Is Rifampin "Sticking" Around?

Rifampin (or Rifampicin) is a class of antibiotics that is mostly associated as part of the 4-drug regimen for active tuberculosis (TB) and as monotherapy for latent TB.^1,2 Outside of TB, it’s been traditionally used for bone, joint, and hardware infections with other antibiotics and not as monotherapy due to the rapid emergence of resistance via a single mutation in the rpoB gene.³ Rifampin works by inhibiting DNA-dependent RNA polymerase preventing bacterial RNA synthesis.² It is particularly bactericidal against Staphylococcal aureus infections due to its ability to achieve high intracellular levels, kill organisms in the sessile phase of growth (non-replicating bacteria) and penetrate biofilms.⁴ Its “anti-biofilm” properties have been closely linked to its use for years. But what exactly is a biofilm? How is it related to S aureus infections? What is its role in bone, joint, and hardware infections?

The “Infamous” Biofilm

The first description of biofilms dates as far back as the 17th century "the Father of Microbiology", Anton Von Leeuwenhoek, observed microbial aggregates (“animalcules”) on the plaque taken from teeth.⁵ At that time, it was not called biofilm yet, but it laid the foundation of how we describe biofilms today. The term itself was first coined in 1978 by J. William Costerton in a paper titled “How Bacteria Stick”- a simple but fitting description of how a “mass of tangled fibers of polysaccharides, or branching sugar molecules, that extend from the bacterial surface and form a feltlike ‘glycocalyx’ surrounding an individual cell or a colony of cells” help bacteria survive, propagate and resist antibiotics6. Donlan and Costerton in a 2002 paper² described biofilm as a “microbially derived sessile community characterized by cells that are irreversibly attached to a substratum or interface or to each other, are embedded in a matrix of extracellular polymeric substances that they have produced and exhibit an altered phenotype with respect to growth rate and gene transcription.”⁷ This partly explained biofilm’s resistance against antibiotics. Biofilm-associated cells grow slower than planktonic cells and, as a result, take up antibiotics more slowly.⁷ This acts as diffusion barriers reducing antimicrobial penetrance towards the deeper layers of the biofilm.⁸ This makes bacteria within biofilms 10 to 1000 times more resistant compared to bacteria not associated with biofilms. Altered metabolic activity of biofilm bacteria is also hypothesized to be a major driver of resistance in addition to decrease in antimicrobial penetration. These 2 mechanisms contribute to the increased risk of persistence and recurrence of infections, specifically those caused by S aureus.

Osteomyelitis (OM)

The use of rifampin had been explored as an adjunctive therapy for OM even in the absence of any prosthesis or hardware to reduce the risk of recurrence and treatment failure.^8,9,10 It has excellent bone penetration reaching mean bone concentrations 1.3±1 µg/mL and 6.5±1.3 µg/mL in cortical and cancellous bones, respectively.¹¹ This would reach levels higher than the minimum inhibitory concentration susceptibility breakpoint of rifampin against S aureus of ≤1 µg/mL.

Biofilms that are historically formed on infected hardware are also observed in bone infections, specifically chronic OM. The reduction in the penetration of antibiotics encourages the formation of small colony variants (SCVs) and persisters.⁸ SCVs are small sized colonies characterized by slow growth, downregulation of virulence factors and upregulation of genes associated with adhesion and biofilm formation. Persisters are dormant variants found within a susceptible bacterial population with increased antibiotic tolerance. These two phenomena are indicative of the changes in the metabolic activity of bacteria within biofilms causing increased antibiotic tolerance. These support the enduring and relapsing nature of chronic OM.

In 2019, Wilson et al conducted an observational cohort study using the Veterans Health Administration database to evaluate the role of adjunctive rifampin in preventing subsequent amputations and deaths in patients with diabetic foot OM (DFO).¹⁰ Lower rates of amputation and death were observed among patients receiving rifampin (35 of 130 [26.9%] vs. 2250 of 6044 [37.2%], P=0.02). Several statistically significant differences between the groups may have affected the outcome given that patients who were given rifampin were younger, had fewer comorbidities, more infectious disease specialist involvement, and more S aureus identified on cultures. A meta-analysis of 4 randomized controlled trials (RCT) (Van der Auwera et al¹², Norden et al¹³, Zimmerli et al¹⁴, and Karlsen et al¹⁵) suggested a potential benefit of adjunctive rifampin in patients with OM with or without hardware.⁹ Van der Auwera et al and Norden et al did not include any hardware while Zimmerli et al and Karlsen et al were studies involving prosthetic joints. It is important to point out the included studies had small sample sizes, different dosing regimens for rifampin, differences in coantibiotics utilized, heterogeneity of patient population, and differences in surgical management.

While the potential advantages might be more noticeable in individuals with chronic OM and DFO, a clear recommendation regarding its use cannot be established in the absence of well-designed RCTs specifically addressing this issue.

Prosthetic Joint Infections (PJIs)

Staphylococcal PJIs have a heterogenous success rate ranging from 23% to 90%.¹⁶ This variability in success rates leads to differing opinions on PJI treatment specifically when it comes to antibiotic management. One of the long standing tenets of PJI, and hardware infections in general, is the addition of rifampin to standard antibiotic management. PJIs occur in 1%-2% of all patients following a large joint replacement.¹⁷ This carries with it considerable comorbidities, decreased quality of life, as well as increased costs both to the patient and the healthcare system in general.^1,17

Debridement, antibiotics, and implant retention (DAIR) has been the surgical intervention of choice for acute PJIs. The variability in the definition of what “acute” means ranges from 30 to 90 days after index arthroplasty, or with an acute hematogenous PJI with symptoms for < 3 weeks.^15,17,18 Despite this, DAIR failure rates are reported to be ranging from 10% to 45%16. The Infectious Diseases Society of America published in 2012 the clinical practice guidelines on PJI and recommended rifampin for susceptible Staphylococcal PJI following debridement and retention of prosthesis.¹ This was influenced by the landmark RCT by Zimmerli et al (1998) showing combination therapy with ciprofloxacin and rifampin resulted in similar cure rates compared to ciprofloxacin monotherapy.¹⁴ The study specifically included only those with retained stable prosthesis. Unfortunately, the sample size was small (33 total patients, 24 of whom fully completed the trial) and the use of ciprofloxacin monotherapy as the comparator had been called into question due to 4/5 failures were due to ciprofloxacin resistance.

The role of rifampin in Staphylococcal PJI has been called into question by a RCT conducted by Karlsen et al that showed no significant difference in remission rate between the rifampin combination group (74%, 17/23) and the monotherapy group (72%, 18/25).¹⁴ Unfortunately, the study was underpowered to draw any definitive conclusion, albeit having a larger number of patients included in the final analysis (48 patients in Karlsen et al¹⁵ vs 24 patients in Zimmerli et al¹⁴). So far, these are the only 2 RCTs looking at the role of rifampin for PJIs while the rest are observational studies.^16,19

One of those observational studies was conducted Davis et al in 27 hospitals across Australia and New Zealand that aimed to look at predictors of treatment success after PJI.¹⁷ DAIR was the main surgical treatment in 352/653 patients where 51% used rifampin (61% where ≥1 causative organisms were gram-positive coccus, and 75% where ≥1 organism was Staphylococcus). The use of rifampin was not independently associated with treatment success (OR = 1.15; 95% CI, 0.82–1.61). These findings were consistent if the analysis is restricted to gram-positive infections, Staphylococcal infections, or those with Staphylococcal infections who received ≥14 days of rifampin. Younger age, hip as the index joint, early infection (<30 days from original arthroplasty), shorter duration of symptoms at diagnosis, high baseline albumin, and absence of chronic renal disease or malignancy were independently associated with treatment success. While knee as the index joint, certain organisms (S aureus, Cutibacterium spp., or gram-negative rods) and late infections (>30 days from original arthroplasty) were associated with lower treatment success rates.

There are 2 meta-analyses^16,19 that tried to evaluate the utility of rifampin for PJIs. Aydin et al conducted a meta-analysis of 13 observational studies and looked at 3 subsets focusing on Staphylococcal spp. (n=568), Streptococcal spp. (n=483) and Propionibacterium spp. (n=80), which were the predominant bacteria in the studies included19. Only the Streptococcal subset was found to favor the use of rifampin adjunctive regimens. The 1 study included in the meta-analysis that specifically examined groups with or without rifampin found that adjunctive rifampin was not superior. There were several limitations, particularly the quality of evidence ie no RCTs, and all the included studies were compromised by selection bias. The authors concluded that the evidence did not favor the addition of rifampin especially for Staphylococcal and Propionibacterium PJIs.

The 2nd meta-analysis was conducted by Scheper et al and included 64 studies (n=4380) published between 1990 and September 2, 2020.¹⁶ There were 62 observational cohort studies (3 prospective, 59 retrospective) and 2 RCTs (Zimmerli et al¹⁴ and Karlsen et al).¹⁵ Out of the 64 studies, 49 studies use rifampin for Staphylococcus PJI. Thirty of the 49 studies have reported outcomes of treatment with or without rifampin. The pooled success rate in all studies was 60%. If stratified based on the causative organism, the pooled success rates for S aureus PJI and Coagulase-Negative Staphylococcus (CONS) PJI after DAIR were 62% (2922 analyzed patients in 54 studies) and 73% (36 studies, 760 patients), respectively.

The addition of rifampin after DAIR had a higher success rate (64% in 34 studies with 2884 patients) compared to those who were not on rifampin (44% in 18 studies with 976 patients) with similar procedure. Staphylococcal knee PJIs (2 studies) with addition of rifampin had higher cure rates (81%, 56/69) than without rifampin (50% 17/34). This was also observed in 24 studies with Staphylococcal knee and hip PJIs (with rifampin 70%, 903/1298 vs without rifampin 5.3%, 186/354). The 3 studies that specifically looked at combined knee and hip PJIs where S aureus was the causative organism also showed higher cure rates with rifampin (80%, 100/125) than without rifampin (40%, 4/10). Whereas Staphylococcal hip PJIs (4 studies) treated with additional rifampin have similar cure rates compared to those not on rifampin (83%, 102/123 vs. 82%, 28/34).

An interesting finding in the study was that the outcomes observed seemed to be attributed to the low ratio of knee-to-hip PJI per study and not by rifampin use. This was supported by the outcomes related to the type of joint where the pooled success rates in patients who underwent DAIR for hip PJIs were higher than knee PJIs both for S aureus (69% vs. 54%) and CONS (83% vs. 73%). They found that the knee-to-hip ratio per study was inversely related to rifampin use. After correcting for the type of joint, the correlation between rifampin use and successful outcomes disappeared.

The authors hypothesized that the addition of rifampin may not increase success rates for hip PJI given its already higher rate of success.The lower successful outcomes seen in knee PJI could be due to anatomical barriers that may impede adequate debridement making rifampin use in this setting more advantageous.This is consistent with Davis et al where success rates were lower with knee PJI (48%) compared to hip PJI (60%).¹⁷ There was no difference in the outcomes for methicillin-resistant S aureus (MRSA) PJI and methicillin-susceptible S aureus (MSSA) PJI.¹⁶ Whether addition of rifampin affects these outcomes was unclear since it was not explored in the study. One of the limitations that seemed to be common in the studies mentioned was that the use of rifampin (dosing, timing, duration) was not standardized.Treatment duration with rifampin was 3 months in most studies included in the meta-analysis by Scheper et al.

Could the dose, drug interactions, or timing of giving rifampin have affected the benefit provided by rifampin? Beldman et al tried to answer these questions in a retrospective study using patient data in in 4 countries (Spain, Portugal, USA, Netherlands) in patients with acute PJI of the hip or knee.¹⁸ The study only included 669 patients treated with DAIR and where the main or one of the causative organisms were Staphylococci (407 patients with rifampin and 262 patients without rifampin). Treatment failure for the total cohort was 40.8% (273/669) while it was 32.2% (131/407) in patients treated with rifampin and 54.2% (142/262) in patients without rifampin. The benefit seemed to be more pronounced with knee PJIs (28.6% treatment failure with rifampin vs. 63.9% without rifampin) compared to hip PJIs (34.6% with rifampin vs. 46.2% without rifampin). After multivariate analysis, there’s no association between treatment failure and dosing for rifampin (600mg QD vs. 600mg BID vs. 450mg BID). Fluoroquinolones, particularly levofloxacin, was found to be superior as a co-antibiotic with rifampin. This is consistent with the OVIVA trial (Li et al, 2019), the landmark study comparing full course intravenous therapy versus early switch to oral antibiotics (≤7 days from definitive surgical intervention or from start of antibiotic therapy) for bone and joint infections, that had fluoroquinolones as the most used class of antibiotics.²⁰ This benefit from fluoroquinolones could be attributed to its excellent bioavailability (about 90 to close to 100%) and extensive penetration to tissues particularly bone and joints.^11,21,22 On the other hand, trimethoprim-sulfamethoxazole (TMP-SMX) was found to have the highest treatment failure (38%) as a co-antibiotic.¹⁸ A possible explanation for this finding was a 30%–40% reduction of serum concentration for antibiotics like TMP-SMX and clindamycin.^23,24 Despite rifampin also being able to lower clindamycin concentration, it didn’t show treatment failure rates observed with TMP-SMX. One possible explanation was that higher doses of co-antibiotics (clindamycin 300mg TID vs 600mg TID) causes less rifampin-related induction of antibiotic metabolism.

The study also showed an association between early administration of rifampin and treatment failure.¹⁸ Depending on when it was given in relation to surgical debridement or source control- within 5 days, between 5 to 9 days and after 10 days, treatment failures were noted to be 40.8%, 20.9% and 20.1%, respectively. This remained significant after multivariate analysis. This inverse relationship between treatment failure and timing of rifampin administration could be due to the high risk of developing resistance when bacterial burden is still high.²⁵ This usually is the case when no surgical intervention was done, during the first few days after initiating antibiotics, or when the patient is still bacteremic.²⁶ The 2 RCTs, Zimmerli et al¹⁴ and Karlsen et al¹⁵, both have started rifampin with the initial intravenous therapy, or day 1 after source control, respectively. Although further studies are necessary to draw definitive conclusions on this matter, this is important to consider when designing future trials dealing with rifampin and PJIs.

The addition of rifampin seemed to be more beneficial for (1) Staphylococcal PJIs, (2) knee PJIs, (3) if given with co-antibiotics that minimally interacts with it or at the least at a higher dose where induction was less pronounced, (4) high bone and tissue penetration, and (5) if given at least 5 days after source control or clearance of bacteremia. Doses greater than 600mg per day of rifampin did not provide added benefits when it came to treatment outcomes. The studies we derived these conclusions from were based on observational studies, most of which were plagued by biases and confounders, and very few RCTs. Given the scarcity of high-quality evidence, definitive conclusions about the true benefit of adjunctive rifampin in PJIs demands clinical equipoise between the risks and benefits in specific populations.

Native Vertebral Osteomyelitis (NVO)

A systematic review and meta-analysis published by Zein et al in 2023 suggested adjunctive rifampin may be associated with lower risk of treatment failure in patients with S aureus NVO.²⁷ Thirteen studies were included in the analysis (2 RCTs and 11 comparative cohort studies). One of the RCTs was the OVIVA trial described in the PJI section.²⁰ The second RCT was the ARREST trial (Thwaites et al, 2018) that showed no overall benefit of adjunctive rifampin for S aureus bacteremia.²⁶ Neither RCTs were specifically designed to address the benefit of rifampin for NVO. There are 244 patients with S aureus NVO (35.9%) with adjunctive rifampin and 435 (64.1%) without rifampin. Blood culture results were available in 367 patients, of which 332 (90.5%) were positive for S aureus (42% MSSA and 38.5% of MRSA received rifampin, out of 331 evaluable patients). The overall clinical failure rates were higher in the standard therapy group (21.8%) compared to the rifampin group (15.6%).

Rifampin was associated with a 14% absolute risk reduction in clinical failure when compared with standard therapy. The most used co-antibiotic class was fluoroquinolones. During a subgroup analysis, the risk of clinical failure was lower where rifampin was used in combination with fluoroquinolone. This is consistent with the findings of the OVIVA trial20 and Beldman et al¹⁸ discussed earlier. Rifampin was given at doses of 600mg per day or 900mg per day, often divided into two doses for a median duration of 42 days (interquartile range, 27–56 days).²⁷ The timing of rifampin administration was not assessed due to lack of patient-level data. As outlined in the PJI section and demonstrated in the ARREST trial,²⁶ the timing of rifampin to source control or clearance of bacteremia can have a substantial impact on treatment outcomes.¹⁸

Despite the favorable outcomes, the authors noted that the studies involved deemed to have a high or uncertain risk of bias and the overall uncertainty of evidence was deemed very low due to the methodological limitations and imprecision.²⁷ For these reasons, the use of adjunctive rifampin for NVO should be a joint decision-making with the patient while carefully weighing the risks and benefits in each case. Before providing a strong recommendation for the use of adjunctive rifampin in NVO, it is essential to conduct future high-quality studies to thoroughly address this matter.

Is Rifampin Here to Stay?

The use of rifampin for its “anti-biofilm” properties has been a long-standing practice in medicine. It has shown efficacy in the treatment of bone, joint, and hardware infections, particularly when used in combination with other antibiotics. Unfortunately, its evidence is plagued by a few RCTs, heterogenous observational studies and inconsistent regimens used (eg dose, timing, and duration of rifampin as well as co-antibiotic used). Nonetheless, some experts stand by its benefits. Its unique mechanism of action, including penetration into biofilms and ability to eliminate intracellular bacteria while remaining bactericidal, make a strong argument for its addition to treatment regimens.

However, rifampin is like a double-edged sword given its high risk of developing resistance when used as a monotherapy and a multitude of drug interactions precluding its administration to patients with several co-morbidities. While rifampin has demonstrated positive outcomes in certain cases, its use should be in careful consideration of the patient's specific condition, bacterial profile, and potential drug interactions. A dedicated RCT with a large homogenous sample size, standardized antibiotic regimen, and a study design specifically addressing the question of its efficacy needs to be done before we can finally say rifampin is sticking around.

References

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