Journal of Antimicrobial Chemotherapy Advance Access published June 5, 2014
J Antimicrob Chemother doi:10.1093/jac/dku167
Pristinamycin: old drug, new tricks? Eden C. Cooper1,2*, Nigel Curtis1–3, Noel Cranswick1–3 and Amanda Gwee2,3 1
Department of Paediatrics, University of Melbourne, Victoria, Australia; 2Infectious Diseases and Clinical Pharmacology Unit, Department of Medicine, The Royal Children’s Hospital Melbourne, Victoria, Australia; 3Murdoch Childrens Research Institute, Victoria, Australia *Corresponding author. Department of General Medicine, The Royal Children’s Hospital Melbourne, Flemington Road, Parkville, 3052 Victoria, Australia. Tel: +613-9345-5522; E-mail: [email protected]
Keywords: quinupristin/dalfopristin, streptogramin, Gram positive infections, bone and joint infections, osteomyelitis, arthritis, prosthesis infections
Background Osteoarticular infections (OAIs) with Gram positive bacteria present an increasing challenge in the era of multidrug-resistant organisms. These infections often require a combination of surgical intervention and prolonged intravenous antibiotics. Prolonged treatment with parenteral antibiotics is not without risk, inconvenience and cost, and therefore an oral option would be ideal in this setting. In the absence of new oral agents, the reintroduction of older antibiotics needs to be considered. Pristinamycin is an oral streptogramin antibiotic with a similar spectrum of activity to macrolides and lincosamides for Grampositive bacteria, with a reduced risk of drug resistance.1 It is bactericidal against Staphylococcus spp. and Streptococcus spp. but has less activity against enterococci.2 Pristinamycin has been used for over 50 years for the treatment of OAIs, principally in Europe. We review here the evidence for the use of pristinamycin in OAIs.
Methods We searched Medline (1946 to present) and Embase (1974 to present) in July 2013 using the OVID interface. The following search terms were used: pristinamycin/ or virginiamycin AND (Gram positive bacteria OR Gram positive bacterial infections OR Gram positive cocci OR Gram positive infection) AND/OR (bone and joint infections OR bone infection OR arthritis, infectious OR bone disease, infectious OR osteitis OR osteomyelitis OR periostitis OR spondylitis OR prosthesis-related infections OR prosthesis infection). This identified a total of 1375 articles. Studies that reported clinical outcomes when pristinamycin was used for the treatment of OAIs were included. Case reports were excluded. No limits were set on language.
A single researcher (E. C. C.) reviewed the search results and identified four relevant publications. 3 – 6 The references for each article were reviewed and one further study was identified.7 Two of the five studies were published in French and translated into English.3,7
Results Of the five identified studies, four were case series in adults and one in children (Table 1).3 These studies included a total of 247 patients (197 adults and 50 children) treated with pristinamycin for OAIs. The treated cases comprised native bone or joint infection (n¼161) and an infected prosthetic joint or device (n¼ 86). Only two studies reported on chronicity of infection.3,5 In the paediatric study, 78.0% of infections were acute and 22.0% were subacute or chronic; however, these classifications were not defined.3 One study classified the subset of prosthetic joint infections (PJIs) as early (90.0%) or late (10.0%) onset.5 Comorbidities were reported in two adult studies, with diabetes mellitus, chronic cardiorespiratory disease and obesity the most common.5,7
Pathogens Two hundred and nine patients had culture-proven OAIs with a total of 306 isolates. Of these, 151 (72.2%) patients were infected with a single pathogen and 58 (27.8%) had a polymicrobial infection. The most commonly isolated organisms were Staphylococcus spp. (69.0% of positive cultures), of which 14.2% were methicillinresistant Staphylococcus aureus (MRSA), 1.9% were methicillinsusceptible S. aureus (MSSA), 45.5% were S. aureus not otherwise defined and 38.4% were coagulase-negative staphylococci (CoNS). Other isolates included Streptococcus spp. (6.9%) and
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
Osteoarticular infections with Gram positive bacteria present an increasing challenge in an era of multidrugresistant organisms. Prolonged intravenous antibiotic treatment is often required, with associated risks, costs and difficulties with administration; a safe, effective oral option would be ideal for this indication. Pristinamycin, an oral streptogramin antibiotic with bactericidal activity against Gram positive organisms including methicillin-resistant Staphylococcus aureus, has been used for over 50 years in Europe for the treatment of osteoarticular infections. We review the published evidence for the treatment of native bone and prosthesisrelated osteoarticular infections with pristinamycin.
Review
Study
Subjects
Organism
Antibiotics prior to pristinamycin
Surgical intervention Pristinamycin therapy
Drug AEs
Ruparelia6 2008 Retrospective case series
Adults with OAIs (n ¼ 21) † OM (5) † PJI (13) † OIOD (3) Median age 68 y (18 –83 y)
55 isolates from 21 patients Single organism (5) † CoNS (3) † Diptheroids (2) Polymicrobial (16) including † ≥1 CoNS (15) † VRE (6) † Pseudomonas aeruginosa (2) † Coliforms (2) † Enterobacter spp. (2) † Enterococcus spp. (1) † Bacillus sp. (1) † Candida parapsilosis (1)
First line VAN + MEMb (19) VAN (2) Second line LZD (6) FUS +minocycline + DOX (1) CIP + LZD (1) DOX (1) Range 2 –6 w
Pristinamycin 1 g bd OM Median duration 3 m † 5/5 tissue (1 w –15 m) resection PJI † 4/13 debridement and retained prosthesis † 9/13 joint revision OIOD † 2/3 metalware removal † 1/3 debridement and retention
Reid5 2010 Retrospective case series
Adults with OAIs (n ¼ 22) † OM (12) † PJI (10) Median age 63.5 y (33 –83 y)
32 isolates from 22 patients Single organism (14) † MRSA (6) † CoNS (6) † VRE (2) Polymicrobial (8) including † ≥1 CoNS (8) † MRSA (2) † MSSA (2) † VRE (2) † Corynebacterium spp. (2) † E. faecalis (2)
First line VAN (12) RIF+ FUS (4) LZD (2) VAN + TIM (1) RIF+ LZD (1) Nil (2) Second line LZD (2) VAN (1) teicoplanin (1) RIF+ FUS (1) Range 13 d –22 m
Not reported PJI † 7/10 retained prostheses
Ng4 2005 Retrospective case series
Adults with OAIs (n ¼ 27) OM (15) PJI (5) OIOD (7) Median age 60 y (18 – 81 y)
32 isolates from 27 patients Single organism (23) † MRSA (19) † MSSA (1) † CoNS (3) Polymicrobial (4) including † MRSA (3) † E. coli (2) † MSSA (1) † P. aeruginosa (1) † Corynebacterium jeikeium (1) † Mixed anaerobes (1)
Glycopeptide (27) Range 24 d –8 w
Drug AEs Pristinamycin OM 8/27 1 g tds † 4/15 debridement Median duration 6 m † GIT (7) PJI † Rash (1) (2 w –18 m) † 1/5 joint revision Drug discontinued OIOD 4/27 † 4/7 removal of Dose reduction to prosthetic 500 mg tds 4/27 material
Dose not stated Median duration 169 d (19 –876 d)
Drug AEs 2/21 † GIT (2) † Lethargy (1) Drug discontinued 1/21 Dose reduction to 500 mg tds 1/21
Concurrent antibiotics Total 9/21 CoNS only (5): RIF (2c) CIP (1) DOX (1) FUS (1) CoNS +VRE (1)d: CIP CoNS + GNB (1): CIP + FUS CoNS +VRE + GNB (1): CIP VRE + GNB (1): CIP
Total 1/22 Drug AEs 8/22 CoNS † GIT (7) RIF + CIP † LOW (1) † Abnormal LFTs (1) Drug discontinued 2/22 Dose reduction to 500 mg tds 1/22
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
2 of 7
Table 1. Summary of evidence
Total 8/27 MRSA only (6): FUS (4) RIF (1) CIP (1) CoNS only (n ¼ 1): FUS MRSA + GNB +anaerobes (n ¼ 1): CIP +clindamycin
Outcome Cure 11/21a (52%) Suppression 4/21 (19%) Failure 6/21 (29%)
Cure 7/22 (32%) Suppression 13/22 (59%) Intolerance 2/22 (9%)
Cure 9/27 (33%) Probable cure 7/27 (26%) Suppression 5/27 (19%) Failure 2/27 (7%) Intolerance 4/27 (15%)
Children with OAIs (n ¼ 50): † OM (15) † SA (19) † SA/OM (5) † Chronic or subacute OM (9) † Chronic or subacute OIOD (2) Age range 7 d –17 y 7 m
28 isolates from 27 patients single organism (n ¼ 26) † S. aureus g (19) † Haemolytic Streptococcus (3) † H. influenzae (3) † S. pneumoniae (1) Polymicrobial (n¼ 1) including † S. aureus (1) † Haemolytic Streptococcus (1)
Nonee
OM † 7/15 debridement SA † 18/19 arthrotomy SA/OM † 2/5 debridement Chronic or subacute † 11/11 debridement
Mean dose 1 g/kg/d (0.5 –1.8 g) tds (age-dependent)h Duration OM 30 –120 di Joint infection 30 –60 d
Drug AEs 4/50: † GIT (4) Drug discontinued 4/27
Total 50 Gentamicin intramuscularly (49) Tobramycin (1) Mean duration 10 d (5 – 20 d)
Cure 44/50 (88%) Failure 1/50 (2%) Intolerance 4/50 (8%) Refusal 1/50 (2%)
Boibieux7 2001 Retrospective case series (abstract only)
Adults with OAIs (n ¼ 127): † OM (13) † Osteitis (100) † SA/OM (14) Synthetic or prosthetic material for 46/127 Age range 37 –77 y
159 isolates from 112 patients Organisms included † S. aureus (n ¼ 76) † CoNS (24) † Streptococcus sp. (n ¼ 16) † Enterobacteriaceae sp. (n ¼ 14) † Enterococcus spp. (n ¼ 8) Single organism (n ¼ 83) Polymicrobial (n¼ 29)
None
59/127 had surgical intervention (not specified)
Dose not reported Mean duration 316 d (169 –463 d)
No reports of drug AEs No reports of drug discontinuation
Total 124j
Outcomes not definedk Suppression 108/ 127 (85%)
Review
Beauvais3 1981 Case seriesf
AEs, adverse events; OM, osteomyelitis; OIOD, other infected orthopaedic device; VAN, vancomycin; MEM, meropenem; LZD, linezolid; FUS, fusidic acid; DOX, doxycycline; CIP, ciprofloxacin; GIT, gastrointestinal tract; RIF, rifampicin; GNB, Gram negative bacilli; TIM, ticarcillin/clavulanate; LOW, loss of weight; LFTs, liver function tests; SA, septic arthritis; d, days; w, weeks; m, months; y, years; bd, twice a day; tds, three times a day; G-, Gram negative. a One patient with an outcome of cure also discontinued treatment due to drug intolerance. b Meropenem was stopped after no G- were cultured for 17/19. c One patient grew CoNS only, although they had a concurrent non-OAI with Mycobacterium marinum treated with clarithromycin, ethambutol and rifampicin. d One patient grew CoNS+VRE+Candida and was treated with pristinamycin and fluconazole. e Surgery was needed for sequelae in two patients. f It is unclear whether the methodology was retrospective or prospective. g Susceptibilities to many antibiotics were reported, but not for methicillin or flucloxacillin. h Doses were age-dependent: 0.5–1.0 g/kg/day for older children and 1.0–1.5 g/kg/day for younger children. i One chronic case required 210 d treatment. j Details of concurrent therapy were not specified except to say that 83/127 received dual therapy (usually pristinamycin+ofloxacin) followed by monotherapy with pristinamycin. k An unclear number of patients was cured.
JAC
3 of 7 Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
Review
Enterococcus spp. (6.9%), of which half were vancomycin-resistant enterococci (VRE).
Pristinamycin therapy
Pristinamycin dosing and duration Pristinamycin dosing was described in only three of five studies.3,4,6 For adults, a dose of 1 g twice or three times a day was used. Children received an age-dependent dose of 0.5 – 1.0 g/kg per day for ‘older children’ or 1.0 – 1.5 g/kg per day for ‘younger children’. The duration of treatment was highly variable and ranged from 1 week to 28.8 months. In the three studies that reported patientspecific treatment details,4 – 6 native OAIs were treated for an average of 10 months (2 weeks – 28.8 months) and device-related infections were treated for an average of 8.8 months (1 week – 18 months).
Adverse drug effects Adverse effects occurred in 18 (25.7%) of 70 adults4 – 6 and 4 (8.0%) of 50 children3 (one study did not report adverse drug reactions7); most of these were gastrointestinal complaints (Table 1). Adverse effects resolved with dose reduction in 27.2% of patients and were severe enough to warrant permanent discontinuation of treatment in 50.0%. Treatment was discontinued in one child who refused to take oral medication.
Patient-specific outcomes of treatment Patient-specific outcomes were reported in three studies that included 70 patients.4 – 6 Fifty-two patients received pristinamycin monotherapy, of whom 25 (48.0%) achieved a cure or probable cure, 18 (34.6%) achieved disease suppression and four (7.7%) failed treatment. Five (9.6%) of the 52 patients on pristinamycin monotherapy discontinued the treatment due to drug intolerance. Of the four patients who failed treatment, two had native bone osteomyelitis that required surgical debridement. One of these infections was due to CoNS and the other due to a polymicrobial infection with CoNS, VRE and Pseudomonas spp. The other two patients who failed treatment had polymicrobial PJIs (CoNS, VRE and Candida spp., and MRSA and Escherichia coli, respectively), including a patient who required a two-stage joint revision.
4 of 7
Discussion There are limited data to guide the optimal treatment of OAIs.8 – 15 Conventionally, clinical guidelines14,15 recommend prolonged antibiotic therapy (3 – 6 weeks) with consideration of surgical intervention. There is insufficient evidence of any differences in efficacy or adverse effects to support the use of any one antibiotic over another.8,11,13 There is some evidence that certain oral antibiotics can achieve clinical outcomes comparable to those of parenteral treatment, specifically oral fluoroquinolones versus parenteral b-lactams.8,10 – 13 The advantages of oral treatment include convenience, reduced healthcare costs, and avoidance of vascular access and the potential associated complications. Pristinamycin is therefore an attractive treatment option for OAIs. Pristinamycin is a streptogramin antibiotic derived from Streptomyces pristinaespiralis, which comprises two structurally unrelated although synergistic components, pristinamycin IA and pristinamycin IIB. Pristinamycin IA is a cyclic hexadepsipeptide and classed as a group B streptogramin while pristinamycin IIA is a macrolide and classed as a group A streptogramin. Pristinamycin IIA binds to the 50S subunit of 70S bacterial ribosomes, first triggering a conformational change and thereby enhancing the affinity for the second component, pristinamycin IA. The consequence is irreversible binding, arrested protein synthesis and a resultant bactericidal effect.2,16 Two genes [vat(D] and [vat(E)] confer resistance to streptogramin A and another two (vgb and the erm) confer resistance to streptogramin B. These genes have been demonstrated in Enterococcus spp., with the erm gene also encoding resistance to macrolides and
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
In the two French studies pristinamycin was used as initial and maintenance therapy in all cases (n ¼ 177).3,7 In the remaining three studies antimicrobial resistance (54.2%) and drug intolerance (45.8%) were the indications for pristinamycin treatment.4 – 6 In these studies, pristinamycin was used as continuing therapy after initial intravenous treatment (in most cases with a glycopeptide). Pristinamycin was used as monotherapy in 55 patients (22.3%). For the remaining patients, it was used in combination with one or more of the following drugs for the treatment of Gram positive OAIs: rifampicin, ciprofloxacin, doxycycline, fusidic acid and clindamycin. In the paediatric case series, pristinamycin was used in combination with an intramuscular aminoglycoside for a period of 5 to 20 days.3
The remaining 18 patients received combination therapy: nine achieved cure or probable cure (50.0%), four (22.2%) achieved suppression and four (22.2%) failed treatment. One (5.6%) patient discontinued treatment due to drug intolerance. Of the four patients who failed treatment, two had native bone osteomyelitis and two had PJIs. Of the two native bone infections, one was due to MRSA and the other due to a combination of CoNS, VRE, Bacillus and Enterobacter. These patients were treated with a combination of pristinamycin and ciprofloxacin; the latter patient was also treated with fusidic acid and underwent surgical debridement. Combination pristinamycin and ciprofloxacin therapy was used for the PJIs that failed treatment. Both infections were polymicrobial (CoNS plus VRE, and Pseudomonas sp. plus VRE, respectively) and required two-stage joint revisions. Thirty-eight of the 70 patients had a prosthetic device-related infection. Of these, 20 (52.6%) achieved cure or probable cure, 13 (34.2%) achieved suppression and four (10.5%) failed treatment (see above). One (2.6%) patient with a PJI required treatment discontinuation due to drug intolerance. Of the 32 patients with native bone or joint infections, 14 (43.8%) achieved cure or probable cure, 9 (28.1%) achieved suppression and four (12.5%) failed treatment (see above). Five patients with native OAIs (15.6%) discontinued treatment due to pristinamycin intolerance. Overall, 191 adults were treated to the end of the study period with pristinamycin, of whom 34 (17.8%) achieved cure or probable cure and 130 (68.0%) achieved suppression. In the paediatric study, 45 children completed treatment and 44 (97.8%) were cured. The duration of follow-up ranged from 3 to 28.8 months.
Review
OAIs.14 This recommendation is derived from non-comparative studies of MSSA OAIs. There have been no randomized controlled trials comparing vancomycin with an alternative agent for the treatment of MRSA OAIs. There are concerns regarding the efficacy of vancomycin for OAIs because of the poor bone penetration (less than 10%) shown in animal models and its bacteriostatic activity.12 – 14,33 Failure rates of up to 46% have been reported in a retrospective case series when vancomycin was used for the treatment of MRSA osteomyelitis.14,34 This is comparable to the cure or probable cure rate of 50.0% for those patients treated with pristinamycin for MRSA infections included in this review for whom patient-specific outcomes were reported. OAIs due to VRE are extremely rare, although the prevalence of these infections in association with diabetic foot lesions is increasing.35 The evidence for the management of VRE OAIs is limited to case reports.33,35,36 These studies primarily use two drugs: linezolid and quinupristin/dalfopristin. Linezolid treats both species of enterococci, while quinupristin/dalfopristin, like pristinamycin, only has activity against Enterococcus faecalis. However, the potential serious side effects of linezolid (pancytopenia, neuropathy) and the greater cost per tablet ($AUS122 for linezolid versus $AUS4 for pristinamycin)4 must be considered. Ten patients with VRE OAIs were included in this review, 50% of whom failed treatment. Ruparelia et al.6 included the most cases of VRE isolates (n ¼6), five of which were associated with treatment failure. Three of the remaining four VRE infections had their infection ‘suppressed’ and the remaining patient did not tolerate treatment.5 Randomized controlled trials of pristinamycin compared with b-lactam antibiotics (penicillin, amoxicillin, oxacillin and cefuroxime) for non-OAIs have found no difference in the rate of adverse drug effects.23 – 27 These studies showed that 8.1% – 27.0% of patients on pristinamycin reported an adverse drug effect compared with 15.7% – 32.0% of those receiving b-lactams.23 – 27 Consistent with the case series in our review, these adverse events were limited to mild to moderate gastrointestinal complaints (nausea, vomiting, diarrhoea, anorexia, abdominal pain or dyspepsia). As with other antibiotics, pseudomembranous colitis following treatment with pristinamycin has been reported.27,37 Other idiosyncratic adverse events such as liver function test abnormalities, rash and lethargy have also been reported.24,25,38,39 There has been one case report of fatal toxic epidermal necrolysis following treatment with pristinamycin for staphylococcal pneumonia.40 This review is subject to limitations similar to those of many other studies of OAIs, particularly those addressing resistant Gram positive infections.14,33,35 The evidence for pristinamycin use in OAIs is limited to non-comparative, retrospective case series. The omission of clinical data such as comorbidities, chronicity of infection, dose and surgical intervention also limits the interpretation of the clinical outcomes. Moreover, a direct comparison between studies was not possible due to differences in the study designs (e.g. heterogeneity in the use of pristinamycin, type of OAI, dosing regimens, outcome definitions and duration of follow-up). The lack of patient-specific outcome data from two of the five studies also restricts any interpretation of the effectiveness of some of the pristinamycin regimens used. Additional pharmacokinetic studies are needed to determine the penetration of pristinamycin into bone as well as the optimal dosing regimen. In vitro evidence of the drug’s effect on biofilm penetration is required to assess the effectiveness of pristinamycin to treat device-related infections.
5 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
lincosamides.17 However, in vitro studies of pristinamycin have demonstrated bactericidal activity against erm-positive isolates, suggesting that the drug is effective against isolates that express these resistance genes.1,18 There are limited published pharmacokinetic data on pristinamycin. It is currently only available for oral administration as 250 or 500 mg tablets. The standard recommended adult dose is 1 g twice or three times a day, and that for children 50 mg/kg three times a day.16 Pristinamycin is rapidly absorbed when administered with meals.19 Its bioavailability and volume of distribution are unknown.20 It is metabolized by the cytochrome p450 – 3A4 enzyme system and therefore interacts with drugs that share this system.16 Time-dependent and concentration-dependent bacterial killing effects have been demonstrated in vitro 18 and a single oral dose of pristinamycin has been shown to produce serum concentrations above the MIC for most S. aureus strains.20 The MIC of pristinamycin for staphylococci (including methicillinand erythromycin-resistant strains) is less than 0.5 mg/L.2,21,22 Although the evidence for the use of pristinamycin in OAIs is limited to case series, multicentre randomized controlled trials of pristinamycin compared with penicillin and oxacillin for the treatment of skin and soft tissue infections have shown comparable clinical efficacy.23,24 Similarly, high cure rates (86.7% – 91.4%) have been reported when pristinamycin was compared with oxacillin, cefuroxime and amoxicillin in controlled trials for the treatment of respiratory tract infections.25 – 27 Of note, one study reported a superior cure rate for pristinamycin compared with penicillin (81% versus 67%), although this difference was not statistically significant.23 The French studies identified in this review included cases with predominantly native OAIs. The cure rate of 88.0% for the paediatric study3 and the cure/suppression rate of 85.8% for the adult study7 are comparable to findings from randomized trials of other conventional therapies for native osteomyelitis. For example, Euba et al.28 compared cloxacillin with rifampicin/co-trimoxazole, with cure rates of 90.4% and 88.9%, respectively; Gentry and Rodriguez-Gomez reported a cure rate of 73.7% for oral ofloxacin and 85.7% for parenteral ceftazidime or cefazolin;29 and a larger multicentre randomized trial found cure rates of 61.4% for linezolid versus 68.8% for an aminopenicillin/b-lactamase inhibitor combination.30 The gold standard for the treatment of PJIs is a combination of surgical intervention and 2 – 6 weeks of a parenteral antibiotic (usually b-lactam or vancomycin) and rifampicin combination followed by 3 –6 months of oral step-down therapy with a combination of fluoroquinolone and rifampicin.15 Variable cure rates have been observed depending on the surgical approach. The success rate for debridement without prosthesis removal ranges from 14% to 100%,15 with risk factors for failure including omission of rifampicin combination therapy, and Gram negative or MRSA infection.31 Cure rates following a one-stage joint revision range from 80% to 90%,15 with a cure rate of 87% reported for twostage joint revision.32 The overall reported cure rate of PJIs with pristinamycin of 52.6% is not directly comparable as the studies included in our review did not all provide details about surgical intervention, and notably only 15.8% of the patients with PJIs were treated with rifampicin combination therapy. OAIs due to resistant Gram positive bacteria such as MRSA present an increasingly frequent management problem. Vancomycin, a bacteriostatic glycopeptide, remains the first-line therapy for MRSA
JAC
Review
Conclusions In the current climate of multidrug-resistant pathogens, there is an urgent need for further research and a reintegration of older antibiotics into the antibiotic arsenal.41 Although the data are limited, this review suggests that pristinamycin is a well-tolerated effective alternative for the treatment of OAIs due to Gram positive bacteria. The use of pristinamycin for OAIs warrants prospective evaluation, ideally in a randomized controlled trial.
Acknowledgements
Transparency declarations None to declare.
References 1 Leclercq R, Soussy CJ, Weber P et al. In vitro activity of the pristinamycin against the isolated staphylococci in the French hospitals in 1999– 2000. Pathol Biol (Paris) 2003; 51: 400– 4. 2 Maskell JP, Sefton AM, Yong J et al. Comparative in-vitro activity of erythromycin, vancomycin and pristinamycin. Infection 1988; 16: 365–70. 3 Beauvais P, Filipe G, Berniere J et al. Oral pristinamycin therapy for bone and joint infections in children. A report of 50 cases (author’s transl). Arch Fr Pediatr 1981; 38: 489–93. 4 Ng J, Gosbell IB. Successful oral pristinamycin therapy for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus spp. J Antimicrob Chemother 2005; 55: 1008 –12. 5 Reid AB, Daffy JR, Stanley P et al. Use of pristinamycin for infections by Gram-positive bacteria: clinical experience at an Australian hospital. Antimicrob Agents Chemother 2010; 54: 3949– 52. 6 Ruparelia N, Atkins BL, Hemingway J et al. Pristinamycin as adjunctive therapy in the management of Gram-positive multi-drug resistant organism (MDRO) osteoarticular infection. J Infect 2008; 57: 191– 7. 7 Boibieux ABX, Brechignac X, Bonheur D et al. Pristinamycine et infections osteo-articulaires: 4 ans de suivi in Abstracts des Communications Affiche´s (CA). Me´d Maladies Infect 2001; 31 Suppl 3: 432s–73s. 8 Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev 2013; issue 9: CD004439. 9 Haidar R, Der Boghossian A, Atiyeh B. Duration of post-surgical antibiotics in chronic osteomyelitis: empiric or evidence-based? Int J Infect Dis 2010; 14: e752–8. 10 Karamanis EM, Matthaiou DK, Moraitis LI et al. Fluoroquinolones versus b-lactam based regimens for the treatment of osteomyelitis: a meta-analysis of randomized controlled trials. Spine 2008; 33: E297– 304. 11 Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis 2005; 9: 127– 38.
15 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: e1–e25. 16 Grayson ML (ed). Kucers’ The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs. London: Hodder Arnold, 2010. 17 Jensen LB, Hammerum AM, Aarestrup FM. Linkage of vat(E) and erm(B) in streptogramin-resistant Enterococcus faecium isolates from Europe. Antimicrob Agents Chemother 2000; 44: 2231– 2. 18 Drudgeon HBJM, Dib-Smahi C. In vitro bacteriostatic and bactericidal activity of pristinamycin against Streptococcus pyogenes: influence of macrolide resistance mechanism. In: Abstracts of the Sixteenth European Congress of Clinical Microbiology and Infectious Diseases, Nice, France, 2006. Abstract p1292. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland. 19 Chevalier P, Paccaly A, Bouriot JP et al. Etude de la pharmacocine´tique des pristinamycines chez des volontaires en bonne sante´. Med Maladies Infect 1995; 25: 1153 –60. 20 Koechlin C, Kempf J-F, Jehl F et al. Single oral dose pharmacokinetics of the two main components of pristinamycin in humans. J Antimicrob Chemother 1990; 25: 651–6. 21 Mutton KJ, Andrew JH. In vitro activity of pristinamycin against methicillin-resistant Staphylococcus aureus. Chemotherapy 1983; 29: 218–24. 22 Barber M, Waterworth PM. Antibacterial activity of lincomycin and pristinamycin: a comparison with erythromycin. BMJ 1964; 2: 603– 6. 23 Bernard P, Chosidow O, Vaillant L et al. Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial. BMJ 2002; 325: 864. 24 Bernard P, Vaillant L, Martin C et al. Pristinamycin versus oxacillin in the treatment of superficial pyoderma. A multicenter, randomized study in 293 outpatients. Ann Dermatol Venereol 1997; 124: 384–9. 25 Bastin R, Rapin M, Kernbaum S. Controlled study of pristinamycin versus oxacillin in staphylococcal infections. Pathol Biol (Paris) 1982; 30: 473– 5. 26 Gehanno P, Berche P, Hercot O et al. Efficiency of a four-day course of pristinamycin compared to a five-day course of cefuroxime axetil for acute bacterial maxillary sinusitis in adult outpatients. Med Maladies Infect 2004; 34: 293– 302. 27 Tremolieres F, Mayaud C, Mouton Y et al. Efficacy and safety of pristinamycin vs amoxicillin in community acquired pneumonia in adults. Pathol Biol (Paris) 2005; 53: 503– 10. 28 Euba G, Murillo O, Fernandez-Sabe N et al. Long-term follow-up trial of oral rifampin-cotrimoxazole combination versus intravenous cloxacillin in treatment of chronic staphylococcal osteomyelitis. Antimicrob Agents Chemother 2009; 53: 2672– 6. 29 Gentry LO, Rodriguez-Gomez G. Ofloxacin versus parenteral therapy for chronic osteomyelitis. Antimicrobial Agents and Chemotherapy 1991; 35: 538–41.
12 Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis 2012; 54: 393–407.
30 Lipsky BA, Itani K, Norden C et al. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38: 17 –24.
13 Stengel D, Bauwens K, Sehouli J et al. Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infect Dis 2001; 1: 175–88.
31 Marculescu CE, Berbari EF, Hanssen AD et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis 2006; 42: 471– 8.
14 Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of
32 Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am 2005; 19: 885–914.
6 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
We would like to acknowledge Poh Chua for her assistance with the literature search.
methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52: e18– 55.
Review
33 Darley ES, MacGowan AP. Antibiotic treatment of Gram-positive bone and joint infections. J Antimicrob Chemother 2004; 53: 928– 35. 34 Dombrowski JC, Winston LG. Clinical failures of appropriately-treated methicillin-resistant Staphylococcus aureus infections. J Infect 2008; 57: 110– 5. 35 Fraimow HS. Systemic antimicrobial therapy in osteomyelitis. Semin Plast Surg 2009; 23: 90–9.
JAC 38 Dancer SJ, Robb A, Crawford A et al. Oral streptogramins in the management of patients with methicillin-resistant Straphylococcus aureus (MRSA) infections. J Antimicrob Chemother 2003; 51: 731–5. 39 Bernard P, Risse L, Bonnetblanc JM. Pristinamycin in the treatment of acute bacterial dermohypodermitis in adults. An open study of 42 patients. Ann Dermatol Venereol 1996; 123: 16 –20.
36 Anagnostakos K, Mosser P. Linezolid in the treatment of orthopaedic bone and joint infections – a systematic literature review. OA Musculoskeletal Medicine 2013; 1: 12.
40 Chanques G, Girard C, Pinzani V et al. Fatal pristinamycin-induced toxic epidermal necrolysis (Lyell’s syndrome): difficulties in attributing causal association in the polymedicated intensive care unit patient. Acta Anaesthesiol Scand 2005; 49: 721–2.
37 Gavazzi G, Barnoud R, Lamloum M et al. Pseudomembranous colitis after pristinamycin. Rev Med Interne 2001; 22: 672–3.
41 Cheng AC, Nation RL. How can we improve access to new (and old) antibiotics in Australia?. Med J Aust 2013; 199: 81 –2.
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
7 of 7
J Antimicrob Chemother doi:10.1093/jac/dku167
Pristinamycin: old drug, new tricks? Eden C. Cooper1,2*, Nigel Curtis1–3, Noel Cranswick1–3 and Amanda Gwee2,3 1
Department of Paediatrics, University of Melbourne, Victoria, Australia; 2Infectious Diseases and Clinical Pharmacology Unit, Department of Medicine, The Royal Children’s Hospital Melbourne, Victoria, Australia; 3Murdoch Childrens Research Institute, Victoria, Australia *Corresponding author. Department of General Medicine, The Royal Children’s Hospital Melbourne, Flemington Road, Parkville, 3052 Victoria, Australia. Tel: +613-9345-5522; E-mail: [email protected]
Keywords: quinupristin/dalfopristin, streptogramin, Gram positive infections, bone and joint infections, osteomyelitis, arthritis, prosthesis infections
Background Osteoarticular infections (OAIs) with Gram positive bacteria present an increasing challenge in the era of multidrug-resistant organisms. These infections often require a combination of surgical intervention and prolonged intravenous antibiotics. Prolonged treatment with parenteral antibiotics is not without risk, inconvenience and cost, and therefore an oral option would be ideal in this setting. In the absence of new oral agents, the reintroduction of older antibiotics needs to be considered. Pristinamycin is an oral streptogramin antibiotic with a similar spectrum of activity to macrolides and lincosamides for Grampositive bacteria, with a reduced risk of drug resistance.1 It is bactericidal against Staphylococcus spp. and Streptococcus spp. but has less activity against enterococci.2 Pristinamycin has been used for over 50 years for the treatment of OAIs, principally in Europe. We review here the evidence for the use of pristinamycin in OAIs.
Methods We searched Medline (1946 to present) and Embase (1974 to present) in July 2013 using the OVID interface. The following search terms were used: pristinamycin/ or virginiamycin AND (Gram positive bacteria OR Gram positive bacterial infections OR Gram positive cocci OR Gram positive infection) AND/OR (bone and joint infections OR bone infection OR arthritis, infectious OR bone disease, infectious OR osteitis OR osteomyelitis OR periostitis OR spondylitis OR prosthesis-related infections OR prosthesis infection). This identified a total of 1375 articles. Studies that reported clinical outcomes when pristinamycin was used for the treatment of OAIs were included. Case reports were excluded. No limits were set on language.
A single researcher (E. C. C.) reviewed the search results and identified four relevant publications. 3 – 6 The references for each article were reviewed and one further study was identified.7 Two of the five studies were published in French and translated into English.3,7
Results Of the five identified studies, four were case series in adults and one in children (Table 1).3 These studies included a total of 247 patients (197 adults and 50 children) treated with pristinamycin for OAIs. The treated cases comprised native bone or joint infection (n¼161) and an infected prosthetic joint or device (n¼ 86). Only two studies reported on chronicity of infection.3,5 In the paediatric study, 78.0% of infections were acute and 22.0% were subacute or chronic; however, these classifications were not defined.3 One study classified the subset of prosthetic joint infections (PJIs) as early (90.0%) or late (10.0%) onset.5 Comorbidities were reported in two adult studies, with diabetes mellitus, chronic cardiorespiratory disease and obesity the most common.5,7
Pathogens Two hundred and nine patients had culture-proven OAIs with a total of 306 isolates. Of these, 151 (72.2%) patients were infected with a single pathogen and 58 (27.8%) had a polymicrobial infection. The most commonly isolated organisms were Staphylococcus spp. (69.0% of positive cultures), of which 14.2% were methicillinresistant Staphylococcus aureus (MRSA), 1.9% were methicillinsusceptible S. aureus (MSSA), 45.5% were S. aureus not otherwise defined and 38.4% were coagulase-negative staphylococci (CoNS). Other isolates included Streptococcus spp. (6.9%) and
# The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
1 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
Osteoarticular infections with Gram positive bacteria present an increasing challenge in an era of multidrugresistant organisms. Prolonged intravenous antibiotic treatment is often required, with associated risks, costs and difficulties with administration; a safe, effective oral option would be ideal for this indication. Pristinamycin, an oral streptogramin antibiotic with bactericidal activity against Gram positive organisms including methicillin-resistant Staphylococcus aureus, has been used for over 50 years in Europe for the treatment of osteoarticular infections. We review the published evidence for the treatment of native bone and prosthesisrelated osteoarticular infections with pristinamycin.
Review
Study
Subjects
Organism
Antibiotics prior to pristinamycin
Surgical intervention Pristinamycin therapy
Drug AEs
Ruparelia6 2008 Retrospective case series
Adults with OAIs (n ¼ 21) † OM (5) † PJI (13) † OIOD (3) Median age 68 y (18 –83 y)
55 isolates from 21 patients Single organism (5) † CoNS (3) † Diptheroids (2) Polymicrobial (16) including † ≥1 CoNS (15) † VRE (6) † Pseudomonas aeruginosa (2) † Coliforms (2) † Enterobacter spp. (2) † Enterococcus spp. (1) † Bacillus sp. (1) † Candida parapsilosis (1)
First line VAN + MEMb (19) VAN (2) Second line LZD (6) FUS +minocycline + DOX (1) CIP + LZD (1) DOX (1) Range 2 –6 w
Pristinamycin 1 g bd OM Median duration 3 m † 5/5 tissue (1 w –15 m) resection PJI † 4/13 debridement and retained prosthesis † 9/13 joint revision OIOD † 2/3 metalware removal † 1/3 debridement and retention
Reid5 2010 Retrospective case series
Adults with OAIs (n ¼ 22) † OM (12) † PJI (10) Median age 63.5 y (33 –83 y)
32 isolates from 22 patients Single organism (14) † MRSA (6) † CoNS (6) † VRE (2) Polymicrobial (8) including † ≥1 CoNS (8) † MRSA (2) † MSSA (2) † VRE (2) † Corynebacterium spp. (2) † E. faecalis (2)
First line VAN (12) RIF+ FUS (4) LZD (2) VAN + TIM (1) RIF+ LZD (1) Nil (2) Second line LZD (2) VAN (1) teicoplanin (1) RIF+ FUS (1) Range 13 d –22 m
Not reported PJI † 7/10 retained prostheses
Ng4 2005 Retrospective case series
Adults with OAIs (n ¼ 27) OM (15) PJI (5) OIOD (7) Median age 60 y (18 – 81 y)
32 isolates from 27 patients Single organism (23) † MRSA (19) † MSSA (1) † CoNS (3) Polymicrobial (4) including † MRSA (3) † E. coli (2) † MSSA (1) † P. aeruginosa (1) † Corynebacterium jeikeium (1) † Mixed anaerobes (1)
Glycopeptide (27) Range 24 d –8 w
Drug AEs Pristinamycin OM 8/27 1 g tds † 4/15 debridement Median duration 6 m † GIT (7) PJI † Rash (1) (2 w –18 m) † 1/5 joint revision Drug discontinued OIOD 4/27 † 4/7 removal of Dose reduction to prosthetic 500 mg tds 4/27 material
Dose not stated Median duration 169 d (19 –876 d)
Drug AEs 2/21 † GIT (2) † Lethargy (1) Drug discontinued 1/21 Dose reduction to 500 mg tds 1/21
Concurrent antibiotics Total 9/21 CoNS only (5): RIF (2c) CIP (1) DOX (1) FUS (1) CoNS +VRE (1)d: CIP CoNS + GNB (1): CIP + FUS CoNS +VRE + GNB (1): CIP VRE + GNB (1): CIP
Total 1/22 Drug AEs 8/22 CoNS † GIT (7) RIF + CIP † LOW (1) † Abnormal LFTs (1) Drug discontinued 2/22 Dose reduction to 500 mg tds 1/22
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
2 of 7
Table 1. Summary of evidence
Total 8/27 MRSA only (6): FUS (4) RIF (1) CIP (1) CoNS only (n ¼ 1): FUS MRSA + GNB +anaerobes (n ¼ 1): CIP +clindamycin
Outcome Cure 11/21a (52%) Suppression 4/21 (19%) Failure 6/21 (29%)
Cure 7/22 (32%) Suppression 13/22 (59%) Intolerance 2/22 (9%)
Cure 9/27 (33%) Probable cure 7/27 (26%) Suppression 5/27 (19%) Failure 2/27 (7%) Intolerance 4/27 (15%)
Children with OAIs (n ¼ 50): † OM (15) † SA (19) † SA/OM (5) † Chronic or subacute OM (9) † Chronic or subacute OIOD (2) Age range 7 d –17 y 7 m
28 isolates from 27 patients single organism (n ¼ 26) † S. aureus g (19) † Haemolytic Streptococcus (3) † H. influenzae (3) † S. pneumoniae (1) Polymicrobial (n¼ 1) including † S. aureus (1) † Haemolytic Streptococcus (1)
Nonee
OM † 7/15 debridement SA † 18/19 arthrotomy SA/OM † 2/5 debridement Chronic or subacute † 11/11 debridement
Mean dose 1 g/kg/d (0.5 –1.8 g) tds (age-dependent)h Duration OM 30 –120 di Joint infection 30 –60 d
Drug AEs 4/50: † GIT (4) Drug discontinued 4/27
Total 50 Gentamicin intramuscularly (49) Tobramycin (1) Mean duration 10 d (5 – 20 d)
Cure 44/50 (88%) Failure 1/50 (2%) Intolerance 4/50 (8%) Refusal 1/50 (2%)
Boibieux7 2001 Retrospective case series (abstract only)
Adults with OAIs (n ¼ 127): † OM (13) † Osteitis (100) † SA/OM (14) Synthetic or prosthetic material for 46/127 Age range 37 –77 y
159 isolates from 112 patients Organisms included † S. aureus (n ¼ 76) † CoNS (24) † Streptococcus sp. (n ¼ 16) † Enterobacteriaceae sp. (n ¼ 14) † Enterococcus spp. (n ¼ 8) Single organism (n ¼ 83) Polymicrobial (n¼ 29)
None
59/127 had surgical intervention (not specified)
Dose not reported Mean duration 316 d (169 –463 d)
No reports of drug AEs No reports of drug discontinuation
Total 124j
Outcomes not definedk Suppression 108/ 127 (85%)
Review
Beauvais3 1981 Case seriesf
AEs, adverse events; OM, osteomyelitis; OIOD, other infected orthopaedic device; VAN, vancomycin; MEM, meropenem; LZD, linezolid; FUS, fusidic acid; DOX, doxycycline; CIP, ciprofloxacin; GIT, gastrointestinal tract; RIF, rifampicin; GNB, Gram negative bacilli; TIM, ticarcillin/clavulanate; LOW, loss of weight; LFTs, liver function tests; SA, septic arthritis; d, days; w, weeks; m, months; y, years; bd, twice a day; tds, three times a day; G-, Gram negative. a One patient with an outcome of cure also discontinued treatment due to drug intolerance. b Meropenem was stopped after no G- were cultured for 17/19. c One patient grew CoNS only, although they had a concurrent non-OAI with Mycobacterium marinum treated with clarithromycin, ethambutol and rifampicin. d One patient grew CoNS+VRE+Candida and was treated with pristinamycin and fluconazole. e Surgery was needed for sequelae in two patients. f It is unclear whether the methodology was retrospective or prospective. g Susceptibilities to many antibiotics were reported, but not for methicillin or flucloxacillin. h Doses were age-dependent: 0.5–1.0 g/kg/day for older children and 1.0–1.5 g/kg/day for younger children. i One chronic case required 210 d treatment. j Details of concurrent therapy were not specified except to say that 83/127 received dual therapy (usually pristinamycin+ofloxacin) followed by monotherapy with pristinamycin. k An unclear number of patients was cured.
JAC
3 of 7 Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
Review
Enterococcus spp. (6.9%), of which half were vancomycin-resistant enterococci (VRE).
Pristinamycin therapy
Pristinamycin dosing and duration Pristinamycin dosing was described in only three of five studies.3,4,6 For adults, a dose of 1 g twice or three times a day was used. Children received an age-dependent dose of 0.5 – 1.0 g/kg per day for ‘older children’ or 1.0 – 1.5 g/kg per day for ‘younger children’. The duration of treatment was highly variable and ranged from 1 week to 28.8 months. In the three studies that reported patientspecific treatment details,4 – 6 native OAIs were treated for an average of 10 months (2 weeks – 28.8 months) and device-related infections were treated for an average of 8.8 months (1 week – 18 months).
Adverse drug effects Adverse effects occurred in 18 (25.7%) of 70 adults4 – 6 and 4 (8.0%) of 50 children3 (one study did not report adverse drug reactions7); most of these were gastrointestinal complaints (Table 1). Adverse effects resolved with dose reduction in 27.2% of patients and were severe enough to warrant permanent discontinuation of treatment in 50.0%. Treatment was discontinued in one child who refused to take oral medication.
Patient-specific outcomes of treatment Patient-specific outcomes were reported in three studies that included 70 patients.4 – 6 Fifty-two patients received pristinamycin monotherapy, of whom 25 (48.0%) achieved a cure or probable cure, 18 (34.6%) achieved disease suppression and four (7.7%) failed treatment. Five (9.6%) of the 52 patients on pristinamycin monotherapy discontinued the treatment due to drug intolerance. Of the four patients who failed treatment, two had native bone osteomyelitis that required surgical debridement. One of these infections was due to CoNS and the other due to a polymicrobial infection with CoNS, VRE and Pseudomonas spp. The other two patients who failed treatment had polymicrobial PJIs (CoNS, VRE and Candida spp., and MRSA and Escherichia coli, respectively), including a patient who required a two-stage joint revision.
4 of 7
Discussion There are limited data to guide the optimal treatment of OAIs.8 – 15 Conventionally, clinical guidelines14,15 recommend prolonged antibiotic therapy (3 – 6 weeks) with consideration of surgical intervention. There is insufficient evidence of any differences in efficacy or adverse effects to support the use of any one antibiotic over another.8,11,13 There is some evidence that certain oral antibiotics can achieve clinical outcomes comparable to those of parenteral treatment, specifically oral fluoroquinolones versus parenteral b-lactams.8,10 – 13 The advantages of oral treatment include convenience, reduced healthcare costs, and avoidance of vascular access and the potential associated complications. Pristinamycin is therefore an attractive treatment option for OAIs. Pristinamycin is a streptogramin antibiotic derived from Streptomyces pristinaespiralis, which comprises two structurally unrelated although synergistic components, pristinamycin IA and pristinamycin IIB. Pristinamycin IA is a cyclic hexadepsipeptide and classed as a group B streptogramin while pristinamycin IIA is a macrolide and classed as a group A streptogramin. Pristinamycin IIA binds to the 50S subunit of 70S bacterial ribosomes, first triggering a conformational change and thereby enhancing the affinity for the second component, pristinamycin IA. The consequence is irreversible binding, arrested protein synthesis and a resultant bactericidal effect.2,16 Two genes [vat(D] and [vat(E)] confer resistance to streptogramin A and another two (vgb and the erm) confer resistance to streptogramin B. These genes have been demonstrated in Enterococcus spp., with the erm gene also encoding resistance to macrolides and
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
In the two French studies pristinamycin was used as initial and maintenance therapy in all cases (n ¼ 177).3,7 In the remaining three studies antimicrobial resistance (54.2%) and drug intolerance (45.8%) were the indications for pristinamycin treatment.4 – 6 In these studies, pristinamycin was used as continuing therapy after initial intravenous treatment (in most cases with a glycopeptide). Pristinamycin was used as monotherapy in 55 patients (22.3%). For the remaining patients, it was used in combination with one or more of the following drugs for the treatment of Gram positive OAIs: rifampicin, ciprofloxacin, doxycycline, fusidic acid and clindamycin. In the paediatric case series, pristinamycin was used in combination with an intramuscular aminoglycoside for a period of 5 to 20 days.3
The remaining 18 patients received combination therapy: nine achieved cure or probable cure (50.0%), four (22.2%) achieved suppression and four (22.2%) failed treatment. One (5.6%) patient discontinued treatment due to drug intolerance. Of the four patients who failed treatment, two had native bone osteomyelitis and two had PJIs. Of the two native bone infections, one was due to MRSA and the other due to a combination of CoNS, VRE, Bacillus and Enterobacter. These patients were treated with a combination of pristinamycin and ciprofloxacin; the latter patient was also treated with fusidic acid and underwent surgical debridement. Combination pristinamycin and ciprofloxacin therapy was used for the PJIs that failed treatment. Both infections were polymicrobial (CoNS plus VRE, and Pseudomonas sp. plus VRE, respectively) and required two-stage joint revisions. Thirty-eight of the 70 patients had a prosthetic device-related infection. Of these, 20 (52.6%) achieved cure or probable cure, 13 (34.2%) achieved suppression and four (10.5%) failed treatment (see above). One (2.6%) patient with a PJI required treatment discontinuation due to drug intolerance. Of the 32 patients with native bone or joint infections, 14 (43.8%) achieved cure or probable cure, 9 (28.1%) achieved suppression and four (12.5%) failed treatment (see above). Five patients with native OAIs (15.6%) discontinued treatment due to pristinamycin intolerance. Overall, 191 adults were treated to the end of the study period with pristinamycin, of whom 34 (17.8%) achieved cure or probable cure and 130 (68.0%) achieved suppression. In the paediatric study, 45 children completed treatment and 44 (97.8%) were cured. The duration of follow-up ranged from 3 to 28.8 months.
Review
OAIs.14 This recommendation is derived from non-comparative studies of MSSA OAIs. There have been no randomized controlled trials comparing vancomycin with an alternative agent for the treatment of MRSA OAIs. There are concerns regarding the efficacy of vancomycin for OAIs because of the poor bone penetration (less than 10%) shown in animal models and its bacteriostatic activity.12 – 14,33 Failure rates of up to 46% have been reported in a retrospective case series when vancomycin was used for the treatment of MRSA osteomyelitis.14,34 This is comparable to the cure or probable cure rate of 50.0% for those patients treated with pristinamycin for MRSA infections included in this review for whom patient-specific outcomes were reported. OAIs due to VRE are extremely rare, although the prevalence of these infections in association with diabetic foot lesions is increasing.35 The evidence for the management of VRE OAIs is limited to case reports.33,35,36 These studies primarily use two drugs: linezolid and quinupristin/dalfopristin. Linezolid treats both species of enterococci, while quinupristin/dalfopristin, like pristinamycin, only has activity against Enterococcus faecalis. However, the potential serious side effects of linezolid (pancytopenia, neuropathy) and the greater cost per tablet ($AUS122 for linezolid versus $AUS4 for pristinamycin)4 must be considered. Ten patients with VRE OAIs were included in this review, 50% of whom failed treatment. Ruparelia et al.6 included the most cases of VRE isolates (n ¼6), five of which were associated with treatment failure. Three of the remaining four VRE infections had their infection ‘suppressed’ and the remaining patient did not tolerate treatment.5 Randomized controlled trials of pristinamycin compared with b-lactam antibiotics (penicillin, amoxicillin, oxacillin and cefuroxime) for non-OAIs have found no difference in the rate of adverse drug effects.23 – 27 These studies showed that 8.1% – 27.0% of patients on pristinamycin reported an adverse drug effect compared with 15.7% – 32.0% of those receiving b-lactams.23 – 27 Consistent with the case series in our review, these adverse events were limited to mild to moderate gastrointestinal complaints (nausea, vomiting, diarrhoea, anorexia, abdominal pain or dyspepsia). As with other antibiotics, pseudomembranous colitis following treatment with pristinamycin has been reported.27,37 Other idiosyncratic adverse events such as liver function test abnormalities, rash and lethargy have also been reported.24,25,38,39 There has been one case report of fatal toxic epidermal necrolysis following treatment with pristinamycin for staphylococcal pneumonia.40 This review is subject to limitations similar to those of many other studies of OAIs, particularly those addressing resistant Gram positive infections.14,33,35 The evidence for pristinamycin use in OAIs is limited to non-comparative, retrospective case series. The omission of clinical data such as comorbidities, chronicity of infection, dose and surgical intervention also limits the interpretation of the clinical outcomes. Moreover, a direct comparison between studies was not possible due to differences in the study designs (e.g. heterogeneity in the use of pristinamycin, type of OAI, dosing regimens, outcome definitions and duration of follow-up). The lack of patient-specific outcome data from two of the five studies also restricts any interpretation of the effectiveness of some of the pristinamycin regimens used. Additional pharmacokinetic studies are needed to determine the penetration of pristinamycin into bone as well as the optimal dosing regimen. In vitro evidence of the drug’s effect on biofilm penetration is required to assess the effectiveness of pristinamycin to treat device-related infections.
5 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
lincosamides.17 However, in vitro studies of pristinamycin have demonstrated bactericidal activity against erm-positive isolates, suggesting that the drug is effective against isolates that express these resistance genes.1,18 There are limited published pharmacokinetic data on pristinamycin. It is currently only available for oral administration as 250 or 500 mg tablets. The standard recommended adult dose is 1 g twice or three times a day, and that for children 50 mg/kg three times a day.16 Pristinamycin is rapidly absorbed when administered with meals.19 Its bioavailability and volume of distribution are unknown.20 It is metabolized by the cytochrome p450 – 3A4 enzyme system and therefore interacts with drugs that share this system.16 Time-dependent and concentration-dependent bacterial killing effects have been demonstrated in vitro 18 and a single oral dose of pristinamycin has been shown to produce serum concentrations above the MIC for most S. aureus strains.20 The MIC of pristinamycin for staphylococci (including methicillinand erythromycin-resistant strains) is less than 0.5 mg/L.2,21,22 Although the evidence for the use of pristinamycin in OAIs is limited to case series, multicentre randomized controlled trials of pristinamycin compared with penicillin and oxacillin for the treatment of skin and soft tissue infections have shown comparable clinical efficacy.23,24 Similarly, high cure rates (86.7% – 91.4%) have been reported when pristinamycin was compared with oxacillin, cefuroxime and amoxicillin in controlled trials for the treatment of respiratory tract infections.25 – 27 Of note, one study reported a superior cure rate for pristinamycin compared with penicillin (81% versus 67%), although this difference was not statistically significant.23 The French studies identified in this review included cases with predominantly native OAIs. The cure rate of 88.0% for the paediatric study3 and the cure/suppression rate of 85.8% for the adult study7 are comparable to findings from randomized trials of other conventional therapies for native osteomyelitis. For example, Euba et al.28 compared cloxacillin with rifampicin/co-trimoxazole, with cure rates of 90.4% and 88.9%, respectively; Gentry and Rodriguez-Gomez reported a cure rate of 73.7% for oral ofloxacin and 85.7% for parenteral ceftazidime or cefazolin;29 and a larger multicentre randomized trial found cure rates of 61.4% for linezolid versus 68.8% for an aminopenicillin/b-lactamase inhibitor combination.30 The gold standard for the treatment of PJIs is a combination of surgical intervention and 2 – 6 weeks of a parenteral antibiotic (usually b-lactam or vancomycin) and rifampicin combination followed by 3 –6 months of oral step-down therapy with a combination of fluoroquinolone and rifampicin.15 Variable cure rates have been observed depending on the surgical approach. The success rate for debridement without prosthesis removal ranges from 14% to 100%,15 with risk factors for failure including omission of rifampicin combination therapy, and Gram negative or MRSA infection.31 Cure rates following a one-stage joint revision range from 80% to 90%,15 with a cure rate of 87% reported for twostage joint revision.32 The overall reported cure rate of PJIs with pristinamycin of 52.6% is not directly comparable as the studies included in our review did not all provide details about surgical intervention, and notably only 15.8% of the patients with PJIs were treated with rifampicin combination therapy. OAIs due to resistant Gram positive bacteria such as MRSA present an increasingly frequent management problem. Vancomycin, a bacteriostatic glycopeptide, remains the first-line therapy for MRSA
JAC
Review
Conclusions In the current climate of multidrug-resistant pathogens, there is an urgent need for further research and a reintegration of older antibiotics into the antibiotic arsenal.41 Although the data are limited, this review suggests that pristinamycin is a well-tolerated effective alternative for the treatment of OAIs due to Gram positive bacteria. The use of pristinamycin for OAIs warrants prospective evaluation, ideally in a randomized controlled trial.
Acknowledgements
Transparency declarations None to declare.
References 1 Leclercq R, Soussy CJ, Weber P et al. In vitro activity of the pristinamycin against the isolated staphylococci in the French hospitals in 1999– 2000. Pathol Biol (Paris) 2003; 51: 400– 4. 2 Maskell JP, Sefton AM, Yong J et al. Comparative in-vitro activity of erythromycin, vancomycin and pristinamycin. Infection 1988; 16: 365–70. 3 Beauvais P, Filipe G, Berniere J et al. Oral pristinamycin therapy for bone and joint infections in children. A report of 50 cases (author’s transl). Arch Fr Pediatr 1981; 38: 489–93. 4 Ng J, Gosbell IB. Successful oral pristinamycin therapy for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus spp. J Antimicrob Chemother 2005; 55: 1008 –12. 5 Reid AB, Daffy JR, Stanley P et al. Use of pristinamycin for infections by Gram-positive bacteria: clinical experience at an Australian hospital. Antimicrob Agents Chemother 2010; 54: 3949– 52. 6 Ruparelia N, Atkins BL, Hemingway J et al. Pristinamycin as adjunctive therapy in the management of Gram-positive multi-drug resistant organism (MDRO) osteoarticular infection. J Infect 2008; 57: 191– 7. 7 Boibieux ABX, Brechignac X, Bonheur D et al. Pristinamycine et infections osteo-articulaires: 4 ans de suivi in Abstracts des Communications Affiche´s (CA). Me´d Maladies Infect 2001; 31 Suppl 3: 432s–73s. 8 Conterno LO, Turchi MD. Antibiotics for treating chronic osteomyelitis in adults. Cochrane Database Syst Rev 2013; issue 9: CD004439. 9 Haidar R, Der Boghossian A, Atiyeh B. Duration of post-surgical antibiotics in chronic osteomyelitis: empiric or evidence-based? Int J Infect Dis 2010; 14: e752–8. 10 Karamanis EM, Matthaiou DK, Moraitis LI et al. Fluoroquinolones versus b-lactam based regimens for the treatment of osteomyelitis: a meta-analysis of randomized controlled trials. Spine 2008; 33: E297– 304. 11 Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis 2005; 9: 127– 38.
15 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: e1–e25. 16 Grayson ML (ed). Kucers’ The Use of Antibiotics: A Clinical Review of Antibacterial, Antifungal, Antiparasitic and Antiviral Drugs. London: Hodder Arnold, 2010. 17 Jensen LB, Hammerum AM, Aarestrup FM. Linkage of vat(E) and erm(B) in streptogramin-resistant Enterococcus faecium isolates from Europe. Antimicrob Agents Chemother 2000; 44: 2231– 2. 18 Drudgeon HBJM, Dib-Smahi C. In vitro bacteriostatic and bactericidal activity of pristinamycin against Streptococcus pyogenes: influence of macrolide resistance mechanism. In: Abstracts of the Sixteenth European Congress of Clinical Microbiology and Infectious Diseases, Nice, France, 2006. Abstract p1292. European Society of Clinical Microbiology and Infectious Diseases, Basel, Switzerland. 19 Chevalier P, Paccaly A, Bouriot JP et al. Etude de la pharmacocine´tique des pristinamycines chez des volontaires en bonne sante´. Med Maladies Infect 1995; 25: 1153 –60. 20 Koechlin C, Kempf J-F, Jehl F et al. Single oral dose pharmacokinetics of the two main components of pristinamycin in humans. J Antimicrob Chemother 1990; 25: 651–6. 21 Mutton KJ, Andrew JH. In vitro activity of pristinamycin against methicillin-resistant Staphylococcus aureus. Chemotherapy 1983; 29: 218–24. 22 Barber M, Waterworth PM. Antibacterial activity of lincomycin and pristinamycin: a comparison with erythromycin. BMJ 1964; 2: 603– 6. 23 Bernard P, Chosidow O, Vaillant L et al. Oral pristinamycin versus standard penicillin regimen to treat erysipelas in adults: randomised, non-inferiority, open trial. BMJ 2002; 325: 864. 24 Bernard P, Vaillant L, Martin C et al. Pristinamycin versus oxacillin in the treatment of superficial pyoderma. A multicenter, randomized study in 293 outpatients. Ann Dermatol Venereol 1997; 124: 384–9. 25 Bastin R, Rapin M, Kernbaum S. Controlled study of pristinamycin versus oxacillin in staphylococcal infections. Pathol Biol (Paris) 1982; 30: 473– 5. 26 Gehanno P, Berche P, Hercot O et al. Efficiency of a four-day course of pristinamycin compared to a five-day course of cefuroxime axetil for acute bacterial maxillary sinusitis in adult outpatients. Med Maladies Infect 2004; 34: 293– 302. 27 Tremolieres F, Mayaud C, Mouton Y et al. Efficacy and safety of pristinamycin vs amoxicillin in community acquired pneumonia in adults. Pathol Biol (Paris) 2005; 53: 503– 10. 28 Euba G, Murillo O, Fernandez-Sabe N et al. Long-term follow-up trial of oral rifampin-cotrimoxazole combination versus intravenous cloxacillin in treatment of chronic staphylococcal osteomyelitis. Antimicrob Agents Chemother 2009; 53: 2672– 6. 29 Gentry LO, Rodriguez-Gomez G. Ofloxacin versus parenteral therapy for chronic osteomyelitis. Antimicrobial Agents and Chemotherapy 1991; 35: 538–41.
12 Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis 2012; 54: 393–407.
30 Lipsky BA, Itani K, Norden C et al. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis 2004; 38: 17 –24.
13 Stengel D, Bauwens K, Sehouli J et al. Systematic review and meta-analysis of antibiotic therapy for bone and joint infections. Lancet Infect Dis 2001; 1: 175–88.
31 Marculescu CE, Berbari EF, Hanssen AD et al. Outcome of prosthetic joint infections treated with debridement and retention of components. Clin Infect Dis 2006; 42: 471– 8.
14 Liu C, Bayer A, Cosgrove SE et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of
32 Sia IG, Berbari EF, Karchmer AW. Prosthetic joint infections. Infect Dis Clin North Am 2005; 19: 885–914.
6 of 7
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
We would like to acknowledge Poh Chua for her assistance with the literature search.
methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011; 52: e18– 55.
Review
33 Darley ES, MacGowan AP. Antibiotic treatment of Gram-positive bone and joint infections. J Antimicrob Chemother 2004; 53: 928– 35. 34 Dombrowski JC, Winston LG. Clinical failures of appropriately-treated methicillin-resistant Staphylococcus aureus infections. J Infect 2008; 57: 110– 5. 35 Fraimow HS. Systemic antimicrobial therapy in osteomyelitis. Semin Plast Surg 2009; 23: 90–9.
JAC 38 Dancer SJ, Robb A, Crawford A et al. Oral streptogramins in the management of patients with methicillin-resistant Straphylococcus aureus (MRSA) infections. J Antimicrob Chemother 2003; 51: 731–5. 39 Bernard P, Risse L, Bonnetblanc JM. Pristinamycin in the treatment of acute bacterial dermohypodermitis in adults. An open study of 42 patients. Ann Dermatol Venereol 1996; 123: 16 –20.
36 Anagnostakos K, Mosser P. Linezolid in the treatment of orthopaedic bone and joint infections – a systematic literature review. OA Musculoskeletal Medicine 2013; 1: 12.
40 Chanques G, Girard C, Pinzani V et al. Fatal pristinamycin-induced toxic epidermal necrolysis (Lyell’s syndrome): difficulties in attributing causal association in the polymedicated intensive care unit patient. Acta Anaesthesiol Scand 2005; 49: 721–2.
37 Gavazzi G, Barnoud R, Lamloum M et al. Pseudomembranous colitis after pristinamycin. Rev Med Interne 2001; 22: 672–3.
41 Cheng AC, Nation RL. How can we improve access to new (and old) antibiotics in Australia?. Med J Aust 2013; 199: 81 –2.
Downloaded from http://jac.oxfordjournals.org/ at Universitaetsbibliothek Muenchen on June 26, 2014
7 of 7
