Evaluation of antibiotic resistance to orally administrable antibiotics in staphylococcal bone and joint infections in one of the largest university hospitals in Germany: is there a role for fusidic acid?

Highlights

• Resistance to commonly used oral antibiotics to treat staphylococcal bone and joint infections (BJIs) is increasing.

• 75% of MRSA and ca. 50% of CoNS causing BJIs were resistant to the commonly used combinations (rifampicin and fluoroquinolone or clindamycin).

• 87% of rifampicin-resistant MRSA strains and 62% of rifampicin-resistant CoNS were susceptible to fusidic acid.

• Fusidic acid should be considered as an alternative/option for rifampicin, especially since this drug is recommended in official guidelines and is available as an oral agent in some European countries.

Abstract

Bone and joint infections (BJIs) are often difficult to treat. Staphylococcus spp. is the major pathogen causing these infections, which is often associated with biofilm formation on prosthetic materials. Therapeutic measures are complex, ranging from surgical intervention to initial intravenous and supportive long-term oral antibiotic therapy. The options for oral antimicrobial therapy are limited, mainly due to the resistance profile of the causative pathogen and the unfavourable pharmacodynamic and pharmacokinetic properties of most antibiotics in biofilm. Data analysis over a 5-year period was performed on staphylococci isolated from BJI patients in the Orthopaedic Department of the University Hospital Heidelberg (Heidelberg, Germany) to assess the plausibility of fusidic acid (FA)-based alternative oral treatment regimens. Six percent of BJIs were caused by meticillin-resistant Staphylococcus aureus (MRSA), and multiresistance was common. Over 75% of MRSA in BJIs were resistant to the commonly used rifampicin (RIF)-based combinations. Resistance to FA-based combinations was high. However, over 80% were susceptible to the combination RIF + FA. In coagulase-negative staphylococci, resistance to RIF-based combinations was similar to FA-based combinations. Almost two-thirds of the isolates tested were susceptible to RIF + FA. These data suggest FA as a possible option as a substitution for RIF or as a combination companion in case of resistance or unavailability.

Introduction

Treatment of bone and joint infections (BJIs) is challenging. Most BJIs in orthopaedic surgery are caused by staphylococci [1], [2]. Staphylococcus aureus is the most common organism causing osteomyelitis, septic arthritis and early postoperative prosthetic joint infections, whereas late postoperative prosthetic joint infections are often caused by coagulase-negative staphylococci (CoNS). Besides surgical procedures, such as implant removal, debridement and drainage, prolonged courses of antibiotic therapy are essential to ensure treatment success by eradicating the bacteria or reducing the bacterial burden [3], [4]. An appropriate antimicrobial chemotherapy strategy is crucial to successfully manage and treat staphylococcal BJIs. Following initial intravenous (i.v.) antibiotic therapy, switch to an oral route of administration over several weeks to months is strived [1], [3]. Selection of an appropriate antibiotic drug depends on numerous factors such as isolated organism, susceptibility profile, pharmacokinetics and penetration into the site of infection [5], [6]. Owing to increasing resistance and limited options for alternative drugs, many experts resort to rediscover ‘old’ antibiotics such as trimethoprim/sulfamethoxazole (SXT) and fusidic acid (FA) [4], [7], [8].

The initial i.v. therapy commonly comprises either β-lactam antibiotics or vancomycin (VAN), depending on the susceptibility profile, combined with rifampicin (RIF) for a course of 2–6 weeks [3], [9]. Depending on the type of infection, continuation of antibiotic therapy via the oral route following i.v. administration is initiated for up to 6 months [3]. Recent recommendations include fluoroquinolones (FQs), clindamycin (CLI), FA and SXT as a possible combination companion for RIF [1], [3], [4], [9]. FA is a bacterial protein synthesis inhibitor that has activity against staphylococcal biofilm with good penetration into bone and joints [6]. Similar to RIF, FA should only be administered in combination with another agent to avoid rapid development of resistance. However, in many countries, including Germany, the FA license is restricted to topical administration only. Nevertheless, orally administered FA is available in some European countries and is even officially recommended for oral treatment of BJIs in several international guidelines, allowing for off-label administration [4], [9]. Despite promising results in several clinical studies [7], [10], data on FA resistance in staphylococci causing BJIs are scarce. This brief report aims to evaluate the potential of FA-based combinations as a possible alternative oral therapy for staphylococcal BJIs. To this end, the antibiotic susceptibility of staphylococci isolated from BJI patients at Heidelberg University Hospital, one of the largest university hospitals in Germany, was analysed.