Role of cephalosporins in the era of Clostridium difficile infection

Mark H Wilcox, James D Chalmers, Carl E Nord, Jane Freeman, Emilio Bouza, Mark H Wilcox, James D Chalmers, Carl E Nord, Jane Freeman, Emilio Bouza

Abstract

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.

© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Figures

Figure 1.
Figure 1.
Incidence of CDI and overall cephalosporin use in (a) the community and (b) hospital settings during 2012–13. The text overlay reports usage of first-, second-, third- and fourth-generation cephalosporins in EU/EEA countries in 2013, expressed as DDD per 1000 inhabitants and per day, if available. Community/hospital usage of second- and third-generation cephalosporins (as a percentage of first-, second-, third- and fourth-generation usage) is: Belgium, 92.8/53.6; Bulgaria, 82.1/87.0; Czech Republic, 94.5/NA; Finland, 2.6/77.9; France, 97.7/75.0; Germany, 97.8/NA; Greece, 100/94.1; Hungary, 99.4/90.1; Ireland, 85.3/95.8; Italy, 96.4/78.8; Netherlands, 100/71.3; Poland, 95.2/NA; Portugal, 77.6/67.4; Slovakia, 95.6/89.2; Spain, 99.4/NA; Sweden, 18.8/94.0; UK, 11.8/73.1. Data are from the ECDC. Regression analyses are based on least-squares means. CDI incidence data for 2012–13 are from Davies et al. aIncludes data for first-, second-, third- and fourth-generation cephalosporins.
Figure 2.
Figure 2.
Use of the most common cephalosporins across Europe, as a proportion of total cephalosporin use in each country, in the year ending August 2013. Countries (from left to right for each agent, arranged by CDI incidence): 4–8: Austria, Czech Republic, Italy, Netherlands, Romania; >8–12: Germany, Ireland, Poland; >12–16: Hungary, Sweden; >20: Finland. CDI incidence data from September 2012 to August 2013 from Davies et al. Prescription data from IMS Health.

References

    1. Kelly CP, LaMont JT. Clostridium difficile—more difficult than ever. N Engl J Med 2008; 359: 1932–40.
    1. PHE. Clostridium difficile: Guidance, Data and Analysis. Annual Counts and Rates of Clostridium difficile (C. difficile) Infections by Acute Trust and Clinical Commissioning Group (CCG) in Patients Aged 2 years and Over. .
    1. Evans CT, Safdar N. Current trends in the epidemiology and outcomes of Clostridium difficile infection. Clin Infect Dis 2015; 60 Suppl 2: S66–71.
    1. Lessa FC, Mu Y, Bamberg WM et al. . Burden of Clostridium difficile infection in the United States. N Engl J Med 2015; 372: 825–34.
    1. Khanna S, Pardi DS. The growing incidence and severity of Clostridium difficile infection in inpatient and outpatient settings. Expert Rev Gastroenterol Hepatol 2010; 4: 409–16.
    1. Bartlett JG, Gerding DN. Clinical recognition and diagnosis of Clostridium difficile infection. Clin Infect Dis 2008; 46 Suppl 1: S12–18.
    1. Wiegand PN, Nathwani D, Wilcox MH et al. . Clinical and economic burden of Clostridium difficile infection in Europe: a systematic review of healthcare-facility-acquired infection. J Hosp Infect 2012; 81: 1–14.
    1. Planche TD, Davies KA, Coen PG et al. . Differences in outcome according to Clostridium difficile testing method: a prospective multicentre diagnostic validation study of C. difficile infection. Lancet Infect Dis 2013; 13: 936–45.
    1. Leffler DA, Lamont JT. Clostridium difficile infection. N Engl J Med 2015; 372: 1539–48.
    1. Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of systematic review and meta-analysis. J Antimicrob Chemother 2014; 69: 881–91.
    1. Deshpande A, Pasupuleti V, Thota P et al. . Community-associated Clostridium difficile infection and antibiotics: a meta-analysis. J Antimicrob Chemother 2013; 68: 1951–61.
    1. Brown KA, Khanafer N, Daneman N et al. . Meta-analysis of antibiotics and the risk of community-associated Clostridium difficile infection. Antimicrob Agents Chemother 2013; 57: 2326–32.
    1. National Institute for Health and Care Excellence. Evidence Summary: Medicines and Prescribing Briefing. Clostridium difficile Infection: Risk with Broad-Spectrum Antibiotics. 2015. .
    1. Freeman J, Bauer MP, Baines SD et al. . The changing epidemiology of Clostridium difficile infections. Clin Microbiol Rev 2010; 23: 529–49.
    1. Davey P, Brown E, Charani E et al. . Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev 2013; issue 4: CD003543.
    1. PHE and Department of Health. Clostridium difficile Infection: How to Deal with the Problem. .
    1. Davies KA, Longshaw CM, Davis GL et al. . Underdiagnosis of Clostridium difficile across Europe: the European, multicentre, prospective, biannual, point-prevalence study of Clostridium difficile infection in hospitalised patients with diarrhoea (EUCLID). Lancet Infect Dis 2014; 14: 1208–19.
    1. ECDC. Antimicrobial Consumption Interactive Database (ESAC-Net). .
    1. Eyre DW, Cule ML, Wilson DJ et al. . Diverse sources of C. difficile infection identified on whole-genome sequencing. N Engl J Med 2013; 369: 1195–205.
    1. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhoea: a systematic review. J Antimicrob Chemother 2003; 51: 1339–50.
    1. Wilcox MH, Mooney L, Bendall R et al. . A case–control study of community-associated Clostridium difficile infection. J Antimicrob Chemother 2008; 62: 388–96.
    1. Hensgens MP, Goorhuis A, van Kinschot CM et al. . Clostridium difficile infection in an endemic setting in the Netherlands. Eur J Clin Microbiol Infect Dis 2011; 30: 587–93.
    1. Borriello SP. The influence of the normal flora on Clostridium difficile colonisation of the gut. Ann Med 1990; 22: 61–7.
    1. Antharam VC, Li EC, Ishmael A et al. . Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea. J Clin Microbiol 2013; 51: 2884–92.
    1. Edlund C, Nord CE. A model of bacterial-antimicrobial interactions: the case of oropharyngeal and gastrointestinal microflora. J Chemother 1991; 3 Suppl 1: 196–200.
    1. Spencer RC. The role of antimicrobial agents in the aetiology of Clostridium difficile-associated disease. J Antimicrob Chemother 1998; 41 Suppl C: 21–7.
    1. Stevens V, Dumyati G, Fine LS et al. . Cumulative antibiotic exposures over time and the risk of Clostridium difficile infection. Clin Infect Dis 2011; 53: 42–8.
    1. Levison ME, Levison JH. Pharmacokinetics and pharmacodynamics of antibacterial agents. Infect Dis Clin North Am 2009; 23: 791–815, vii.
    1. Karachalios G, Charalabopoulos K. Biliary excretion of antimicrobial drugs. Chemotherapy 2002; 48: 280–97.
    1. Kalman D, Barriere SL. Review of the pharmacology, pharmacokinetics, and clinical use of cephalosporins. Tex Heart Inst J 1990; 17: 203–15.
    1. Brogard JM, Blickle JF, Jehl F et al. . High biliary elimination of ceftriaxone in man. Int J Clin Pharmacol Ther Toxicol 1988; 26: 167–72.
    1. Hayton WL, Schandlik R, Stoeckel K. Biliary excretion and pharmacokinetics of ceftriaxone after cholecystectomy. Eur J Clin Pharmacol 1986; 30: 445–51.
    1. Nord CE, Movin G, Stalberg D. Impact of cefixime on the normal intestinal microflora. Scand J Infect Dis 1988; 20: 547–52.
    1. Edlund C, Stark C, Nord CE. The relationship between an increase in β-lactamase activity after oral administration of three new cephalosporins and protection against intestinal ecological disturbances. J Antimicrob Chemother 1994; 34: 127–38.
    1. Nord CE, Heimdahl A, Lundberg C et al. . Impact of cefaclor on the normal human oropharyngeal and intestinal microflora. Scand J Infect Dis 1987; 19: 681–5.
    1. Adamsson I, Edlund C, Sjostedt S et al. . Comparative effects of cefadroxil and phenoxymethylpenicillin on the normal oropharyngeal and intestinal microflora. Infection 1997; 25: 154–8.
    1. Pletz MW, Rau M, Bulitta J et al. . Ertapenem pharmacokinetics and impact on intestinal microflora, in comparison to those of ceftriaxone, after multiple dosing in male and female volunteers. Antimicrob Agents Chemother 2004; 48: 3765–72.
    1. Backstrom T, Panagiotidis G, Beck O et al. . Effect of ceftobiprole on the normal human intestinal microflora. Int J Antimicrob Agents 2010; 36: 537–41.
    1. Panagiotidis G, Backstrom T, Asker-Hagelberg C et al. . Effect of ceftaroline on normal human intestinal microflora. Antimicrob Agents Chemother 2010; 54: 1811–14.
    1. Baines SD, Chilton CH, Crowther GS et al. . Evaluation of antimicrobial activity of ceftaroline against Clostridium difficile and propensity to induce C. difficile infection in an in vitro human gut model. J Antimicrob Chemother 2013; 68: 1842–9.
    1. Ednie L, Shapiro S, Appelbaum PC. Antianaerobe activity of ceftobiprole, a new broad-spectrum cephalosporin. Diagn Microbiol Infect Dis 2007; 58: 133–6.
    1. Thornsberry C. Review of the in vitro antibacterial activity of cefprozil, a new oral cephalosporin. Clin Infect Dis 1992; 14 Suppl 2: S189–94; discussion S95–6.
    1. Pierard D, De Meyer A, Rosseel P et al. . In vitro activity of amoxycillin plus clavulanic acid and ticarcillin plus clavulanic acid compared with that of other antibiotics against anaerobic bacteria. Acta Clin Belg 1989; 44: 228–36.
    1. Simon C, Simon M, Plieth C. In vitro activity of flomoxef in comparison to other cephalosporins. Infection 1988; 16: 131–4.
    1. Spangler SK, Jacobs MR, Appelbaum PC. Activity of WY-49605 compared with those of amoxicillin, amoxicillin-clavulanate, imipenem, ciprofloxacin, cefaclor, cefpodoxime, cefuroxime, clindamycin, and metronidazole against 384 anaerobic bacteria. Antimicrob Agents Chemother 1994; 38: 2599–604.
    1. Bauernfeind A. Comparative antimicrobial spectrum and activity of ceftibuten against clinical isolates from West Germany. Diagn Microbiol Infect Dis 1991; 14: 63–74.
    1. Chow AW, Cheng N, Bartlett KH. In vitro susceptibility of Clostridium difficile to new β-lactam and quinolone antibiotics. Antimicrob Agents Chemother 1985; 28: 842–4.
    1. Noren T, Alriksson I, Akerlund T et al. . In vitro susceptibility to 17 antimicrobials of clinical Clostridium difficile isolates collected in 1993-2007 in Sweden. Clin Microbiol Infect 2010; 16: 1104–10.
    1. Freeman J, Wilcox MH. Antibiotic activity against genotypically distinct and indistinguishable Clostridium difficile isolates. J Antimicrob Chemother 2001; 47: 244–6.
    1. Buchler AC, Rampini SK, Stelling S et al. . Antibiotic susceptibility of Clostridium difficile is similar worldwide over two decades despite widespread use of broad-spectrum antibiotics: an analysis done at the University Hospital of Zurich. BMC Infect Dis 2014; 14: 607.
    1. Rolfe RD, Finegold SM. Comparative in vitro activity of new β-lactam antibiotics against anaerobic bacteria. Antimicrob Agents Chemother 1981; 20: 600–9.
    1. Snydman DR, Jacobus NV, McDermott LA. In vitro activity of ceftaroline against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother 2011; 55: 421–5.
    1. Nerandzic MM, Donskey CJ. Effect of ceftobiprole treatment on growth of and toxin production by Clostridium difficile in cecal contents of mice. Antimicrob Agents Chemother 2011; 55: 2174–7.
    1. Freeman J, O'Neill FJ, Wilcox MH. Effects of cefotaxime and desacetylcefotaxime upon Clostridium difficile proliferation and toxin production in a triple-stage chemostat model of the human gut. J Antimicrob Chemother 2003; 52: 96–102.
    1. Nord CE, Hedberg M. Resistance to β-lactam antibiotics in anaerobic bacteria. Rev Infect Dis 1990; 12 Suppl 2: S231–4.
    1. Rashid MU, Rosenborg S, Panagiotidis G et al. . Ecological effect of ceftazidime/avibactam on the normal human intestinal microbiota. Int J Antimicrob Agents 2015; 46: 60–5.
    1. Rashid MU, Rosenborg S, Panagiotidis G et al. . Ecological effect of ceftaroline-avibactam on the normal human intestinal microbiota. Antimicrob Agents Chemother 2015; 59: 4504–9.
    1. Zhanel GG, Lawson CD, Adam H et al. . Ceftazidime-avibactam: a novel cephalosporin/β-lactamase inhibitor combination. Drugs 2013; 73: 159–77.
    1. Citron DM, Tyrrell KL, Merriam V et al. . In vitro activity of ceftazidime-NXL104 against 396 strains of β-lactamase-producing anaerobes. Antimicrob Agents Chemother 2011; 55: 3616–20.
    1. Dubreuil LJ, Mahieux S, Neut C et al. . Anti-anaerobic activity of a new β-lactamase inhibitor NXL104 in combination with β-lactams and metronidazole. Int J Antimicrob Agents 2012; 39: 500–4.
    1. Kelly CP. Can we identify patients at high risk of recurrent Clostridium difficile infection? Clin Microbiol Infect 2012; 18 Suppl 6: 21–7.
    1. Dingle KE, Didelot X, Quan P et al. . Elimination of healthcare associated fluoroquinolone-resistant, but not fluoroquinolone-susceptible Clostridium difficile. Lancet Infect Dis 2016. In press.
    1. Bruns AH, Oosterheert JJ, Kuijper EJ et al. . Impact of different empirical antibiotic treatment regimens for community-acquired pneumonia on the emergence of Clostridium difficile. J Antimicrob Chemother 2010; 65: 2464–71.
    1. Chalmers JD, Akram AR, Singanayagam A et al. . Risk factors for Clostridium difficile infection in hospitalized patients with community-acquired pneumonia. J Infect 2016; 73: 45–53.
    1. Sandiumenge A, Diaz E, Rodriguez A et al. . Impact of diversity of antibiotic use on the development of antimicrobial resistance. J Antimicrob Chemother 2006; 57: 1197–204.
    1. Abel zur Wiesch P, Kouyos R, Abel S et al. . Cycling empirical antibiotic therapy in hospitals: meta-analysis and models. PLoS Pathog 2014; 10: e1004225.
    1. Sales JE, Sutcliffe M, O'Grady F. Cephalexin levels in human bile in presence of biliary tract disease. Br Med J 1972; 3: 441–3.
    1. Brogard JM, Dorner M, Pinget M et al. . The biliary excretion of cefazolin. J Infect Dis 1975; 131: 625–33.
    1. Nishida M, Murakawa T, Matsubara T et al. . Characteristics of biliary excretion of cefazolin and other cephalosporins with reference to the relationship between serum levels and administration conditions. Chemotherapy 1976; 22: 30–6.
    1. Ratzan KR, Baker HB, Lauredo I. Excretion of cefamandole, cefazolin, and cephalothin into T-tube bile. Antimicrob Agents Chemother 1978; 13: 985–7.
    1. Ram MD, Watanatittan S. Levels of cefazolin in human bile. J Infect Dis 1973; 128: S361–3.
    1. Brogard JM, Pinget M, Comte F et al. . Biliary excretion of cefaclor. Experimental and clinical study. Chemotherapy 1982; 28: 189–99.
    1. Brogard JM, Pinget M, Arnaud JP et al. . Biliary excretion of cefuroxime. Experimental and human study. Chemotherapy 1981; 27: 18–28.
    1. Thomas MH, Dash CH, Burnand KG et al. . The excretion of cefuroxime in human bile. Br J Surg 1981; 68: 290–1.
    1. Severn M, Powis SJ. Biliary excretion and tissue levels of cefuroxime. A study in eleven patients undergoing cholecystectomy. J Antimicrob Chemother 1979; 5: 183–8.
    1. Westphal JF, Jehl F, Schloegel M et al. . Biliary excretion of cefixime: assessment in patients provided with T-tube drainage. Antimicrob Agents Chemother 1993; 37: 1488–91.
    1. Moorthi K, Fleckenstein G, Nies B. Concentration of cefixime in bile, gallbladder wall and serum after preoperative administration in patients undergoing cholecystectomy. Methods Find Exp Clin Pharmacol 1990; 12: 287–90.
    1. Brogard JM, Jehl F, Paris-Bockel D et al. . Biliary elimination of ceftazidime. J Antimicrob Chemother 1987; 19: 671–8.
    1. Bouza E, Hellin T, Rodriguez-Creixems M et al. . Comparison of ceftazidime concentrations in bile and serum. Antimicrob Agents Chemother 1983; 24: 104–6.
    1. Tanimura H, Kobayashi N, Miki K et al. . Chemotherapy in biliary tract infections (XVIII) with special reference to the concentration of ceftazidime in gallbladder tissue, the secretion in bile and ascitic fluid, and its clinical efficacy. Chemotherapy (Tokyo) 1983; 31 Suppl 3: 717–38.
    1. Shiramatsu K, Hirata K, Yamada T et al. . Ceftazidime concentration in gallbladder tissue and excretion in bile. Antimicrob Agents Chemother 1988; 32: 1588–9.
    1. Walstad RA, Wiig JN, Thurmann-Nielsen E et al. . Pharmacokinetics of ceftazidime in patients with biliary tract disease. Eur J Clin Pharmacol 1986; 31: 327–31.
    1. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc 1999; 74: 187–95.
    1. Murthy B, Schmitt-Hoffmann A. Pharmacokinetics and pharmacodynamics of ceftobiprole, an anti-MRSA cephalosporin with broad-spectrum activity. Clin Pharmacokinet 2008; 47: 21–33.
    1. AstraZeneca UK Limited. Zinforo 600 mg Powder for Concentrate for Solution for Infusion—Summary of Product Characteristics. .
    1. Posada MM, Smith DE. In vivo absorption and disposition of cefadroxil after escalating oral doses in wild-type and PepT1 knockout mice. Pharm Res 2013; 30: 2931–9.
    1. Marino EL, Dominguez-Gil A, Muriel C. Influence of dosage form and administration route on the pharmacokinetic parameters of cefadroxil. Int J Clin Pharmacol Ther Toxicol 1982; 20: 73–7.
    1. Griffith RS. The pharmacology of cephalexin. Postgrad Med J 1983; 59 Suppl 5: 16–27.
    1. Gaya H, Adnitt PI, Turner P. Changes in gut flora after cephalexin treatment. Br Med J 1970; 3: 624–5.
    1. Takesue Y, Yokoyama T, Akagi S et al. . Changes in the intestinal flora after the administration of prophylactic antibiotics to patients undergoing a gastrectomy. Surg Today 2002; 32: 581–6.
    1. Lode H, Muller C, Borner K et al. . Multiple-dose pharmacokinetics of cefprozil and its impact on intestinal flora of volunteers. Antimicrob Agents Chemother 1992; 36: 144–9.
    1. Barriere SL. Review of in vitro activity, pharmacokinetic characteristics, safety, and clinical efficacy of cefprozil, a new oral cephalosporin. Ann Pharmacother 1993; 27: 1082–9.
    1. Novelli A, Mazzei T, Fallani S et al. . Betalactam therapy and intestinal flora. J Chemother 1995; 7 Suppl 1: 25–31.
    1. Foord RD. Cefuroxime: human pharmacokinetics. Antimicrob Agents Chemother 1976; 9: 741–7.
    1. Borin MT. A review of the pharmacokinetics of cefpodoxime proxetil. Drugs 1991; 42 Suppl 3: 13–21.
    1. Brismar B, Edlund C, Nord CE. Impact of cefpodoxime proxetil and amoxicillin on the normal oral and intestinal microflora. Eur J Clin Microbiol Infect Dis 1993; 12: 714–9.
    1. Bodey GP, Fainstein V, Garcia I et al. . Effect of broad-spectrum cephalosporins on the microbial flora of recipients. J Infect Dis 1983; 148: 892–7.
    1. Edlund C, Nord CE. Ecological impact of antimicrobial agents on human intestinal microflora. In: Heidt P, Rusch V, van der Waaij D, eds. Old Herborn University Seminar Monograph 7: Immune System and Microflora. Herborn-Dill: Herborn Litterae, 2003; 37–65.
    1. Goldstein EJ, Citron DM, Merriam CV et al. . In vitro activity of ceftobiprole against aerobic and anaerobic strains isolated from diabetic foot infections. Antimicrob Agents Chemother 2006; 50: 3959–62.

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