Drs Sivakumar, Vijaysegaran, Crawford, and Ottley are from the Department of Orthopedic Surgery, and Dr Chaudhuri is from the Department of Infectious Diseases, The Prince Charles Hospital, Chermside, Australia.
Drs Sivakumar, Vijaysegaran, Chaudhuri, Crawford, and Ottley have no financial relationships to disclose.
Correspondence should be addressed to: Praveen Vijaysegaran, MD, Department of Orthopedic Surgery, The Prince Charles Hospital, Rode Rd, Chermside, QLD 4032, Australia (firstname.lastname@example.org).
The rapid evolution of antimicrobial resistance poses a serious challenge in the treatment of infection and creates a need for new agents with novel mechanisms of bactericidal activity. This article describes a prosthetic joint infection demonstrating resistance to daptomycin, reviews the literature on diminished susceptibility to this agent, and discusses mechanisms by which resistance may be acquired. We also recommend potential strategies to manage and diminish antimicrobial resistance.
An 82-year-old man undergoing elective left total knee arthroplasty (TKA) presented with a complex cardiac history requiring warfarinization and was methicillin-resistant Staphylococcus aureus (MRSA)-positive at admission. The TKA (Cemented Vanguard Complete Knee System with no tourniquet; Biomet, North Ryde, New South Wales, Australia) was uncomplicated, and he received vancomycin as standard antimicrobial prophylaxis. He was discharged on postoperative day 11.
The patient presented the next day with excessive bleeding from his wound. Examination revealed superficial dehiscence of the proximal 7 cm, which was cleansed and closed with loose tacking sutures. The patient was admitted in an extension splint for wound observation. Despite repeated instruction over the next week, the patient was noncompliant with the extension splint and flexed his knee persistently, with continued dehiscence. Negative pressure wound therapy (Vacuum Assisted Closure Dressing; KCI, Lane Cove, New South Wales, Australia) was applied as per plastic surgical opinion. Wound swab revealed polymicrobial growth of S aureus sensitive to flucloxacillin, MRSA sensitive to vancomycin, and Klebsiella pneumoniae sensitive to gentamicin. Although he remained apyrexial and inflammatory markers were not raised, the patient was started on dual antibiotic therapy of vancomycin and gentamicin. Despite these measures, the wound continued to deteriorate, and he underwent irrigation and debridement on postoperative day 22.
Intraoperatively, hemopurulent fluid and a large congealed hematoma were evacuated. The majority of the patient’s extensor mechanism (patellar tendon, patella, retinacula, and quadriceps tendon) was nonviable and was debrided to reactive margins. The polyethylene liner was removed, the joint was thoroughly lavaged, and the liner was reinserted. Figure 1 demonstrates the extent of the debridement. The vacuum-assisted closure dressing was replaced. Microbiological samples revealed polymicrobial growth (S aureus, P aeruginosa, K pneumoniae, and Bacteroides fragilis). However, no evidence existed of the MRSA on initial swabs, and this, coupled with worsening renal failure, led to the change of antibiotics to timentin and metronidazole.
Figure 1: Intraoperative photograph of the left knee after debridement.
Following 3 further irrigations (days 24, 27, and 30), the wound was sterile, and the tissue defect was covered by medial and lateral gastrocnemius flaps and a split skin graft on day 37. However, due to the patient’s nonexistent extensor mechanism and resultant unopposed knee flexion, the wound began to dehisce superiorly at the margin of the gastrocnemius flap and split skin graft, with the prosthesis showing. Repeated attempts to close the breach with sutures failed, and the plastic surgery team advised that further mobilization of the flaps was not viable (Figure 2).
Figure 2: Photograph of the nonviable gastrocnemius flap and split skin graft dehiscence with prosthesis.
The patient and his family elected for knee fusion, and an antegrade fusion nail (Smith & Nephew, Mount Waverly, Victoria, Australia) was inserted on postoperative day 46. Operative cultures revealed pure growth of MRSA, which was sensitive to vancomycin on routine susceptibility testing. Vancomycin was restarted. However, due to the nonresolving nature of the infection, population analysis profiling was also performed, which initially revealed reduced susceptibility to vancomycin, placing it in a subgroup known as heterogeneous vancomycin intermediate-resistant S aureus (hVISA). The patient was switched to another glycopeptide, teicoplanin. Final profiling revealed that the isolate was also resistant to teicoplanin and a newer antimicrobial agent, daptomycin, rendering it the first identified case of daptomycin-resistant S aureus in Queensland, Australia. He was subsequently placed on life-long dual therapy of pristinamycin and ciprofloxacin. Regular wound inspection and analysis of inflammatory markers revealed clinical and biochemical resolution (Figures 3–5). Twelve months postoperatively, he has returned to his retirement home, where he remains on long-term suppressive therapy and mobilizes with a cane.
Figure 3: Plain anteroposterior left lower limb radiograph after knee fusion.
Figure 5: Photograph of the left knee 4 months after fusion on long-term suppressive antibiotic therapy.
Caused primarily by multiresistant gram-positive organisms, such as MRSA and vancomycin-resistant enterococci, prosthetic joint infections are difficult to treat, often requiring repeated surgical intervention and prolonged antibiotics.1–3 A subgroup of MRSA, hVISA, demonstrates variable and reduced susceptibility to the traditional first-line therapeutic option of vancomycin, via a thickened cell wall with peripheral decoy peptidoglycan binding sites, which divert the antibiotic from its central site of action. Evidence suggests that it is more likely to infect bones, joints, and prosthetic materials, be associated with initial treatment failure, demonstrate longer durations of bacteremia and antibiotic requirements, and result in longer, more expensive hospital stays.3,4
Heterogeneous vancomycin intermediate-resistant S aureus was initially isolated in Australia in 2001, although it was first recognized internationally in Japan in 1997, and reports of its presence have increased since.5 The true global prevalence of hVISA is unknown and difficult to estimate due to the lack of universally agreed-upon diagnostic laboratory criteria, primarily because laboratory methodologies for the identification of hVISA are labor intensive, expensive, and not widely available.6
The emergence of multiresistant sub-populations, such as hVISA, has generated the need for new agents with novel mechanisms of bactericidal activity. Daptomycin, a cyclic lipopeptide naturally produced by Streptomyces roseosporus, works in a unique manner, inserting onto the bacterial cytoplasmic membrane in a calcium-dependent fashion and disrupting its integrity, triggering a release of intracellular ions and cell death. This method of action is novel compared with other classes of antimicrobials. In vitro and in vivo studies have revealed rapid bactericidal activity against a wide range of gram-positive organisms, and quicker resolution of clinical signs with shorter duration of therapy when compared with vancomycin or beta-lactamase-resistant penicillins.7,8 Its once-daily intravenous dosing (4–6 mg/kg) and lack of monitoring requirements add to its utility.9 Thus, daptomycin is a valid therapeutic option for multiresistant gram-positive organisms, against which few alternatives exist.4
Few cases of daptomycin resistance have been reported in orthopedics.10–16 The global incidence of daptomycin resistance is difficult to determine, and assumptions regarding this based on current evidence are likely to be incorrect. Five case reports (all referencing a single patient) describe resistance to daptomycin in osteomyelitis treatment.10–14 Two case reports describe the use of daptomycin in prosthetic joint infections.15,16 The first report describes a series of 13 patients and reports a failure rate of 46% (6/13 patients) for the use of daptomycin to treat prosthetic joint infections, although whether these treatment failures were due to laboratory-proven daptomycin resistance is not reported.15 The other report, 1 case from Portugal, describes a laboratory-proven, daptomycin-resistant hVISA isolate from a patient with a prosthetic joint infection, although the patient was not treated with daptomycin.16 To our knowledge, our article is the first to describe treatment failure in a prosthetic joint infection due to a laboratory-proven case of daptomycin-resistant hVISA in which the patient received daptomycin.
Daptomycin resistance is thought to develop through a process of vertical evolution, whereby a step-wise accumulation of chromosomal mutations impart specific survival mechanisms, allowing survival and proliferation of resistant organisms.17,18 A single mutation is rarely sufficient to confer high-level, clinically significant resistance on an organism; rather, it may allow for its initial survival until the addition of further mutations results in full-fledged resistance.19 Prior prolonged exposure to vancomycin in our patient led to colonization, with a heterogeneous population of MRSA, some of which possessed multiple genetic mutations, conferring survival advantages. When the selection pressure of lengthy antibiotic treatment was applied, this resistant subpopulation was able to survive and flourish, leading to initial treatment failure and lengthy periods of bacteremia.
Few recommendations exist in the literature regarding daptomycin use in prosthetic joint infections. In general, clinicians should be guided by knowledge of pathogen occurrence and regional resistance patterns when choosing appropriate antibiotics. Implicated hardware should be removed promptly. Early susceptibility testing has been suggested to detect resistance if the infection is slow to clear.14 Others have advocated that higher doses of daptomycin (as high as 12mg/kg) to prevent resistance development, is not proof against impaired susceptibility.19 The use of other last-resort antibiotics, such as pristinamycin, teicoplanin and linezolid, may also be considered.13
- Collignon P, Gosbell I, Vickery A, Nimmo G, Stylianopoulos T, Gottlieb T. Community-acquired methicillin-resistant Staphylococcus aureus in Australia. Australian Group on Antimicrobial Resistance. Lancet. 1998; 352(9122):145–146. doi:10.1016/S0140-6736(98)85051-4 [CrossRef]
- Coombs GW, Nimmo GR, Pearson JC, et al. Prevalence of MRSA strains among Staphylococcus aureus isolated from outpatients, 2006. Commun Dis Intell. 2009; 33(1):10–20.
- Bell J, Turnidge J, Coombs G, O’Brien F. Emergence and epidemiology of vancomycin-resistant enterococci in Australia. Commun Dis Intell. 1998; 22(11):249–252.
- Fong RK, Low J, Koh TH, Kurup A. Clinical features and treatment outcomes of vancomycin-intermediate Staphylococcus aureus (VISA) and heteroresistant vancomycin-intermediate Staphylococcus aureus (hVISA) in a tertiary care institution in Singapore [published online ahead of print April 22, 2009]. Eur J Clin Microbiol Infect Dis. 2009; 28(8):983–987. doi:10.1007/s10096-009-0741-5 [CrossRef]
- Howden BP. Recognition and management of infections caused by vancomycin-intermediate Staphylococcus aureus (VISA) and heterogenous VISA (hVISA). Intern Med J. 2005; 35(suppl 2):S136–S140. doi:10.1111/j.1444-0903.2005.00986.x [CrossRef]
- Cheong JW, Harris P, Oman K, Norton R. Challenges in the microbiological diagnosis and management of hVISA infections. Pathology. 2011; 43(4):357–361. doi:10.1097/PAT.0b013e3283464ca3 [CrossRef]
- Streit JM, Jones RN, Sader HS. Daptomycin activity and spectrum: a worldwide sample of 6737 clinical Gram-positive organisms [published online ahead of print February 25, 2004]. J Antimicrob Chemother. 2004; 53(4):669–674. doi:10.1093/jac/dkh143 [CrossRef]
- Arbeit RD, Maki D, Tally FP, Campanaro E, Eisenstein BIDaptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections [published online ahead of print May 20, 2004]. Clin Infect Dis. 2004; 38(12):1673–1681. doi:10.1086/420818 [CrossRef]
- Rice DA, Mendez-Vigo L. Daptomycin in bone and joint infections: a review of the literature [published online ahead of print November 7, 2008]. Arch Orthop Trauma Surg. 2009; 129(11):1495–1504. doi:10.1007/s00402-008-0772-x [CrossRef]
- Vikram HR, Havill NL, Koeth LM, Boyce JM. Clinical progression of methicillin-resistant Staphylococcus aureus vertebral osteomyelitis associated with reduced susceptibility to daptomycin. J Clin Microbiol. 2005; 43(10):5384–5387. doi:10.1128/JCM.43.10.5384-5387.2005 [CrossRef]
- Marty FM, Yeh WW, Wennerstein CB, et al. Emergence of a clinical daptomycin-resistant Staphylococcus aureus isolate during treatment of methicillin-resistant Staphylococcus aureus bacteremia and osteomyelitis. J Clin Microbiol. 2006; 44(2):595–597. doi:10.1128/JCM.44.2.595-597.2006 [CrossRef]
- Hayden MK, Rezai K, Hayes RA, Lolans K, Quinn JP, Weinstein RA. Development of daptomycin resistance in vivo in methicillin-resistant Staphylococcus aureus. J Clin Microbiol. 2005: 43(10):5285–5287. doi:10.1128/JCM.43.10.5285-5287.2005 [CrossRef]
- Hsu LY, Leong M, Balm M, et al. Six cases of daptomycin-non-susceptible Staphylococcus aureus bacteraemia in Singapore [published online ahead of print August 12, 2010]. J Med Microbiol. 2010; 59(pt 12):1509–1513. doi:10.1099/jmm.0.022533-0 [CrossRef]
- Skiest DJ. Treatment failure resulting from resistance of Staphylococcus aureus to daptomycin. J Clin Microbiol. 2006; 44(2):655–656. doi:10.1128/JCM.44.2.655-656.2006 [CrossRef]
- Rao N, Regalla DM. Uncertain efficacy of daptomycin for prosthetic joint infections: a prospective case series. Clin Orthop Relat Res. 2006. 451:34–37. doi:10.1097/01.blo.0000224021.73163.61 [CrossRef]
- Gardete S, Aires-De-Sousa M, Faustino A, Ludovice AM, de Lencastre H. Identification of the first vancomycin intermediate-resistant Staphylococcus aureus (VISA) isolate from a hospital in Portugal. Microb Drug Resist. 2008; 14(1):1–6. doi:10.1089/mdr.2008.0816 [CrossRef]
- Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Med. 2006; 119(6 suppl 1):S3–S10. doi:10.1016/j.amjmed.2006.03.011 [CrossRef]
- Julian K, Kosowska-Shick K, Whitener C, et al. Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis [published online ahead of print July 9, 2007]. Antimicrob Agents Chemother. 2007; 51(9):3445–3448. doi:10.1128/AAC.00559-07 [CrossRef]
- Lee CH, Wang MC, Huang IW, et al. Development of daptomycin nonsusceptibility with heterogenous vancomycin-intermediate resistance and oxacillin susceptibility in methicillin-resistant Staphylococcus aureus during high-dose daptomycin treatment [published online ahead of print June 28, 2010]. Antimicrob Agents Chemother. 2010; 54(9):4038–4040. doi:10.1128/AAC.00533-10 [CrossRef]
Figure 4: Photograph of the left knee 2 weeks after fusion on long-term suppressive antibiotic therapy.