Evaluation of antimicrobial activity of ceftaroline against Clostridium difficile and propensity to induce C. difficile infection in an in vitro human gut model

Baines, Simon D.; Chilton, Caroline H.; Crowther, Grace S.; Todhunter, Sharie L.; Freeman, Joseph T.; Wilcox, Mark H.

doi:10.1093/jac/dkt107

Cited by 16 publications

(30 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using PolyFermS models, we showed that CD vegetative cells or spores only colonize in TDC reactors after a time period of 7–10 days. Our data are in agreement with previous studies that reported an absence of CD colonization added as spores in the proximal colon section of a three stage colonic fermentation model [29, 30], which may be explained by pH inhibition effect [31]. …”

Section: Discussionsupporting

confidence: 93%

“…This result suggests that either the spores were washed out of the system, or that they were able to grow, but remained below the detection limit of the qPCR method (4.4 GC mL −1 ). A quiescent state of CD spores for a period of at least 7 days was previously reported in a three-stage model, and was tentatively explained by the absence of antibiotic treatment [29, 30]. Our data demonstrate that application of antibiotic may not be required for CD spore germination and colonization of an in vitro continuous colonic fermentation model mimicking TDC conditions of an elderly microbiota.…”

Section: Discussionsupporting

confidence: 80%

See 1 more Smart Citation

Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation

et al. 2016

View full text Add to dashboard Cite

Background Clostridium difficile (CD), a spore-forming and toxin-producing bacterium, is the main cause for antibiotic-associated diarrhea in the elderly. Here we investigated CD colonization in novel in vitro fermentation models inoculated with immobilized elderly fecal microbiota and the effects of antibiotic treatments.MethodsTwo continuous intestinal PolyFermS models inoculated with different immobilized elder microbiota were used to investigate selected factors of colonization of CD in proximal (PC, model 1) and transverse-distal (TDC, model 1 and 2) colon conditions. Colonization of two CD strains of different PCR ribotypes, inoculated as vegetative cells (ribotype 001, model 1) or spores (ribotypes 001 and 012, model 2), was tested. Treatments with two antibiotics, ceftriaxone (daily 150 mg L−1) known to induce CD infection in vivo or metronidazole (twice daily 333 mg L−1) commonly used to treat CD, were investigated in TDC conditions (model 2) for their effects on gut microbiota composition (qPCR, 16S pyrosequencing) and activity (HPLC), CD spore germination and colonization, and cytotoxin titer (Vero cell assay).ResultsCD remained undetected after inoculating vegetative cells in PC reactors of model 1, but was shown to colonize TDC reactors of both models, reaching copy numbers of up to log10 8 mL−1 effluent with stable production of toxin correlating with CD cell numbers. Ceftriaxone treatment in TDC reactors showed only small effects on microbiota composition and activity and did not promote CD colonization compared to antibiotic-free control reactor. In contrast, treatment with metronidazole after colonization of CD induced large modifications in the microbiota and decreased CD numbers below the detection limit of the specific qPCR. However, a fast CD recurrence was measured only 2 days after cessation of metronidazole treatment.ConclusionsUsing our in vitro fermentation models, we demonstrated that stable CD colonization in TDC reactors can be induced by inoculating CD vegetative cells or spores without the application of ceftriaxone. Treatment with metronidazole temporarily reduced the counts of CD, in agreement with CD infection recurrence in vivo. Our data demonstrate that CD colonized an undisturbed microbiota in vitro, in contrast to in vivo observations, thus suggesting an important contribution of host-related factors in the protection against CD infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13099-016-0144-y) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 80%

Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation

et al. 2016

View full text Add to dashboard Cite

show abstract

“…In general, cephalosporins have poor in vitro activity against C. difficile (Table 4). 40–52 These studies also showed that Gram-negative anaerobic bacteria, such as Bacteroides spp., which make up a substantial proportion of the gastrointestinal microbiota, typically had low susceptibility to cephalosporins. Ceftaroline and ceftobiprole showed the greatest activity against C. difficile isolates, with an MIC 50 of 2–4 mg/L for both agents; 40,41,52 one review also reported good activity of cefprozil.…”

Section: Are All Cephalosporins the Same With Regard To CDI Risk?mentioning

confidence: 94%

“…40–52 These studies also showed that Gram-negative anaerobic bacteria, such as Bacteroides spp., which make up a substantial proportion of the gastrointestinal microbiota, typically had low susceptibility to cephalosporins. Ceftaroline and ceftobiprole showed the greatest activity against C. difficile isolates, with an MIC 50 of 2–4 mg/L for both agents; 40,41,52 one review also reported good activity of cefprozil. 42 As noted earlier, however, most cephalosporins are excreted primarily by the kidney, and thus antimicrobial activity against C. difficile may be of limited clinical relevance for drugs that do not penetrate the gut at therapeutic levels (Table 3).…”

Section: Are All Cephalosporins the Same With Regard To CDI Risk?mentioning

confidence: 94%

Role of cephalosporins in the era ofClostridium difficileinfection

Wilcox

Chalmers

Nord

et al. 2016

J. Antimicrob. Chemother.

View full text Add to dashboard Cite

The incidence of Clostridium difficile infection (CDI) in Europe has increased markedly since 2000. Previous meta-analyses have suggested a strong association between cephalosporin use and CDI, and many national programmes on CDI control have focused on reducing cephalosporin usage. Despite reductions in cephalosporin use, however, rates of CDI have continued to rise. This review examines the potential association of CDI with cephalosporins, and considers other factors that influence CDI risk. EUCLID (the EUropean, multicentre, prospective biannual point prevalence study of CLostridium difficile Infection in hospitalized patients with Diarrhoea) reported an increase in the annual incidence of CDI from 6.6 to 7.3 cases per 10 000 patient bed-days from 2011–12 to 2012–13, respectively. While CDI incidence and cephalosporin usage varied widely across countries studied, there was no clear association between overall cephalosporin prescribing (or the use of any particular cephalosporin) and CDI incidence. Moreover, variations in the pharmacokinetic and pharmacodynamic properties of cephalosporins of the same generation make categorization by generation insufficient for predicting impact on gut microbiota. A multitude of additional factors can affect the risk of CDI. Antibiotic choice is an important consideration; however, CDI risk is associated with a range of antibiotic classes. Prescription of multiple antibiotics and a long duration of treatment are key risk factors for CDI, and risk also differs across patient populations. We propose that all of these are factors that should be taken into account when selecting an antibiotic, rather than focusing on the exclusion of individual drug classes.

show abstract

“…difficile infection has been described in patients receiving ceftaroline (Lin et al, 2013). Although the effect of the drug on the human gut flora was shown to be minimal (Panagiotidis et al, 2010), ceftaroline like other cephalosporins can induce simulated C. difficile infection in a human gut model (Baines et al, 2013). In addition, ceftaroline was thought to be responsible for an alteration of coagulation in one patient receiving warfarin (Bohm &Crosby, 2012).…”

Section: Accepted Manuscriptmentioning

confidence: 99%

Ceftaroline: clinical and microbiology experience with focus on methicillin-resistant Staphylococcus aureus after regulatory approval in the USA

Stryjewski¹,

Jones²,

Corey³

2015

Diagnostic Microbiology and Infectious Disease

View full text Add to dashboard Cite

Evaluation of antimicrobial activity of ceftaroline against Clostridium difficile and propensity to induce C. difficile infection in an in vitro human gut model

Cited by 16 publications

References 37 publications

Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation

Clostridium difficile colonization and antibiotics response in PolyFermS continuous model mimicking elderly intestinal fermentation

Role of cephalosporins in the era ofClostridium difficileinfection

Ceftaroline: clinical and microbiology experience with focus on methicillin-resistant Staphylococcus aureus after regulatory approval in the USA

Contact Info

Product

Resources

About