What remains against carbapenem-resistant Enterobacteriaceae? Evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline

TL;DR: The activity of colistin, fosfomycin and tigecycline was unrelated to the isolates' carbapenem resistance mechanisms, and studies with transconjugants and transformants confirmed the small effect of KPC enzymes against temocillin, whereas OXA-48 and NDM-1 conferred clear resistance.

About: This article is published in International Journal of Antimicrobial Agents.The article was published on 2011-05-01 and is currently open access. It has received 318 citations till now. The article focuses on the topics: Temocillin & Carbapenem-resistant enterobacteriaceae.

Summary

1. Introduction

• Carbapenem-resistant Enterobacteriaceae are increasingly prevalent in many parts of the world.
• They are diverse, variously producing metallo-carbapenemases (mostly NDM [1] or VIM [2] enzymes) or non-metallo-types (principally KPC [3] or OXA-48 [4]).
• Here the authors present susceptibility data for chloramphenicol, ciprofloxacin, colistin, fosfomycin, nitrofurantoin, minocycline and tigecycline against carbapenemase- producers collected in the UK, selected as non--lactam and non-aminoglycoside drugs.
• The -lactam temocillin was also included as it has been suggested by others to have specific activity against strains with KPC carbapenemases [8].

2.1. Bacteria

• The strain set has been described previously [6].
• It represents a diversity of carbapenem resistance types and host species, including organisms with carbapenemases and with combinations of ESBL or AmpC and impermeability, but does not comprise consecutive producer isolates, nor was it matched to the relative prevalence of different resistance types.
• Transformants and transconjugants of Escherichia coli DH5 and J62-1 with carbapenemase-encoding plasmids were prepared as described previously [7].

3. Results and discussion

• Ac ce pt ed M an us cr ip t 2 omits temocillin since, uniquely among the compounds tested, it is a -lactam directly affected by some of the carbapenemases; it is therefore implausible that species would be the major determinant of its activity.
• In the case of fosfomycin, 16/20 carbapenem-resistant Enterobacter spp. and C. freundii were susceptible at the EUCAST/British Society for Antimicrobial Page 7 of 21 Ac ce pt ed M an us cr ip t Chemotherapy (BSAC) systemic and urinary breakpoint of 32 mg/L, whereas four were resistant; corresponding proportions for Klebsiella spp. were 25/52 susceptible and 27/52 resistant.
• Moreover, in some cases, colistin resistance is selected during therapy, and this may apply for the resistant E. cloacae with NDM-1 enzyme in the present study, which was from a child who had already received colistin for Acinetobacter and Pseudomonas infections [12].
• Ac ce pt ed M an us cr ip t Temocillin only showed potential when reviewed against urinary breakpoints and, on these criteria, had activity against all of the isolates with carbapenem resistance contingent on combinations of ESBL or AmpC and impermeability, as well as onehalf those with KPC enzymes.
• First, these results provide only a wide-angle snapshot.

Figures

Table 3 Minimum inhibitory concentrations (MICs) of temocillin for Escherichia coli transconjugants and transformants with acquired carbapenemases

Frequently asked questions

Q1. What have the authors contributed in "What remains against carbapenem-resistant enterobacteriaceae? evaluation of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline" ?

Livermore et al. this paper presented susceptibility data for chloramphenicol, ciprofloxacin, colistin, fosfomycin, nitrofurantoin, minocycline and tigecycline against carbapenemase-resistant Enterobacteriaceae. 

Q2. What is the role of the DML?

DML has accepted sponsorship to attend conferences and to speak for Pfizer and Eumedica; and holds shares in AstraZeneca, Merck, Pfizer and Dechra, amounting to <10% of all portfolio holdings. 

Q3. How many isolates were resistant to tigecycline?

ciprofloxacin (the quinolone with greatest inherent activity against Enterobacteriaceae) and nitrofurantoin had activity against only 15–25% of the isolates, again with little relationship to species or carbapenem resistance mechanism; minocycline was much less active than tigecycline, with 60/81 isolate MICs ≥ 8 mg/L. Temocillin also had limited activity, with only 4/81 isolates susceptible at the BSAC systemic breakpoint of susceptible ≤8 mg/L and resistant >8 mg/L; however, a total of 26/81 were susceptible at the BSAC urinary breakpoint of ≤32/>32 mg/L. 

Q4. What is the name of the study?

In this study, the activity of chloramphenicol, ciprofloxacin, colistin, fosfomycin, minocycline, nitrofurantoin, temocillin and tigecycline was evaluated against 81 carbapenem-resistant Enterobacteriaceae isolates from the UK. 

Q5. What is the active enzyme against 81 carbapenem-resistant Enterobacteriace?

Fosfomycin was active against 49/81 isolates (60.5%), including 7/7 Escherichia coli, 16/20 Enterobacter and Citrobacter spp., but only 25/52 Klebsiella spp. 

Q6. What is the common type of resistance to carbapenem?

The -lactam temocillin was also included as it has been suggested by othersto have specific activity against strains with KPC carbapenemases [8]. 

Q7. What is the reason for the lack of use of tigecycline?

it is licensed for use only in intra-abdominal and complicated skin and skin-structure infections, and proved inferior to imipenem/cilastatin in ventilator-associated pneumonia, providing a caution against off-label use in this infection [17]. 

Q8. What is the MIC of the edM anus crip?

Temocillin was fully active [minimum inhibitory concentration (MIC) ≤8 mg/L] against only 4/81 isolates (4.9%), but inhibited a further 22 isolates (27.2%) at the British Society for Antimicrobial Chemotherapy (BSAC) urinary breakpoint (32 mg/L), predominantly comprising those isolates with combinations of impermeabilityPage 3 of 21Ac cept edM anus crip tand an ESBL or AmpC enzyme, along with 6/11 isolates producing KPC carbapenemases. 

Q9. What is the purpose of the study?

The HPA received funding from Eumedica to evaluate temocillin against carbapenemase-producers and, in another context, has a research contract with Meiji, who market fosfomycin in Japan. 

Q10. What compounds had the highest activity against Enterobacter spp.?

MIC determinations with E. coli constructs confirmed that acquisition of a KPC carbapenemase caused only a one dilution rise in the temocillin MIC, whereas NDM (metallo-) and OXA-48 enzymes had a greater effect (Table 3). 

Q11. What is the role of the HPA in the evaluation of carbapenemase-?

The Health Protection Agency (HPA) received funding from Eumedica to evaluate temocillin against carbapenemase-producers and, in another context, has a research contract with Meiji, who market fosfomycin in Japan. 

Q12. What are the main limitations of the compounds?

Page 8 of 21Ac cept edM anus crip tAlthough colistin, fosfomycin and tigecycline were active or intermediately active against more than one-half of the study population, all have significant limitations. 

Q13. What is the common resistance to carbapenem?

Most carbapenemase-producers are almost completely resistant to -lactamantibiotics except that: (i) those with OXA-48 alone remain susceptible to several oxyimino-cephalosporins [5]; and (ii) those with metallo-carbapenemases alone,lacking AmpC or extended-spectrum -lactamases (ESBLs), remain susceptible toaztreonam [6]. 

Q14. How many isolates of Enterobacter spp. were susceptible to tigecycline?

Among 20 isolates of Enterobacter spp. and Citrobacter freundii, 10 were susceptible to tigecycline (MIC ≤ 1 mg/L), five were intermediate (MIC = 2 mg/L) and five were resistant (MIC > 2 mg/L); corresponding numbers among 52 Klebsiella spp. were 21 susceptible, 22 intermediate and 9 resistant.