FIDSSA

Case of the Month

September 2016

A prosthetic hip infection caused by linezolid-resistant Staphylococcus epidermidis

Heidi Orth, Marthinus Senekal and Catherine Samuel - Clinical Microbiologists, PathCare; Adriaan van Huyssteen, Orthopaedic surgeon, Panorama Medi-Clinic hospital

Linezolid resistance in staphylococci is rarely observed in our setting. An increase in the therapeutic use of linezolid may cause selective pressure and lead to the emergence of resistance. We report a case of prosthetic hip joint infection caused by a linezolid-resistant Staphylococcus epidermidis. A 60-year old female had a total hip replacement in August 2013. A joint revision was performed in April 2014 due to loosening of the acetabular component. Cefuroxime was administered as peri-operative prophylaxis. She also received amoxicillin-clavulanate treatment for an E. coli urinary tract infection. The patient was subsequently taken back to theatre three times with recurrent dislocation of the prosthesis due to avulsion of the gluteus medius. A second revision of the left total hip replacement was performed in September 2014. At surgery there was no evidence of infection but amoxicillin-clavulanate was administered for post-operative wound infection. Fluid aspirates from the draining wound and tissue specimen cultures showed no growth. The synovial fluid white cell count was 0.5 x109/l with 13% neutrophils. In November 2014, following another dislocation, a third revision was performed due to rupture of the external rotator muscles. Intra-operatively, there was no evidence of deep-seated infection. Post-operatively, amoxicillin-clavulanate was again initiated for a wound infection indicated by a persistently draining wound and CRP of 45 mg/l. The clinicians noted an initial improvement on amoxicillin-clavulanate , but the wound again began to drain fluid and the antimicrobial therapy was changed to ciprofloxacin, cotrimoxazole and rifampicin. Two weeks after the third revision, the patient underwent debridement and joint washout. Treatment was changed to linezolid and ciprofloxacin. Large amounts of purulent fluid were drained and the synovial fluid aspirate showed a white cell count of 32 x 109/l with 88% neutrophils. Other infective parameters included a blood white cell count of 8.1 x 109/l; CRP 323mg/l and ESR 101mm/hr. Two days post-debridement, rifampicin was added to the linezolid and ciprofloxacin as empiric treatment of prosthetic joint infection.

Question 1 How is the aetiology of prosthetic joint infection determined?

Answer to Q1

Prosthetic Joint Infeciton (PJI) should be suspected with a persistent draining wound over a joint prosthesis. Synovial fluid analysis as well as culture of at least 3, and optimally 6 peri-prosthetic tissue samples collected at the time of surgical debridement or prosthesis removal is recommended to obtain a microbiological diagnosis.1 Prolonged incubation of up to 14 days can help to improve the yield of isolation, particularly with Propionibacterium species. Two or more positive cultures with the same coagulase negative staphylococcus (CoNS) species (and same antibiogram) provide evidence of infection whereas a single positive isolate may reflect contamination.

In this case, four of the six intra-operative tissue samples collected in cooked meat broth medium during the debridement procedure, cultured methicillin-resistant Staphylococcus epidermidis (MRSE) resistant also to moxifloxacin and cotrimoxazole. Three of the four isolates were identical on antibiogram and showed resistance to linezolid, and the fourth isolate was susceptible to linezolid (see table 1). It was evident that this patient has different strains of the same organism, most likely residing in a biofilm on the prosthetic joint. The linezolid results were confirmed by repeat testing on the Vitek 2 automated system, disk diffusion and E-test methods (table 1). Disk diffusion testing showed no zone of inhibition. Ciprofloxacin was subsequently stopped and therapy continued with oral linezolid, rifampicin and fusidic acid. The patient responded well to the debridement procedure and antimicrobials and her CRP decreased three weeks later to 5.4 mg/l.

Table 1: The susceptibility results obtained with the Vitek® 2 system (bioMérieux Worldwide) of four MRSE isolates, interpreted according to CLSI breakpoints.2 MIC values obtained by Vitek for selected agents are shown in brackets. Linezolid MICs determined by the E-test method (bioMérieux France) are shown in last column. MRSE isolate number Ery Clin Gent Tet Fuci Rif Cotr Moxi Vanc Teico Dapto Lzd Lzd MIC (µg/ml)

Answer to Q2

Staphylococci remains the most common bacterial agent in PJI. S.aureus and CoNS are each implicated in up to 25% of all infections.3 Gram-negative organisms account for the next most common aetiological agent, implicated in approximately 10% of cases. Propionibacterium acnes has a particular association with prosthetic shoulder joint infections, and may occur in up to 40% of cases.

Question 3 Has Linezolid resistance in Staphylococci been described?

Answer to Q3

Linezolid resistance was first described in 2001 in the United States, one year after being approved for clinical use.4 The patient presented with dialysis-related peritonitis and was treated with linezolid for one month prior to the isolation of a linezolid resistant S. aureus (LRSA). Since then surveillance studies have shown a very low incidence of linezolid resistance in S. aureus isolates, but higher incidence rates in CoNS. The USA Linezolid Experience and Accurate Determination of Resistance (LEADER) surveillance programme reported linezolid resistance in 0.05% of S. aureus and 1.4% of CoNS. The Zyvox Annual Appraisal of Potency and Spectrum (ZAAPS) programme documented only one LRSA isolate and 10 LRCoNS between 2002 and 2010, with a total resistance rate of 0.14% among staphylococci.5

Question 4 What is the mechanism of Linezolid resistance?

Answer to Q4

Linezolid is an oxazolidinone that inhibits bacterial ribosomal protein synthesis. Resistance may be due to mutations in the 23S rRNA binding site, the ribosomal proteins L3 and/or L4 of the peptide translocation centre of the ribosome or by acquiring the ribosomal methyltransferase gene, cfr, which is carried on a plasmid. Recent findings on the Cfr methyltransferase underscore the modification of 23S rRNA as a highly effective and transferable form of linezolid resistance. In addition, detailed knowledge of the linezolid binding site has facilitated the design of a new generation of oxazolidinones that show improved properties against the known resistance mechanisms.6

The only clear nonribosomal linezolid resistance mechanism reported is related to mutations causing increased expression of ABC transporter genes in Streptococcus pneumoniae.7,8 It has also been shown that Staphylococcus aureus possesses a gene for a major-facilitator-superfamily-type multidrug efflux pump named LmrS that is capable of forcing out linezolid from the bacterial cell.9

Our case illustrates LRCoNS may arise in patients who have not previously received linezolid therapy. This is however unusual as LRS infection occurs mostly in patients who were treated with linezolid prior to isolation of LRS. In a systematic review of the literature, Gu et al. reported that in cases with available clinical information, linezolid resistance followed prolonged treatment.5 The mean time of linezolid therapy prior to isolation of LRS was 11 days for LRCoNS versus 20 months for LRSA. Our patient had multiple exposure to beta-lactam agents and the amoxicillin-clavulanate treatment received for post-operative wound infection can be considered inappropriate due to the high prevalence of MRSA in the hospital setting. The role of this exposure in selecting for linezolid-resistant S. epidermidis in the environment and in this patient can only be speculated.

Question 5: Does Linezolid resistant staphylococci have the potential to spread and cause outbreaks?

Answer to Q5

Clonal spread of LRS has been documented in both institutional and multi-institutional outbreaks. Kelly et al. reported on linezolid-resistant S. epidermidis strains from 16 colonized patients in an intensive care unit (ICU) in Ireland that were genetically related.10 The same strain was also isolated from the environment. The majority of patients had received linezolid prior to isolation of the resistant isolate, but 6 patients did not receive linezolid, indicating possible cross-infection. A significant increase in the usage of linezolid in the ICU in the 6 month period during which the linezolid-resistant isolates emerged, was noted. Similarly an outbreak of LRSA in an ICU in Spain found that 7 of 12 infected patients had negative surveillance cultures, implying exogenous infection.11

Conclusion

CoNS cause hospital-acquired infections such as catheter-related bloodstream infection, prosthetic valve endocarditis and infections of prosthetic joints. Increasing antimicrobial resistance in CoNS has limited the therapeutic options. Linezolid is a useful agent to treat infections caused by multi-resistant Gram positive organisms such as methicillin-resistant staphylococci and vancomycin-resistant enterococci and has the advantage that it may be given orally, which is useful in the treatment of bone and joint infections to reduce the length of hospitalisation. Infection control measures such as contact precautions, reinforcing hand hygiene procedures and antibiotic stewardship has been shown to prevent the spread of linezolid-resistant S. epidermidis in the outbreak described by Kelly et al.10 The emergence of linezolid-resistance in South Africa is a great concern. With limited alternative agents, the appropriate use of broad-spectrum agents is very important to prevent the emergence and spread of these multi-resistant organisms.

References:

Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and Management of Prosthetic joint infection: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2013; 56(1) 1-25
CLSI. Performance standards for antimicrobial susceptibility testing. Wayne: Clinical and Laboratory Standards Institute; 2014.
Peel TN, Cheng AC, Buising KL, Choong PF. The microbiological aetiology, epidemiology and clinical profile of prosthetic joint infections: are current antibiotic prophylaxis guidelines effective Antimicrob Agents Chemother 2012; 56:2386–2391
Tsiodras S, Gold HS, Sakoulas G, et al. Linezolid resistance in a clinical isolate of Staphylococcus aureus. Lancet 2001; 358: 207-8.
Gu B, Kelesidis T, Tsiodras S, et al. The emerging problem of linezolid-resistant Staphylococcus. J Antimicrob Chemother 2012; doi: 10.1093/jac/dks354.
Long KS, Vester B. Resistance to Linezolid Caused by Modifications at Its Binding Site on the Ribosome Antimicrob Agents Chemother 2012; 56 (2): 603-612.
Billal DS, Feng J, Leprohon P, et al. Whole genome analysis of linezolid resistance in Streptococcus pneumoniae reveals resistance and compensatory mutations. BMC 2011; Genomics 12:512.
Feng J, Lupien A, Gingras H, et al. 2009. Genome sequencing of linezolid-resistant Streptococcus pneumoniae mutants reveals novel mechanisms of resistance. Genome Res.19:1214–1223.
Floyd JL, Smith KP, Kumar SH, et al. LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Antimicrob. Agents Chemother 2010; 54:5406–5412
Kelly S, Collins J, Maguire M, et al. An outbreak of colonization with linezolid-resistant Staphylococcus epidermidis in an intensive therapy unit. J Antimicrob Chemother 2008; 61: 901-907.
Garcia MS, De la Torre MA, Morales G, et al. Clinical Outbreak of linezolid-resistant Staphylococcus aureus in an Intensive Care Unit. JAMA 2010; 303 (22): 2260-2264.

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