- Email: [email protected]
Ceftazidime-avibactam in ceftazidime-resistant infections
Correspondence
Ceftazidime-avibactam in ceftazidime-resistant infections One of the important causes of the development of resistance to β-lactam drugs is their overuse. β-lactamase inhibitors have been combined with many β-lactam drugs to resume their efficacy since the emergence of multidrugresistant organisms. Yahuda Carmeli and colleagues 1 recommended the combination of ceftazidimeavibactam as a potential alternative to carbapenems for the treatment of multidrug-resistant Gram-negative bacteria. However, for bacteria producing metallo-β-lactamase, carbapenems are still the last-resort drug. Discovery of new inhibitors that are active against different types of β-lactamases, including metallo-βlactamases, is still a great challenge. High-income countries should limit the use of these last-resort drugs for the future. In the study by Carmeli and colleagues,1 ceftazidime-avibactam and carbapenems were both ineffective in 9% of participants. Patients included in their study were those with complicated cases of urinary tract infection and intra-abdominal infection, which were resistant to ceftazidime. Additionally, the complete antibiotic profile of the organisms was not reported in the study. If these cases were resistant to β-lactam drugs only, non-β-lactam antibiotics and some other β-lactam– β-lactamase inhibitor combinations might have potential. Additionally, ceftazidime-avibactam and carbapenems are very expensive drugs. On average, the cost of carbapenem treatment is US$100 per day2 and the cost of ceftazidime-avibactam is estimated to be $750 per day.3 Almost all patients in lower-income and middleincome countries cannot afford these antibiotics. The scope of other β-lactam
inhibitor combinations for treating multidrug-resistant organisms should not be underestimated. In a tertiary hospital in Nepal, cefoperazonesulbactam was 95% sensitive against extended-spectrum β-lactamase organisms.4 Even the antibiotics that are not in use for a long time (those on a so-called antibiotic holiday) might have regained their efficacy. The burden of infections and the consequent overuse of antibiotics (over the counter), often without antibiotic susceptibility testing in lower-income and middle-income countries, are alarming, which makes these countries the hub of antibiotic resistance.5 Consideration of cheaper alternatives through further research in lower-income and middle-income countries is therefore imperative to tackle antibiotic resistance globally. We declare no competing interests.
*Shristi Raut, Bipin Adhikari [email protected] Department of Microbiology, Lumbini Medical College, Palpa GPO box-05, Nepal (SR); and Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (BA) 1
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Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 2016; 16: 661–73. Pharmacist’s letter/Prescriber’s letter. Comparison of carbapenem antibiotics. December 2007. http://pharmacistsletter. therapeuticresearch.com/pl/ArticlePDF.aspx?c s=&s=PL&dd=231205&segment=77&usg=AF QjCNHsCvEAEbd_y1YxJ0apbKkHca9vKw&sig2 =AtOJoYv39dEtDG4CS3P38A&bvm=bv.1279 84354,d.c2 (accessed July 25, 2016). Harald. Avycaz approval and labeling restrictions. Allphase Pharma Consulting, LLC, August 26, 2015. http://allphasepharma. com/dir/2015/08/26/1887/avicaz-approvaland-labeling-restrictions/ (accessed May 29, 2016). Raut S, Gokhale S, Adhikari B. Prevalence of extended spectrum beta-lactamases among Escherichia coli and Klebsiella spp isolates in Manipal Teaching Hospital, Pokhara, Nepal. J Microbiol Infect Dis 2015; 5: 69–75. Raut S, Adhikari B. Global leadership against antimicrobial resistance ought to include developing countries. Lancet Infect Dis 2016; 16: 775.
We are pleased to provide additional data in response to three specific issues raised in the insightful Comment1 by Florian Wagenlehner and Kurt Naber on our REPRISE study.2 First, of 27 (9%) of 302 patients in the microbiologically modified intention-to-treat (mMITT) analysis set without a clinical cure at the testof-cure visit, four (all patients with complicated urinary tract infection, two in each treatment group) were deemed clinical failures because they received additional antibiotics (not stated for two patients) for the index infection: one woman without acute pyelonephritis (three complicating factors, including catheterisation), one man without acute pyelonephritis (two complicating factors), and two women with acute pyelonephritis (one of whom received intravenous ertapenem and the other oral cotrimoxazole). All four were aged at least 65 years, had a complex medical history, and monomicrobial infection at baseline with an Enterobacteriaceae pathogen (susceptible to study treatment received); all were alive at the last follow-up visit (28–32 days after randomisation). The other 23 patients had an in determinate response (appendix). Second, as described in the Article,2 baseline Pseudomonas aeruginosa in nine of the 14 patients with complicated urinary tract infection in the ceftazidime-avibactam group (mMITT set) had a ceftazidimeavibactam minimum inhibitory concentration greater than 8 mg/L (provisionally resistant). Seven of the nine patients had a favourable microbiological response at test-ofcure visit (two with and five without acute pyelonephritis), none of whom had a catheter. Possible explanations for these unexpected successes are described in the Article.2 Third, all patients entering the study needed to have a ceftazidime-resistant Gram-negative pathogen isolated from the infection site, and most
See Online for appendix
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Ceftazidime-avibactam in ceftazidime-resistant infections One of the important causes of the development of resistance to β-lactam drugs is their overuse. β-lactamase inhibitors have been combined with many β-lactam drugs to resume their efficacy since the emergence of multidrugresistant organisms. Yahuda Carmeli and colleagues 1 recommended the combination of ceftazidimeavibactam as a potential alternative to carbapenems for the treatment of multidrug-resistant Gram-negative bacteria. However, for bacteria producing metallo-β-lactamase, carbapenems are still the last-resort drug. Discovery of new inhibitors that are active against different types of β-lactamases, including metallo-βlactamases, is still a great challenge. High-income countries should limit the use of these last-resort drugs for the future. In the study by Carmeli and colleagues,1 ceftazidime-avibactam and carbapenems were both ineffective in 9% of participants. Patients included in their study were those with complicated cases of urinary tract infection and intra-abdominal infection, which were resistant to ceftazidime. Additionally, the complete antibiotic profile of the organisms was not reported in the study. If these cases were resistant to β-lactam drugs only, non-β-lactam antibiotics and some other β-lactam– β-lactamase inhibitor combinations might have potential. Additionally, ceftazidime-avibactam and carbapenems are very expensive drugs. On average, the cost of carbapenem treatment is US$100 per day2 and the cost of ceftazidime-avibactam is estimated to be $750 per day.3 Almost all patients in lower-income and middleincome countries cannot afford these antibiotics. The scope of other β-lactam
inhibitor combinations for treating multidrug-resistant organisms should not be underestimated. In a tertiary hospital in Nepal, cefoperazonesulbactam was 95% sensitive against extended-spectrum β-lactamase organisms.4 Even the antibiotics that are not in use for a long time (those on a so-called antibiotic holiday) might have regained their efficacy. The burden of infections and the consequent overuse of antibiotics (over the counter), often without antibiotic susceptibility testing in lower-income and middle-income countries, are alarming, which makes these countries the hub of antibiotic resistance.5 Consideration of cheaper alternatives through further research in lower-income and middle-income countries is therefore imperative to tackle antibiotic resistance globally. We declare no competing interests.
*Shristi Raut, Bipin Adhikari [email protected] Department of Microbiology, Lumbini Medical College, Palpa GPO box-05, Nepal (SR); and Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand (BA) 1
2
3
4
5
www.thelancet.com/infection Vol 16 September 2016
Carmeli Y, Armstrong J, Laud PJ, et al. Ceftazidime-avibactam or best available therapy in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa complicated urinary tract infections or complicated intra-abdominal infections (REPRISE): a randomised, pathogen-directed, phase 3 study. Lancet Infect Dis 2016; 16: 661–73. Pharmacist’s letter/Prescriber’s letter. Comparison of carbapenem antibiotics. December 2007. http://pharmacistsletter. therapeuticresearch.com/pl/ArticlePDF.aspx?c s=&s=PL&dd=231205&segment=77&usg=AF QjCNHsCvEAEbd_y1YxJ0apbKkHca9vKw&sig2 =AtOJoYv39dEtDG4CS3P38A&bvm=bv.1279 84354,d.c2 (accessed July 25, 2016). Harald. Avycaz approval and labeling restrictions. Allphase Pharma Consulting, LLC, August 26, 2015. http://allphasepharma. com/dir/2015/08/26/1887/avicaz-approvaland-labeling-restrictions/ (accessed May 29, 2016). Raut S, Gokhale S, Adhikari B. Prevalence of extended spectrum beta-lactamases among Escherichia coli and Klebsiella spp isolates in Manipal Teaching Hospital, Pokhara, Nepal. J Microbiol Infect Dis 2015; 5: 69–75. Raut S, Adhikari B. Global leadership against antimicrobial resistance ought to include developing countries. Lancet Infect Dis 2016; 16: 775.
We are pleased to provide additional data in response to three specific issues raised in the insightful Comment1 by Florian Wagenlehner and Kurt Naber on our REPRISE study.2 First, of 27 (9%) of 302 patients in the microbiologically modified intention-to-treat (mMITT) analysis set without a clinical cure at the testof-cure visit, four (all patients with complicated urinary tract infection, two in each treatment group) were deemed clinical failures because they received additional antibiotics (not stated for two patients) for the index infection: one woman without acute pyelonephritis (three complicating factors, including catheterisation), one man without acute pyelonephritis (two complicating factors), and two women with acute pyelonephritis (one of whom received intravenous ertapenem and the other oral cotrimoxazole). All four were aged at least 65 years, had a complex medical history, and monomicrobial infection at baseline with an Enterobacteriaceae pathogen (susceptible to study treatment received); all were alive at the last follow-up visit (28–32 days after randomisation). The other 23 patients had an in determinate response (appendix). Second, as described in the Article,2 baseline Pseudomonas aeruginosa in nine of the 14 patients with complicated urinary tract infection in the ceftazidime-avibactam group (mMITT set) had a ceftazidimeavibactam minimum inhibitory concentration greater than 8 mg/L (provisionally resistant). Seven of the nine patients had a favourable microbiological response at test-ofcure visit (two with and five without acute pyelonephritis), none of whom had a catheter. Possible explanations for these unexpected successes are described in the Article.2 Third, all patients entering the study needed to have a ceftazidime-resistant Gram-negative pathogen isolated from the infection site, and most
See Online for appendix
997