Daptomycin for treatment of patients with bone and joint infections: a systematic review of the clinical evidence

International Journal of Antimicrobial Agents 30 (2007) 202–209

Review

Daptomycin for treatment of patients with bone and joint infections: a systematic review of the clinical evidence Matthew E. Falagas a,b,∗ , Konstantina P. Giannopoulou a , Fotinie Ntziora a , Panayiotis J. Papagelopoulos a,c a

Alfa Institute of Biomedical Sciences (AIBS), 9 Neapoleos Street, 151 23 Marousi, Athens, Greece b Department of Medicine, Tufts University School of Medicine, Boston, MA, USA c First Department of Orthopaedics, Athens University Medical School, Attikon General University Hospital, Athens, Greece

Abstract The treatment of bone and joint infections, mainly caused by Gram-positive pathogens, can be difficult and quite challenging since it frequently involves prolonged administration of antibiotics as well as appropriate surgical procedures. First-line drugs have failed in some cases to cure the underlying infection. We performed a systematic review of the available evidence to clarify further the effectiveness and safety of daptomycin in the treatment of bone and joint infections. Cure of infection was achieved in 43/53 cases (81.1%). The results of the reviewed articles are promising with regard to the effectiveness and safety profile of this new antibiotic for bone and joint infections that are not responsive to other traditionally used antimicrobial agents. Although these reports are encouraging, the relatively frequent emergence of antimicrobial resistance associated with prolonged administration of daptomycin should be considered seriously. © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. Keywords: Daptomycin; Bone; Osteomyelitis; Joint infection; Prosthetic; Orthopaedic; Septic arthritis; Gram-positive; Enterococcus; MRSA; VRE

1. Introduction Bone and joint infections such as osteomyelitis and septic joint arthritis with or without the presence of implanted prosthetic material caused by Gram-positive bacteria are common [1,2]. Treatment of these infections can be difficult and quite challenging because of the need for prolonged duration of antimicrobial administration frequently combined with appropriate surgical procedures. In addition, the already wellknown fact that Gram-positive pathogens show a growing resistance pattern to various antibacterial drugs such as methicillin and occasionally vancomycin (antibiotics that have been considered among the main options for the treatment of patients with these kind of infections) complicates matters further. ∗

Corresponding author. Tel.: +30 694 61 10 000; fax: +30 210 68 39 605. E-mail address: [email protected] (M.E. Falagas).

A new lipopeptide antibiotic, daptomycin, has been approved by the US Food and Drug Administration for the treatment of patients with complicated skin and skin-structure infections and became available for use in clinical practice in 2003 in the USA and 2006 in Europe [3]. Daptomycin has a different mechanism of action from other antibacterial agents, such as vancomycin, against Gram-positive bacteria, acting through disruption and depolarisation of the cell membrane with subsequent inhibition of protein, DNA and RNA synthesis [4]. It has a concentrationdependent bactericidal action through cell membrane lysis against not only growing but also stationary phases of multidrug-resistant (MDR) Gram-positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus and vancomycin-resistant enterococci (VRE) [5].

0924-8579/$ – see front matter © 2007 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved. doi:10.1016/j.ijantimicag.2007.02.012

M.E. Falagas et al. / International Journal of Antimicrobial Agents 30 (2007) 202–209

We performed a systematic review of the available evidence to evaluate the effectiveness and safety of daptomycin in the treatment of patients with bone and joint infections.

2. Methods 2.1. Data sources PubMed and Scopus databases (publications archived until January 2007) were searched for data regarding the effectiveness and safety of daptomycin for treating patients with bone and joint infections. No language or other limitations were applied to this search in any of the two databases. The search terms used were: ‘daptomycin’ and (bone or osteomyelitis or ‘joint infection’ or arthritis or prosthetic or orthopaedic or septic or ‘gram positive’ or enterococcus or MRSA or VRE)’. 2.2. Study selection and definition of terms Studies were eligible for inclusion in this review if they assessed the effectiveness and safety of daptomycin for the treatment of patients with bone and joint infections. Consequently, case reports, case series, randomised controlled trials (RCTs), and prospective and retrospective studies providing data such as patient characteristics, pathogen responsible for the infection, dosage, duration, outcome, follow-up and adverse effects regarding daptomycin use were extracted, tabulated and evaluated. Review articles and studies using animal models were excluded. Cure was defined as complete resolution of all patient’s symptoms and signs with subsequent improvement of his/her general status verified by negative microbiological culture results or imaging tests. On the contrary, persistence of patient’s symptoms and signs and/or positive microbiological or imaging tests was defined as failure of the applied treatment. In some cases, there was an initial improvement of the infection verified by negative cultures; however, on follow-up cultures the pathogen responsible for the infection was present again, leading to a relapse of the infection despite appropriate treatment of the patient. Finally, osteomyelitis was defined as the presence of positive imaging and radiological findings, isolation and identification of the responsible pathogen in blood, bone or surrounding tissue or biopsy specimen culture, and symptoms indicating the presence of infection.

3. Results 3.1. Case reports A total of 10 articles [6–15] reporting 12 cases were retrieved through our search (Table 1). Six male and six female patients, with a mean age of 60 years, were reported

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to have received daptomycin for the treatment of bone and joint infections. Discitis and osteomyelitis (mainly concerning the thoracic vertebrae T10, T11 and T12 and lumbar vertebrae L3, L4 and L5), hip and knee infection, finger tendonitis, iliopsoas bursitis, septic arthritis and infection of prosthetic knee arthroplasty were the main infections reported. MRSA was the predominant pathogen responsible in 10/12 cases (83.3%) (1/10 MRSA being a small-colony variant) isolated either from blood (5/12; 41.7%) or the infected osteoarticular area, i.e. hip, finger, knee, disc space biopsy, prosthesis or lumbar laminectomy infection site in the remaining cases. In all cases, the decision to switch to daptomycin treatment was taken after failure of the previously administered antibiotic treatment, containing vancomycin monotherapy or in combination with other antimicrobial agents. Daptomycin was given intravenously at a standard dose of 6 mg/kg/day in 9/12 cases (75%). In three studies the administered dose was adapted to 6 mg/kg every 2 days after a slight increase in serum creatinine levels (from 1.7 mg/dL to 2.3 mg/dL) or a decrease of creatinine clearance was noted or due to already pre-existing renal failure. In the other reviewed cases, daptomycin was given at an initial dose of 8 mg/kg/day followed by the standard dose of 6 mg/kg/day for the rest of the treatment duration in one case, and at a dose of 6.5 mg/kg/day in the other case. Daptomycin was given as monotherapy in 6/12 cases (50%); cure of infection was achieved in only two of these cases. In two additional cases, daptomycin was initially given as monotherapy but after relapse of the infection it was given in combination with vancomycin and rifampicin leading to cure of the infection. In the other cases (3/12; 25%) daptomycin was given in combinations including gentamicin, also leading to an initial cure of the infection. Resistance to daptomycin was seen in 5/7 cases (71.4%) with relevant reported data, leading to failure of treatment in three cases and initial remission of the infection followed by relapse in another case. The mean duration of daptomycin administration in the reviewed cases was 45 days. The mean follow-up period was 13 days, although three cases with follow-ups of 3, 7 and 11 months were also found. Initial full remission of the infection was seen in 7/12 cases (58.3%); however, in three of these cases follow-up blood cultures after 12 days, 7 days and 3 months, respectively, were positive for MRSA, leading to relapse of the infection. Two cases (16.7%) with discontinuation of daptomycin due to adverse events associated with its use were reported. Adverse events associated with the use of daptomycin were muscle pain and weakness, elevated creatine phosphokinase (CPK) (20 771 U/L and 21 243 U/L in two studies), elevated transaminases, acute renal failure in one case, slight elevation of the serum creatinine level in one case and a decrease in creatinine clearance in another case. No adverse events were observed in three cases, whilst in the rest of the case reports no information regarding adverse events was provided.

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Table 1 Case reports regarding the use of daptomycin (DAP) for treatment of patients with bone or joint infections Sex/age (years)

Co-morbidity

Infection

Antony [6]

M/64

Lumbar laminectomy, spinal prosthesis placement for spinal stenosis DM, TKAS, osteoarthritis, open reduction and right ankle internal fixation

Vertebral osteomyelitis

F/57

Isolated pathogens/culture site MRSA/lumbar laminectomy incision site

Previous antibiotic treatment (days)

Reason for DAP administration

VAN/RIF (42), LIN

Treatment failure

Dosage and duration of DAP treatment (days) DAP 6 mg/kg/day (42); relapse, DAP/VAN/RIF 6 mg/kg/day (42)

Development of DAP resistance during treatment N/A

L3–L4 discitis, osteomyelitis, prosthetic left knee infection

MRSA/left TKA prosthesis

VAN/RIF (42), LIN (42)

Treatment failure

DAP 6 mg/kg/day (42); relapse, DAP/VAN/RIF 6 mg/kg/day (42)

N/A

Outcome

Spinal prosthesis removal and debridement

Cure

Cure

6; no recurrence

N/A

Cure

3 months; relapse, patient died due to MOF

None

Discontinuation of treatment due to adverse effects

14; resolution of adverse effects after discontinuation of DAP N/A

Muscle pain and weakness, CPK (20 771 U/L), elevated AST, ALT and ALP

Carlyn et al. [7]

M/70

RA, DM, AF, AV and MV disease, CM, RF, neuropathy, resected rectal adenocarcinoma, right TKR

Right knee prosthesis infection, bacteraemia

1st MSSA/blood, operation site; 2nd MSSA, MRSA SCV/blood, tibial tissue

1st, OXA (42), CEF (7); 2nd, VAN (54)/RIF (21), LIN (14), VAN (12)/RIF (10)/MIN (4)/GEN (7)

Treatment failurea

DAP 6 mg/kg every 2 days; DAP/RIF/MIN (74)/GEN (5)

N/A

Echevarria et al. [8]

M/52

Intravenous drug abuse, HCV, IT, HL

L3–L4 discitis, osteomyelitis

Gram-positive cocci/biopsy

VAN

Adverse effects while on VAN

DAP 6.5 mg/kg/day (9)

N/A

Prosthesis removal, lumbar laminectomy, discectomy, removal and debridement of infected knee Prosthesis removal, synovectomy, debridement of infected knee, bone cement with TOB inserted, which was later removed, arthrodesis with bone bank grafting, external fixation removed after debridement, knee fusion, right knee amputation N/A

Kazory et al. [9]

F/53

DM, HT, peripheral vascular disease

L5–S1 discitis, osteomyelitis

MRSA, VRE (E. faecium), Candida glabrata/biopsy

VAN/LEV (56)

Treatment failure

DAP/VOR 6 mg/kg once daily (10)

N/A

N/A

Discontinuation of treatment due to adverse effects

Marty et al. [10]

M/61

AML, AHSCT, LI, GVHD, previous MRSA bacteraemia

T11–T12 discitis, osteomyelitis, bacteraemia

MRSA/blood

LIN (23), VAN/GEN (3)

Treatment failure

DAP/GEN 6 mg/kg/day (>10)b

Yes

N/A

Cure

Skiest [11]

F/64

DM, HT, HL, treated breast cancer in remission, osteoarthritis, bilateral knee prosthesis, morbid obesity, bimalleolar left ankle fracture

Septic arthritis, bacteraemia

MRSA/blood, after amputation MSSA

VAN (42, 42), RIF, LIN (2)

Patient refused surgery for removal of prosthesis, adverse effects with previous antibiotics, possible treatment failure

DAP 8 mg/kg/day then 6 mg/kg/day (42); after amputation 6 mg/kg/day (21)

Yes

Left ankle debridement, open reduction, internal fixation of left ankle prosthesis, below the knee amputation

Failure

Follow-up duration (days) 12; no recurrence

Adverse effects

Surgical treatment

12; relapse, blood cultures positive for MRSA 7 monthsc

None

Muscle weakness, rhabdomyolysis, ARF, CPK (21 243 U/L), elevated AST and ALT N/A

N/A

M.E. Falagas et al. / International Journal of Antimicrobial Agents 30 (2007) 202–209

Reference

M/54

Past total right hip arthroplasty infected with MRSA, morbid obesity

Right hip infection, 3rd finger septic tendonitis, bacteraemia

MRSA/right hip and finger

LEV (2), VAN (3), VAN/GEN (4)

Treatment failure

DAP/RIF/VAN/GEN No 6 mg/kg/day (4), DAP/RIF 6 mg/kg/day (4), 6 mg/kg every 2 days (37), 6 mg/kg/day (14)

Debridement of infected hip, removal of right hip prosthesis

Cure

Dretler and Branch [13]

F/45

Schizophrenia, osteoarthritis

Left knee infection

MRSA/knee

VAN (42), VAN/RIF (56)

Treatment failured

DAP 6 mg/kg/day (42)

No

Several debridements of left knee, synovectomy

Cure

Hayden et al. [14]

F/86

N/A

Prosthetic septic knee arthritis, bacteraemia

MRSA/blood, epidural tissue

VAN (7)

Treatment failure

DAP 6 mg/kg/day (22), 6 mg/kg every 2 days (13)

Yes

Failure

F/61

Heart surgery

MRSA/blood

VAN (42)

Treatment failure

DAP 6 mg/kg/day (42)

Yes

M/52

Parkinson’s-like illness, cirrhosis, pulmonary fibrosis, CS therapy, DM

Sternal and lumbar L4–L5 osteomyelitis, bacteraemia T10–T11 discitis, osteomyelitis, septic iliopsoas bursitis of right hip

Debridement, synovectomy, revision arthroplasty N/A

Vikram et al. [15]

Cure

28 days after discharge no relapse, blood cultures and right hip aspirate negative for MRSA 11 months after end of treatment, no relapse 13; relapse after increasing the DAP interval 7; relapse

Serum Cr elevated (1.7 mg/dL to 2.3 mg/dL)

None

Decrease of Cr clearance

N/A

After end of N/A DAP treatment, still positive blood cultures MRSA, methicillin-resistant Staphylococcus aureus; VAN, vancomycin; RIF, rifampicin; LIN, linezolid; N/A, not available; DM, diabetes mellitus; TKAS, total knee arthroscopy; TKA, total knee arthroplasty; RA, rheumatoid arthritis; AF, atrial fibrillation; AV, aortic valve; MV, MRSA/T10–T11 disc space biopsy

VAN (42)

Treatment failure

DAP 6 mg/kg/day (28)

Yes (DAP MICs increased from 0.5 ␮g/mL to 4.0 ␮g/mL)

Drainage and irrigation of right hip and iliac bursa

Failure

mitral valve; CM, cardiomyopathy; RF, renal failure; TKR, total knee replacement; MSSA, methicillin-susceptible S. aureus; SCV, small-colony variant; OXA, oxacillin; CEF, cefazolin; MIN, minocycline; TOB, tobramycin; MOF, multiple organ failure; HCV, hepatitis C virus; IT, idiopathic thrombocytopenia; HL, hyperlipidaemia; CPK, creatine phosphokinase; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; HT, hypertension; VRE, VAN-resistant enterococci; LEV, levofloxacin; VOR, voriconazole; ARF, acute renal failure; AML, acute myelogenous leukaemia; AHSCT, allogeneic haematopoietic stem cell transplantation; LI, lymphocyte infusions; GVHD, graft-vs.-host disease; GEN, gentamicin; Cr, creatinine; CS, corticosteroid; MIC, minimal inhibitory concentration. a Patient developed complications (5 mm mobile density on the AV verified by transoesophageal echocardiography, C3–6 osteomyelitis, a posterior epidural abscess verified by magnetic resonance imaging, an embolic splenic infarct and progressive RF) while being treated for bacteraemia that necessitated cardiac and neurosurgical interventions. b After discharge, patient continued treatment with DAP. c No evidence of osteomyelitis, no fluid collection, no evidence of infection of the prosthesis; however, wound drainage culture after minor local trauma to anterior tibia grew MRSA. d Patient had persistent pain, poor range of motion and inability to ambulate; Gram stain identified MRSA in knee joint aspirate.

M.E. Falagas et al. / International Journal of Antimicrobial Agents 30 (2007) 202–209

Burns [12]

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Table 2 Case series regarding the use of daptomycin (DAP) for treatment of patients with bone or joint infections Reference Antony et

Infection al. [16]a

Previous antibiotic treatment (days) VAN VAN/RIF VAN None VAN/RIF VAN/CIP

Dosage and duration of DAP treatment (days) 6 mg/kg/day (42) 6 mg/kg/day (42) 6 mg/kg/day (42) 6 mg/kg/day (42) 4 mg/kg every 2 days (42) 4 mg/kg every 2 days (42)

Surgical treatment

Outcome

Prosthesis removal Prosthesis removal Prosthesis removal Incision and drainage Prosthesis removal Incision and drainage

Failure Failure Cure Cure Cure Cure

VAN/LIN

4 mg/kg every 2 days (42)

Prosthesis removal

Cure

LEV

6 mg/kg/day (42)

Prosthesis removal

Cure

MRSA, Pseudomonas/osteomyelitis wound, blood MRSA/osteomyelitis wound

VAN/LEV, CEFP

4 mg/kg every 2 days (42)

None

Cure

VAN

6 mg/kg/day (42)

Prosthesis removal

Cure

MRSA/laminectomy site

VAN

6 mg/kg/day (42)

Prosthesis removal

Failure

MRSA/prosthetic MRSA/osteomyelitis wound MSSA/prosthetic MRSA/osteomyelitis wound MRSA CoNS/blood, AV, osteomyelitis wound MRSA/laminectomy site

VAN VAN/RIF CEF LEV VAN, LIN, CEF

6 mg/kg/day (42) 4 mg/kg every 2 days (56) 6 mg/kg/day (14) 6 mg/kg/day (28) 4 mg/kg every 2 days (14)

Prosthesis removal Prosthesis removal Prosthesis removal Incision and drainage Incision and drainage

Failure Cure Cure Cure Cure

VAN

6 mg/kg/day (42)

Prosthesis removal

Cure

MRSA/laminectomy site

VAN

6 mg/kg/day (42)

Incision and drainage

Cure

MRSE/laminectomy site

VAN

6 mg/kg/day (42)

Prosthesis removal

Cure

MRSA/prosthetic

CEPH

6 mg/kg/day (42)

Prosthesis removal

Cure

CEF CEF VAN, LEV

6 mg/kg/day (35) 6 mg/kg/day (42) 4 mg/kg every 2 days (42)

Amputation Prosthesis removal Incision and drainage

Cure Cure Cure

Spinal osteomyelitis Spinal osteomyelitis

MRSA/osteomyelitis wound MSSA/prosthetic MRSA, Streptococcus, Escherichia coli/osteomyelitis wound MRSA/osteomyelitis wound MSSA/spinal wound

None CEF, VAN

6 mg/kg/day (42) 6 mg/kg/day (42)

Cure Cure

TKA infection

MRSE, MSSA/knee

VAN

6 mg/kg/day (28)

T9 discitis, MRSA bacteraemia Osteomyelitis of the toe

MRSA/blood

VAN, LIN

6 mg/kg/day (42)

Incision and drainage Incision and drainage, prosthesis removal Incision and drainage, prosthesis removal None

MRSA/toe wound

VAN

6 mg/kg/day (14)

Sternal wound infection, osteomyelitis Osteomyelitis of the hip

MRSA/sternal cultures

VAN

6 mg/kg/day (28)

MSSA/hip cultures

VAN, CEF

6 mg/kg/day (42)

Lumbar (L2–L3) laminectomy infection

MRSA/laminectomy culture

None

6 mg/kg/day (42)

TKA infection Laminectomy infection TKA infection Sternal osteomyelitis TKA infection Endocarditis, osteomyelitis

Laminectomy infection, spinal osteomyelitis Bilateral osteomyelitis of the hip Spinal osteomyelitis, bacteraemia Tibial and fibular osteomyelitis Lumbar (L4–L5) laminectomy infection TEA infection Spinal osteomyelitis TKA infection Tibial osteomyelitis Bacteraemia, endocarditis, osteomyelitis of the foot Cervical laminectomy infection Lumbar (L4–L5) laminectomy infection Lumbar (L3–L5) laminectomy infection TKA infection, medial knee abscess Osteomyelitis, diabetic foot TKA infection Osteomyelitis

Incision and drainage, toe amputation, BKA of leg Incision and drainage, debridement, rewiring Incision and drainage, prosthesis removal Incision and drainage, prosthesis removal

Cure Cure Cure Cure Cure Cure

M.E. Falagas et al. / International Journal of Antimicrobial Agents 30 (2007) 202–209

Isolated pathogens/culture site MRSA/prosthetic MRSA/laminectomy site MRSE/prosthetic MRSA/osteomyelitis wound MRSA/prosthetic MRSA, Pseudomonas/osteomyelitis wound MRSA, MRSE/site of laminectomy, osteomyelitis wound MRSA/osteomyelitis wound

Rao et al. [17] (prospective series)

THA infection

MRCoNS

None

TKA infection TKA infection TKA infection TKA infection TKA infection TKA infection TKA infection TKA infection TKA infection TSA infection THA infection Osteomyelitis

MRCoNS MSSA MRSA MRSA MRSA MRCoNS MRSA MRSA MRSA MRSA MRCoNS MRSA

None None None None None None None None None None None VAN

4 mg/kg/day (minimum 42)

Severalb

Died of unrelated cause

MSSA, methicillin-sensitive S. aureus; CEF, cefazolin; CoNS, coagulase-negative staphylococci; AV, aortic valve; CEPH, cefalexin; BKA, below the knee amputation; THA, total hip arthroplasty; MRCoNS, methicillin-resistant coagulase-negative staphylococci; TSA, total shoulder arthroplasty; N/A, not available; GEN, gentamicin; Q/D, quinupristin/dalfopristin; MIN, minocycline. a Main co-morbidities include diabetes mellitus/vascular disease in 15 patients, hypertension/coronary artery disease in 10 patients and osteoarthritis in 13 patients. b Five patients had acute infection (signs and symptoms for < 2 weeks); seven patients had chronic infection (signs and symptoms for ≥2 weeks). Chronic infection was treated with prosthesis removal, irrigation and debridement, placement of antibiotic-impregnated cement spacers, daptomycin and re-implantation when infection free. c Patient was successfully treated with ampicillin, once the pathogen was identified after receiving 4 days of treatment with DAP. d No cultures available to confirm streptococcal infection.

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4 mg/kg/day (minimum 42) Cure 4 mg/kg/day (minimum 42) Cure 4 mg/kg/day (minimum 42) Failure 4 mg/kg/day (minimum 42) Failure 4 mg/kg/day (minimum 42) Cure 4 mg/kg/day (minimum 42) Failure 4 mg/kg/day (minimum 42) Cure 4 mg/kg/day (minimum 42) Failure 4 mg/kg/day (minimum 42) Cure 4 mg/kg/day (minimum 42) Failure 4 mg/kg/day (minimum 42) Cure Finney et al. [18] 4–6 mg/kg/day or every 2 N/A Cure days (8) Septic joint, bacteraemia MRSA None 4–6 mg/kg/day or every 2 N/A Cure days (44) Septic arthritis, bacteraemia MRSA VAN, GEN 6 mg/kg every 2 days (41) N/A Cure Septic joint Enterococcus faecalis VAN 4–6 mg/kg/day or every 2 N/A Curec days (4) Septic arthritis, osteomyelitis MRSA VAN, LIN, Q/D 4–6 mg/kg/day or every 2 N/A Cure bacteraemia days (42) Osteomyelitis, wound MRSA VAN 4–6 mg/kg/day or every 2 N/A Cure infection days (35) Osteomyelitis MRSA VAN, Q/D, LIN, MIN/RIF 4–6 mg/kg/day or every 2 N/A Cure days (28) Osteomyelitis MRSA VAN 4–6 mg/kg/day or every 2 N/A Cure days (21) Osteomyelitis, septic arthritis MRSA VAN, Q/D, CEF, LIN 4–6 mg/kg/day or every 2 N/A Cure days (28) CEF 4–6 mg/kg/day or every 2 N/A Cure Osteomyelitis Possible streptococcal days (42) infectiond TKA, total knee arthroplasty; MRSA, methicillin-resistant Staphylococcus aureus; VAN, vancomycin; RIF, rifampicin; MRSE, methicillin-resistant Staphylococcus epidermidis; CIP, ciprofloxacin; LIN, linezolid; LEV, levofloxacin; CEFP, cefepime; TEA, total elbow arthroplasty;

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3.2. Case series Three case series [16–18] were available reporting the use of daptomycin for bone and joint infections in 53 patients (Table 2). A total of 22 male and 31 female patients, with a mean age of 65.8 years, received daptomycin for the treatment of bone and joint infections. Osteomyelitis was the most common infection (23/53; 43.4%), followed by total joint arthroplasty (including total knee arthroplasty, total elbow arthroplasty and total hip arthroplasty) infection in 20/53 (37.7%) cases. Other types of infection included laminectomy site infection, knee abscess, discitis, bacteraemia associated with septic joint and septic arthritis. The dominant responsible pathogen was again MRSA (39/53; 73.6%); other pathogens isolated were methicillinsusceptible S. aureus (6/53; 11.3%), MRSE (4/53; 7.5%), methicillin-resistant coagulase-negative staphylococci (4/53; 7.5%), Pseudomonas spp. (2/53; 3.8%), Escherichia coli (1/53; 1.9%) and Enterococcus faecalis (1/53; 1.9%). More than one pathogen was isolated in 6/53 cases (11.3%). Daptomycin was given intravenously at a dose 4–6 mg/kg/day or every 2 days for a mean duration of 37.4 days. The mean duration of treatment may actually be a little longer as in one study with 12 patients it was only reported that daptomycin was applied for a minimum of 42 days [17]. The reason for treatment of bone and joint infections with daptomycin was failure of previously administered antibiotics, intolerable adverse events, allergy or drug–drug interactions with other medications. Previously used antibiotics were vancomycin, rifampicin, ciprofloxacin, levofloxacin, cefepime, linezolid, cefazolin, gentamicin and quinupristin/dalfopristin. In the prospective study by Rao et al. [17], daptomycin was the first antibiotic administered for the particular infection, as eligible patients were, by definition, unable to receive standard vancomycin therapy because of resistance, allergy, adverse reaction or previously failed vancomycin therapy. Of note, development of resistance to daptomycin was not seen in any of the 53 patients evaluated in these case series except one [18] that had isolation of MRSA with reduced susceptibility to daptomycin (minimum inhibitory concentration = 4 ␮g/mL) from an epidural abscess. Cure of infection was achieved in 43/53 (81.1%) of the cases. In particular, all patients with osteomyelitis were cured when daptomycin was administered (23/23; 100%), whilst 12/20 patients (60%) with total joint arthroplasty infection were also cured with daptomycin treatment. Surgical manipulations, such as prosthesis removal, debridement of the infected area, incision and drainage, appear to have contributed to cure of the infection. Patients’ follow-up period ranged from 4 months to 13 months. Not enough data were available regarding adverse events associated with the use of daptomycin. In only two patients, adverse events were clearly stated, including nausea in one case and mild elevation of CPK levels in the other, which were not enough to necessitate discontinuation of therapy. In the study by Antony et al.

[16], seven patients with reduced renal function were treated with 4 mg/kg every 2 days; all were cured of their infection without reporting any adverse events.

4. Discussion The main finding of our systematic review is that daptomycin represents a promising option for use in patients with bone and joint infections. Cure was achieved in the majority of patients receiving daptomycin in the reviewed articles, even after failure of previously administered recommended antibiotics for these infections, such as vancomycin. However, it is rather difficult to determine whether the effectiveness of treatment in the reviewed patients with bone and joint infections can be attributed solely to daptomycin, since in most cases daptomycin was co-administered with other antibacterial agents. Despite this noteworthy limitation in interpreting the reviewed evidence, the fact that daptomycin was effective in treating osteomyelitis must be kept in mind in decision-making for patients with this particular infection. Many physicians have awaited the introduction of daptomycin in clinical practice with the hope that this new antibacterial agent would prove to be an alternative solution for problematic areas of infectious disease therapeutics such as bone and joint infections by MDR Gram-positive pathogens. Also, there are a few ongoing studies aimed at evaluating the effectiveness and safety of daptomycin for the treatment of patients with endocarditis and/or bacteraemia at a dosage level of 6 mg/kg/day. In addition, so far a few experimental rabbit meningitis studies [19] have shown that daptomycin exhibits good penetration of ca. 5% into inflamed meningeal tissue, but the same does not hold for infections originating from pulmonary tissue, such as pneumonia, since the mechanism of action of daptomycin is inhibited by pulmonary surfactant [20]. The fact that daptomycin has a strong bactericidal action against stationary phase organisms and bacterial biofilm [21] may prove helpful for patients with infections such as osteomyelitis, although we should emphasise that the relevant clinical information is limited. Most of the adverse events associated with the use of daptomycin were mild or moderate in intensity; even more serious adverse events observed resolved fully soon after drug discontinuation. Renal excretion is the main route of daptomycin elimination; consequently, dosage adjustment with increase of the drug intervals is necessary in patients with renal insufficiency. No significant drug–drug interactions have been reported until now following use of daptomycin. Caution has been recommended when tobramycin, warfarin and HMG-CoA reductase inhibitors are co-administered. Synergistic interactions with aminoglycosides, ␤-lactam antibiotics and rifampicin have been shown in vitro against some staphylococci and enterococci isolates; however, the clinical relevance of these findings is uncertain. The frequent development of resistance to daptomycin is noteworthy and is of utmost importance in patients with

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infections requiring prolonged treatment. Although the exact mechanism of resistance of Gram-positive bacteria such as S. aureus to daptomycin is not known, some possible explanations are through thickening of the bacterial cell wall as well as gene mutations in the bacterial genome rendering daptomycin unable to exert its bactericidal action [22,23]. Some researchers attribute the identification of resistant bacterial isolates to subinhibitory concentrations of daptomycin in the therapeutic combination. Our synthesis of the available published clinical data regarding the use of daptomycin in patients with bone and joint infections is not without limitations. The available evidence is limited and thus experience from the use of daptomycin for the treatment of patients with such infections is short. It is interesting that cases of both cure of the infection and failure of the administered treatment have been published; however, one cannot be certain that a publication bias, mainly in favour of good results, is excluded. Unfortunately, until now no RCTs comparing the effectiveness and safety of daptomycin with other relevant antibiotics for bone and joint infections have been performed. More information is also needed regarding the mechanisms with which the pathogens become resistant to daptomycin; such information may help to decrease the probability of emergence of resistant strains, for example by making use of different dosages or combinations of daptomycin with other antimicrobial agents. In summary, the limited published clinical evidence suggests that daptomycin is a bactericidal drug that appears to be effective against MDR Gram-positive pathogens causing osteomyelitis and joint infections, even in cases where other first-line antibacterial agents have failed. In addition, it appears that this antibiotic is reasonably well tolerated and has a low potential for adverse events. Thus, daptomycin may serve as an alternative therapeutic agent for patients with bone and joint infections who are intolerant to or did not show improvement with administration of other traditionally used appropriate antibiotics. A major drawback of daptomycin for this type of infection, which necessitates prolonged treatment, appears to be the relatively frequent development of emergence of resistance in the implicated Gram-positive pathogens to this new antibiotic.

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