Evolution of clinical guidelines for antimicrobial management of Clostridioides difficile infection

Abstract

Clostridioides difficile infection (CDI) has been an epidemic for many years. Our biggest challenge in treating CDI is preventing recurrence, which is seen in approximately 25% of patients with initial infection and in 40–60% of those with subsequent episodes. Given the major disease burden of this infection, appropriate data-driven treatment remains essential. Clinical treatment guidelines provide an unbiased critical analysis of the literature, integrating the quality of the available data to make recommendations. As CDI has been evolving and more research has become available, the frequency of guideline issue from various global societies has increased, as has the detail of the recommendations to fit more relevant clinical scenarios. In this review, we will discuss clinical guideline recommendations over three time periods: The Initial Guidelines 1995–1997, The Second Wave 2009–2013, and The Modern Era 2014–present. We see the changing recommendations from metronidazole or vancomycin for initial infection during earlier times to preferential treatment with fidaxomicin within the Infectious Diseases Society of America (IDSA) and Society of Healthcare Epidemiology of America (SHEA) joint guidelines provisional update in late 2020. The recommended treatments for first recurrence were initially with the same antimicrobial as the first episode but have since changed to having multiple options for one or more recurrences. We have also seen the addition of immune boosting treatments, including fecal microbiota transplantation (FMT)/microbiota restoration therapy (MRT) and bezlotoxumab in the more modern recommendations. As the guidelines are evolving with the times, it remains important to understand the differences among them so we can apply this information clinically and optimize patient outcomes.

Make It Less difficile: Understanding Genetic Evolution and Global Spread of Clostridioides difficile

“…Although resistance to antimicrobials recommended by guidelines for the treatment of CDI remains quite rare [ 32 , 33 ], these guidelines have been modified and reshaped over the years, also to address this issue. In particular, the first guidelines (1995–1997) were focused on the administration of vancomycin and metronidazole, while from 2014 to date they also include treatment with fidaxomicin [ 67 ]. Fortunately, most countries in a pan-European study [ 32 ] reported metronidazole, vancomycin and fidaxomicin resistance below 10% (most of them reported 0%), and a species-wide genomic study [ 33 ] could identify pCD-METRO plasmid (conferring metronidazole resistance) in only 15 of > 10,000 strains tested.…”

“…Below, we discuss the antimicrobial resistance mechanisms for medications commonly recommended for the treatment of CDI. Regarding the mechanisms of resistance, C. difficile strains can encode a vanG-type gene cluster ( vanGCd ), conferring resistance to vancomycin, an antimicrobial glycopeptide that inhibits bacterial cell wall biosynthesis [ 67 ]. Specifically, resistance is conferred by the production of an alternative lipid II carrying a D-alanine-D-serine terminus that is seven times less bound by vancomycin than the D-alanine-D-alanine terminus [ 68 ].…”

“…The authors suggest that C. difficile may use heme in oxidative stress responses to metronidazole, as a source of iron and cofactor for redox-associated proteins, as shown in other bacteria [ 70 , 71 ]. Metronidazole belongs to the nitroimidazole class of antimicrobials that can block the helical structure of DNA, leading to strand breakage, inhibition of protein synthesis and cell death [ 67 ]. As anticipated above, resistance to metronidazole appears to be mediated by a high-copy-number plasmid, pCD-METRO [ 72 ].…”

The Role of Microbiome-Based Therapeutics in Clostridioides difficile Infection: Durable, Long-Term Results of RBX2660

“…The development of LBPs stemmed from the concept of FMT, and are defined by the US FDA as a biological product containing live organisms, such as bacteria, that are applicable to the prevention, treatment, or cure of a disease [ 10 ]. The best example of this is the role that microbiota-based LBPs play in the reduction of rCDI [ 11 , 12 ]. The relationship between intestinal microbial diversity in a healthy state, and dysbiosis resulting in rCDI risk, has led to the development of new therapeutic approaches that include LBPs, which have demonstrated efficacy in reducing future CDI recurrences [ 13 , 14 ].…”

Clostridioides difficile infection: curbing a difficult menace

“…The treatment guidelines for management of CDI have changes over the last three decades. Chaar and Feuerstadt 10 review the evolution of clinical guidelines for antimicrobial management of CDI including initial guidelines from the 1990s, a second wave from 2009 up to 2013, and a modern era of treatment guidelines from 2014 to date. Initial guidelines recommended metronidazole as a preferred treatment which changed to vancomycin owing to high failure rates with metronidazole.…”