialise, patient load, perceived patient's expectation for an antibiotic, or the score for knowledge of streptococcal tonsillitis. Prescribing behaviours and record-keeping practices requiring correction were identified.
Study site: Klinik Kesihatan Seremban, Negeri Sembilan, Malaysia
Lung transplant (LTx) patients have an increased risk of developing invasive fungal infections (IFIs), particularly invasive aspergillosis. Rapid identification of the causative fungal pathogen, to allow for early administration of appropriate initial antifungal therapy, in LTx patients has been challenging due to the limited sensitivity and specificity of the diagnostic tools. Hence, there is increasing emphasis on antifungal prophylaxis in the LTx setting, given the high mortality rates and substantial cost of treating IFIs. Evidence for the optimal antifungal prophylactic approach in this setting, however, remains scant and inconsistent. This review will briefly discuss the epidemiology, risk factors, timing and clinical manifestations of fungal infections in LTx patients and will focus primarily on the available evidence related to the efficacy, safety and practicality of current prophylactic strategies in LTx recipients as well as challenges and gaps for future research.
Treatment of fungal keratitis remains challenging. To date, only the polyenes and azoles are commonly used topically in the management of fungal keratitis. Natamycin, a polyene, is the only antifungal eye drop that is commercially available; the remainder are prepared in-house and are used in an 'off-label' manner. Failure of medical treatment for fungal keratitis is common, hence there is a need for more effective topical antifungal therapy. To increase the antifungal eye drop armamentarium, it is important to investigate the utility of other classes of antifungal agents for topical use. Caspofungin, an echinocandin antifungal agent, could potentially be used to address the existing shortcomings. However, little is known about the usefulness of topically administered caspofungin. This review will briefly explore the incidence, epidemiology and antifungal treatment of fungal keratitis. It will focus primarily on evidence related to the efficacy, safety and practicality of using caspofungin eye drops in fungal keratitis.
Candidaemia and invasive candidiasis (IC) complicate modern medical therapy, contributing to high morbidity and mortality. Managing candidiasis is costly, with an additional healthcare expenditure of nearly US$300 million annually. Recent consensus guidelines have suggested the use of newer antifungal agents, such as echinocandins, for the treatment of candidaemia and IC owing to promising clinical outcomes compared with older-generation antifungal agents, but at higher drug acquisition and administration costs. Comprehensive cost-effectiveness data for echinocandins in treating candidaemia and IC remain relatively scant, underlining the need for more studies to incorporate robust economic analyses into clinical decisions. Assessment of the cost efficiencies of these expensive antifungal agents is essential for maximising health outcomes within the constraints of healthcare resources. This review will explore the epidemiology of candidaemia and IC in the context of clinical and economic aspects of the antifungal agents used to treat IC, especially the echinocandins. Standardising the outcome measure, methodology and reporting of results used in economic studies is central to ensure validity and comparability of the findings. Future studies comparing the economic advantages of all available antifungal treatment options and in the context of new diagnostic tools for fungal infections are anticipated.
Multidrug microbial resistance poses major challenges to the management of infection, particularly with the paucity of new drugs with activity against these bacteria. Since the turn of this century a few new antibiotics have been licensed, including linezolid, daptomycin and tigecycline. This supplement reports data presented at the 13th International Congress of Infectious Diseases held in Kuala Lumpur in June 2008. Dr R. Isturiz reviews the data on global resistance trends and the potential impact on empirical therapy; Dr J.-H. Song reviews new agents on the antimicrobial horizon; and the final paper in the supplement, by Dr L.R. Peterson, reviews the role of tigecycline in the management of complicated intra-abdominal and skin and soft tissue infections.