Antimicrobial resistance and treatment: an unmet clinical safety need

ABSTRACT

Introduction: Infections due to multidrug-resistant (MDR) bacteria are burdened by high mortality rates. The development of new compounds to face the global threat of resistance is urgently needed. Combination regimens including “old” high-dose antimicrobials are currently limited by the risk of toxicity, resistance selection, and reduced efficacy. Following the Infectious Diseases Society of America call to develop 10 new antibacterials by 2020, new molecules are currently under development or have become available for use in clinical practice.

Areas covered: We have reviewed safety characteristics and tolerability of old antimicrobials that are currently employed in combination regimens as well as new antimicrobials, including beta-lactams/beta-lactamase inhibitors, new cephalosporins, quinolones, and aminoglycosides.

Expert opinion: The availability of new compounds that show in vitro efficacy against MDR represents a unique opportunity to face the threat of resistance and to optimize the current use of antimicrobials, potentially reducing toxicity. Agents that are potentially active against MDR Gram-negatives are ceftozolane/tazobactam, new carbapenems and cephalosporins, the combination of avibactam with ceftazidime, and plazomicin. Further data from clinical trials and post-marketing studies for drugs targeting MDR pathogens are crucial to confirm their efficacy and safety.

KEYWORDS:

• Multidrug-resistant gram-negative infections
• drug toxicity
• colistin
• tigecycline
• fosfomycin
• new antibiotics

Article highlights

• The use of increased doses and prolonged regimens in to overcome resistance to Gram-negative bacteria has been associated over the years with reports of relevant adverse effects

• Among old antibiotics, regimens including aminoglycosides and high-dose colistin have been associated by increased rates of nephrotoxicity

• New antimicrobials that are currently used in clinical practice (e.g. ceftolozane/tazobactam and ceftazidime/avibactam) are usually well tolerated

• Novel antimicrobials that are currently under development showed favorable safety profiles in clinical trials, but real-world studies are needed to confirm their efficacy and safety

This box summarizes key points contained in the article.

Acknowledgments

None.

Reviewer disclosure

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Conflict of interest

In the past five years MB has participated in advisory boards and/or received speaker honoraria from Achaogen, Angelini, Astellas, AstraZeneca, Bayer, Basilea, Cidara, Gilead, Melinta, Menarini, MSD, Nabriva, Paratek, Pfizer, Roche, The Medicine Company, Shionogi, Tetraphase, VenatoRX, and Vifor. The remaining authors have no conflicts of interest.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This article has not been funded.