Adrian Brink

In Vivo Development of Ertapenem Resistance in a Patient with Pneumonia Caused by Klebsiella pneumoniae with an Extended-Spectrum β-Lactamase

Four sequential extended-spectrum beta -lactamase-producing isolates of Klebsiella pneumoniae were obtained from a patient after treatment with ertapenem and cultured. The first and fourth isolates were susceptible to ertapenem, whereas the second and third were resistant. All 4 isolates belonged to the same strain and produced a group 1 CTX-M enzyme; additionally, the resistant isolates had lost a porin.

Serotype 19F Multiresistant Pneumococcal Clone Harboring Two Erythromycin Resistance Determinants [erm(B) and mef(A)] in South Africa

ABSTRACT One hundred eighteen erythromycin-resistant Streptococcus pneumoniae (ERSP) strains (MICs of ≥0.5 μg/ml) from five laboratories serving the private sector in South Africa were analyzed for the genes encoding resistance to macrolides. Sixty-seven ERSP strains (56.8%) contained the erm(B) gene, and 15 isolates (12.7%) contained the mef(A) gene. Thirty-six isolates (30.5%) harbored both the erm(B) and mef(A) genes and were highly resistant to erythromycin and clindamycin. DNA fingerprinting by BOX-PCR and pulsed-field gel electrophoresis identified 83% of these strains as belonging to a single multiresistant serotype 19F clone.

Emergence of New Delhi Metallo-Beta-Lactamase (NDM-1) and Klebsiella pneumoniae Carbapenemase (KPC-2) in South Africa

ABSTRACT This report documents emergence of New Delhi metallo-beta-lactamase (NDM-1) and Klebsiella pneumoniae carbapenemase (KPC-2) in K. pneumoniae and Enterobacter cloacae in South Africa. NDM-1 producers have not been described in South Africa, and this is the first instance that KPC producers have been identified in Africa. The two patients infected with these carbapenemase-producing bacteria demised.

Emergence of OXA-48 and OXA-181 Carbapenemases among Enterobacteriaceae in South Africa and Evidence of In Vivo Selection of Colistin Resistance as a Consequence of Selective Decontamination of the Gastrointestinal Tract

ABSTRACT This study reports on the emergence of OXA-48-like carbapenemases among isolates of Enterobacteriaceae in South Africa. In addition, the emergence during therapy of a colistin-resistant OXA-181-producing Klebsiella pneumoniae isolate was documented following selective digestive tract decontamination with oral colistin, which is therefore strongly discouraged.

Genetic Features of MCR-1-Producing Colistin-Resistant Escherichia coli Isolates in South Africa

ABSTRACT A series of colistin-resistant Escherichia coli clinical isolates was recovered from hospitalized and community patients in South Africa. Seven clonally unrelated isolates harbored the mcr-1 gene located on different plasmid backbones. Two distinct plasmids were fully sequenced, and identical 2,600-bp-long DNA sequences defining a mcr-1 cassette were identified. Promoter sequences responsible for the expression of mcr-1, deduced from the precise identification of the +1 transcription start site for mcr-1, were characterized.

Resistance to Colistin Associated with a Single Amino Acid Change in Protein PmrB among Klebsiella pneumoniae Isolates of Worldwide Origin

ABSTRACT A series of colistin-resistant Klebsiella pneumoniae isolates recovered from different countries was investigated in order to evaluate the involvement of the PmrA/PmrB two-component system in this resistance. Six isolates possessed a mutated PmrB protein, which is encoded by the pmrB gene, part of the pmrCAB operon involved in lipopolysaccharide modification. The same amino acid substitution (Thr157Pro) in PmrB was identified in the six isolates. The six isolates belonged to four distinct clonal groups, recovered in South Africa (sequence type 14 [ST14]), Turkey (ST101), and Colombia (ST258 and ST15). Three out of the four clones produced a carbapenemase, OXA-181, OXA-48, or KPC-3, while a single isolate did not produce any carbapenemase. Expression assays revealed an overexpression of the pmrA (70-fold), pmrB (70-fold), pmrC (170-fold), and pmrK (40-fold) genes in the pmrB-mutated isolate compared to expression of the pmrB wild-type isogenic K. pneumoniae isolate, confirming that the PmrB substitution was responsible for increased expression levels of those genes. Complementation assays leading to the expression of a wild-type PmrB protein restored the susceptibility to colistin in all isolates, confirming that the substitution in PmrB was responsible for the resistance phenotype. This study identified a key amino acid located in the PmrB protein as being responsible for the overexpression of pmrCAB and pmrHFIJKLM operons, leading to resistance to colistin.

Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis

BACKGROUND The spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide. Due to its large public health and societal implications, multidrug-resistant tuberculosis has been long regarded by WHO as a global priority for investment in new drugs. In 2016, WHO was requested by member states to create a priority list of other antibiotic-resistant bacteria to support research and development of effective drugs. METHODS We used a multicriteria decision analysis method to prioritise antibiotic-resistant bacteria; this method involved the identification of relevant criteria to assess priority against which each antibiotic-resistant bacterium was rated. The final priority ranking of the antibiotic-resistant bacteria was established after a preference-based survey was used to obtain expert weighting of criteria. FINDINGS We selected 20 bacterial species with 25 patterns of acquired resistance and ten criteria to assess priority: mortality, health-care burden, community burden, prevalence of resistance, 10-year trend of resistance, transmissibility, preventability in the community setting, preventability in the health-care setting, treatability, and pipeline. We stratified the priority list into three tiers (critical, high, and medium priority), using the 33rd percentile of the bacteriums total scores as the cutoff. Critical-priority bacteria included carbapenem-resistant Acinetobacter baumannii and Pseudomonas aeruginosa, and carbapenem-resistant and third-generation cephalosporin-resistant Enterobacteriaceae. The highest ranked Gram-positive bacteria (high priority) were vancomycin-resistant Enterococcus faecium and meticillin-resistant Staphylococcus aureus. Of the bacteria typically responsible for community-acquired infections, clarithromycin-resistant Helicobacter pylori, and fluoroquinolone-resistant Campylobacter spp, Neisseria gonorrhoeae, and Salmonella typhi were included in the high-priority tier. INTERPRETATION Future development strategies should focus on antibiotics that are active against multidrug-resistant tuberculosis and Gram-negative bacteria. The global strategy should include antibiotic-resistant bacteria responsible for community-acquired infections such as Salmonella spp, Campylobacter spp, N gonorrhoeae, and H pylori. FUNDING World Health Organization.

Pharmacokinetics of once-daily dosing of ertapenem in critically ill patients with severe sepsis.

Adequate data on the pharmacokinetics of once-daily administration of ertapenem in critically ill patients are largely lacking. This single-centre, prospective, open-label study was performed on a cohort of eight critically ill patients with severe sepsis with normal renal function treated with 1g of ertapenem once daily. Samples of venous blood and urine were collected before infusion and at specific time points in the 24-h post-infusion period. Plasma and urine ertapenem levels were determined by reverse-phase high-performance liquid chromatography (HPLC) with ultraviolet detection. The non-protein-bound fraction was determined in the filtrate by HPLC using a Centrifree device. The current study showed a lower maximum plasma concentration (C(max)) (52.3.0mg/L vs. 253 mg/L) and area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)) (188 mg h/L vs. 817 mg h/L) but higher volume of distribution at steady state (V(ss)) (26.8L vs. 5.7 L) compared with those observed in young healthy volunteers. For unbound ertapenem, geometric means of C(max) and AUC(0-infinity) were 29.5mg/L and 103.5 mg h/L, respectively, and correlated negatively with hypoalbuminaemia. Unbound levels failed to exceed a minimum inhibitory concentration of 1mg/L for more than 7.1h (30%) of the dosing interval in two patients. The highly variable and unpredictable intersubject pharmacokinetic parameters documented in this study resulted in suboptimal unbound concentrations in some patients. This raises the question as to whether ertapenem is an appropriate agent for initial use in critically ill patients with severe sepsis.

Heteroresistance to Colistin in Klebsiella pneumoniae Associated with Alterations in the PhoPQ Regulatory System

ABSTRACT A multidrug-resistant Klebsiella pneumoniae isolate exhibiting heteroresistance to colistin was investigated. The colistin-resistant subpopulation harbored a single amino acid change (Asp191Tyr) in protein PhoP, which is part of the PhoPQ two-component system that activates pmrHFIJKLM expression responsible for l-aminoarabinose synthesis and polymyxin resistance. Complementation assays with a wild-type phoP gene restored full susceptibility to colistin. Then, analysis of the colistin-susceptible subpopulation showed a partial deletion (25 bp) in the phoP gene compared to that in the colistin-resistant subpopulation. That deletion disrupted the reading frame of phoP, leading to a longer and inactive protein (255 versus 223 amino acids long). This is the first report showing the involvement of mutation(s) in PhoP in colistin resistance. Furthermore, this is the first study to decipher the mechanisms leading to colistin heteroresistance in K. pneumoniae.

A global call from five countries to collaborate in antibiotic stewardship: united we succeed, divided we might fail

In February, 2016, WHO released a report for the development of national action plans to address the threat of antibiotic resistance, the catastrophic consequences of inaction, and the need for antibiotic stewardship. Antibiotic stewardship combined with infection prevention comprises a collaborative, multidisciplinary approach to optimise use of antibiotics. Efforts to mitigate overuse will be unsustainable without learning and coordinating activities globally. In this Personal View, we provide examples of international collaborations to address optimal prescribing, focusing on five countries that have developed different approaches to antibiotic stewardship-the USA, South Africa, Colombia, Australia, and the UK. Although each countrys approach differed, when nurtured, individual efforts can positively affect local and national antimicrobial stewardship programmes. Government advocacy, national guidelines, collaborative research, online training programmes, mentoring programmes, and social media in stewardship all played a role. Personal relationships and willingness to learn from each others successes and failures continues to foster collaboration. We recommend that antibiotic stewardship models need to evolve from infection specialist-based teams to develop and use cadres of health-care professionals, including pharmacists, nurses, and community health workers, to meet the needs of the global population. We also recommend that all health-care providers who prescribe antibiotics take ownership and understand the societal burden of suboptimal antibiotic use, providing examples of how countries can learn, act globally, and share best antibiotic stewardship practices.