27 October 2016
Carbapenems are a major last-line class of antibiotics to treat serious bacterial infections. They are currently among the most important antibiotics globally for treating drug-resistant infections, as they are broad-spectrum antibiotics with high potency against many different types of bacteria.
Faropenem – an overlooked case
Faropenem is a poorly studied drug from the antibiotic class of penems, which is structurally similar to the carbapenem antibiotic class. Faropenem has seen a significant increase in use over the last two decades in China and India. Just between 2010 and 2014, faropenem consumption rates rose by more than 150% in India. Consumption was then higher than total carbapenem consumption. In contrast to most carbapenems in use, faropenem is available as an oral agent. It is obtainable in many parts of Asia, but in other parts of the world it has never reached the market, as it has not been approved by regulatory agencies. There are several concerns related to the use of faropenem that warrants attention, for example:
- Oral availability of the drug makes it easier to obtain and use inappropriately
- The lack of oversight of off-label use (such as use for clinical indications that differs from those it has been approved for)
- The risk of development of cross-resistance to carbapenems
Cross-resistance to carbapenems
Perhaps the most worrying aspect of increased faropenem use is that it may fuel development and spread of carbapenem-resistant bacteria. Carbapenems share structurally similar elements with penems. Thus, resistance to faropenem could potentially also provide bacteria with protection against carbapenems. Such cross-resistance would further endanger the effectiveness of one of our most important antibiotic classes.
Alarming reports of resistance to carbapenems
In the last years, antibiotic resistance has started to compromise the effectiveness of carbapenems. Especially concerning is increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE). Mortality rates in patients with CRE infections are often high. Read more here.
Several recent studies highlight the gravity of the problem:
- A Brazilian study reports a dramatic increase in carbapenem resistance in isolates of Klebsiella pneumonia – from around 7% in 2011 to more than 35% in 2015. Read article here.
- A smaller study focus on hospitalized Syrian children. More than 80% of the children were found to carry multidrug-resistant pathogens. Of multidrug-resistant infections, 15% were attributable to CRE. – Read article here.
- A retrospective study of patient blood cultures in India highlights the urgent need for new antibiotics and better antibiotic stewardship. In 2014, the prevalence of carbapenem-resistant E. coli was 11.5% – the highest reported to date globally. Carbapenem resistance increased also in Klebsiella pneumonia, from already high levels to more than 55%. Read article here.
- Alarming resistance levels were also identified in pathogens that cause sepsis in neonates in India, both to commonly and more sparingly used antibiotics. More than 75% of Acinetobacter isolates, 30% of Klebsiella isolates, and 10% of E. coli isolates displayed resistance to carbapenems. Read article here.
Resistance to new treatments
Ceftazidime-avibactam is a combination therapy with activity against CRE that only reached the market in 2015. It is still not available in all countries. A study has now reported resistance emergence in CRE in a group of patients treated with ceftazidime-avibactam. Overall mortality among the 37 treated patients was higher than 30%. 3 patients developed re-infection with bacteria in which ceftazidime-avibactam resistance had emerged. Although only a small and uncontrolled retrospective study, the results are worrisome. Read article here.
Limited options for treatment
The situation is especially concerning as CRE is one of the top unmet medical needs for new antibiotic treatments. The call for increased investments (both scientific and financial) to find new ways to treat such infections has been sounding for years, but not enough has been done. Read more here.
Making the case for concerted global action
The faropenem case demonstrates how interconnected individual issues are in the field of infectious diseases, but also more broadly in global health. Unregulated use of faropenem regimens may fuel carbapenem resistance emergence via cross-resistance. Thus, from a global perspective faropenem resistance represent a threat to some of our most important last-resort antibiotics. Faropenem is a good example of why we need to have a common framework to ensure that antibiotics of last resort are preserved for those in need. Further research into how widespread use of faropenem is, as well as studies examining the risk and mechanisms for cross-resistance to carbapenems are needed. Also, innovation efforts seeking novel treatments must be intensified.
Gandra et al 2016. Faropenem consumption is increasing in India, http://cid.oxfordjournals.org/content/early/2016/02/21/cid.ciw055.extract; Gonzalez Sanz et al. The elephant in the room: could the unregulated marketing of generic faropenem sodium be contributing to penem overuse? Conference abstract ECCMID 2016