Successful oral pristinamycin therapy for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA) and other Staphylococcus spp.

John Ng1 and Iain B. Gosbell1,2,*

1 Department of Microbiology and Infectious Diseases, South Western Area Pathology Service, Liverpool, New South Wales, Australia; 2 Department of Pathology, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia


* Corresponding author. Tel: +61-2-9828-5124; Fax: +61-2-9828-5129; Email: i.gosbell{at}unsw.edu.au

Received 23 December 2004; returned 24 January 2005; revised 22 February 2005; accepted 1 March 2005


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objectives: Oral treatment regimens for multiresistant methicillin-resistant Staphylococcus aureus (MRSA) infections are limited. In Australia, rifampicin plus fusidic acid is the usual treatment regimen following glycopeptide therapy but many patients are intolerant of this; some isolates are resistant; new oxazolidinones are expensive for routine use. Pristinamycin is a possible alternative and we report our experience with this agent.

Methods: The Department of Microbiology and Infectious Diseases, South Western Area Pathology Service treats patients drawn from the South Western Sydney Area Health Service that houses ~800 000 people and contains ~2000 acute care public hospital beds. Patients prescribed pristinamycin between 1 September 2000 and 31 January 2000 were identified from hospital pharmacy records. A retrospective chart review was performed. Accepted clinical definitions of osteomyelitis and septic arthritis were used.

Results: Twenty-seven patients were identified with osteoarticular infections. Twenty-four cases involved Staphylococcus aureus (multiresistant MRSA in 21 cases); three involved Staphylococcus epidermidis sensu stricto; four cases involved multiple organisms. Nineteen cases received pristinamycin monotherapy; the others received various combinations (fusidic acid with five; other antibiotics with three). Therapy was generally well tolerated; no haematological or biochemical toxicity was detected. Seven patients had minor gastrointestinal disturbance; and one developed rash. Four patients required dose reduction. Only four patients ceased pristinamycin due to intolerance. Treatment outcome was evaluated in 23 cases; cure was effected in 16 cases, five were successfully suppressed and two failed. There were no deaths.

Conclusions: Oral pristinamycin is well tolerated and an important additional agent to treat osteoarticular infections with multiresistant MRSA and other staphylococci.

Keywords: oral antimicrobials , staphylococcal infections , streptogramins


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Methicillin-resistant Staphylococcus aureus (MRSA), particularly if multiresistant, is an increasing cause of nosocomial infection.1,2 At the Liverpool Hospital, the strain of MRSA is typically resistant to macrolides, tetracyclines, clindamycin, aminoglycosides, quinolones and sulfamethoxazole/trimethoprim but susceptible to glycopeptides, quinupristin/dalfopristin, linezolid, rifampicin and fusidic acid. For osteoarticular infections, the usual regimen is rifampicin plus fusidic acid after parenteral glycopeptide. Since 2000 at the Liverpool Hospital, there has been limited use of pristinamycin as an oral alternative, mainly for the treatment of MRSA infection but also for other staphylococcal infections. Pristinamycin is not licensed in Australia and must be obtained from overseas under the Special Access Scheme.

Pristinamycin is a mixture of water insoluble pristinamycin IA and pristinamycin IIA, derived from Streptomyces pristinaespiralis. The former is a group B streptogramin (a peptidic macrolactone or depsipeptide) whereas the latter is a group A streptogramin (a polyunsaturated macrolactone).3 Separately, group A and group B streptogramins are bacteriostatic by reversible binding of the 50S subunit of 70S bacterial ribosomes. Together, however, streptogramins from each group are synergic and bactericidal.4 The conformational change induced by the binding of group A streptogramins to 50S produces an increased affinity for group B streptogramins that consequently bind irreversibly. In the resulting complex, the group A streptogramin prevents peptide bond formation during the chain elongation step of protein synthesis whereas the group B streptogramin causes the incomplete peptide chain to dissociate from the 50S ribosomal subunit.

Pristinamycin is active mainly against Gram-positive bacteria, specifically staphylococci and streptococci. However, Neisseria spp., Mycoplasma spp., Ureaplasma spp., Chlamydia spp. and Haemophilus influenzae are also susceptible.57 Enterococci are typically resistant to group A streptogramins and consequently have reduced susceptibility to streptogramin combinations such as pristinamycin.8 Pristinamycin is generally well tolerated and its most common side effects are gastrointestinal disturbance (anorexia, nausea, vomiting, epigastric discomfort and diarrhoea), glossitis as well as rash. This report describes the Liverpool Hospital experience of using pristinamycin in osteomyelitis and septic arthritis.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
All patients were derived from the Liverpool Hospital, which is a 450 bed, tertiary referral centre and teaching hospital for the University of New South Wales, Australia. Patients prescribed pristinamycin were identified from hospital pharmacy records in the period from 1 September 2000 to 31 January 2004. Pristinamycin was not used at Liverpool Hospital prior to this period. Medical records of identified cases were reviewed regarding age, gender, infection site, blood tests, microbiology, radiology, nuclear medicine scans, operation reports, antibiotic therapy, indications for pristinamycin, complications, clinical outcomes and mortality. An infection site was defined as osteomyelitis based on a typical clinical picture (fever, pain, local inflammatory signs) and either a positive sterile site culture, a positive nuclear medicine scan (bone, gallium or white cell scan), a characteristic radiological picture (radiolucent lesions) or a sinus/ulcer that clinically extended to bone in the absence of a more likely alternative diagnosis. Accepted sterile site cultures included blood, joint fluid or surgical specimens. An infection was defined as septic arthritis based on a typical clinical picture and a positive culture of either joint fluid or a surgically collected, joint specimen in the absence of a more likely alternative diagnosis.

Clinical isolates were identified initially from their characteristic morphological features using standard microbiological techniques and subsequently based upon their biochemical reactions using an automated system (GPI cards, Vitek 2 system; bioMérieux, Hazelwood, MO, USA). Antibiotic susceptibilities were determined using the accepted NCCLS methods.9 MRSA isolates were defined as multiresistant if resistant to ≥ 3 non-ß-lactam antibiotics. Pristinamycin susceptibility is not standardized using the NCCLS methods and instead, quinupristin/dalfopristin susceptibility was used as a surrogate. During the study period, multiresistant isolates of MRSA were also tested for pristinamycin susceptibility using the ATB Staph strip (bioMérieux). This was not routinely done for other Gram-positive isolates (non-multiresistant MRSA, methicillin-susceptible S. aureus, S. epidermidis). The pristinamycin used was ‘Pyostacine’ from Rhone-Poulenc Rorer. The literature was reviewed using the Medline database.

Patients were included in this study if given pristinamycin for osteomyelitis or septic arthritis meeting the above definitions and due to a Staphylococcus spp. Patients were excluded from the study if pristinamycin was not administered despite being prescribed, if non-compliant with pristinamycin therapy for reasons other than drug intolerance or if pristinamycin was given for soft tissue infection only. Outcomes were categorized as cure, probable cure, suppressed infection or failure. Cure was defined as absence of clinical evidence for ongoing infection with normal or falling inflammatory markers (erythrocyte sedimentation rate and C-reactive protein) off antibiotic treatment at last follow-up. Probable cure was defined as absence of clinical evidence for ongoing infection with normal or falling inflammatory markers at last review plus no known relapse after antibiotic cessation but no actual follow-up off antibiotic treatment. Suppressed infection was defined as either reduced infective symptoms, improved signs of infection or falling inflammatory markers without evidence of disease progression while on ongoing pristinamycin therapy at the time of this study. Failure was defined as evidence of disease progression while on antibiotic therapy. Outcome was not assessed if pristinamycin was ceased due to drug intolerance.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Thirty-two patients were identified and their medical records extracted. One individual was excluded because pristinamycin was not given despite having been prescribed. Another was not included due to general non-compliance without evidence of intolerance to pristinamycin. This manifested as refusal to follow recommended treatment or to attend outpatient clinic for medical review. One case was excluded for infection not involving a Staphylococcus spp. Two other cases affected soft tissue alone and therefore were not included. Twenty-seven cases were used in this study comprising eight females and 19 males. Mean age was 58 years but the age range was wide from 18 to 81 years.

There were twenty-two patients with osteomyelitis and five patients with septic arthritis. Seven osteomyelitis infections involved prosthetic material with internal fixation devices (Table 1). In four of these (cases 2, 11, 20, 24), the prosthetic material was removed therapeutically while in three infections (cases 7, 19, 25), treatment was given with retention of the prosthetic material. All five septic arthritic infections involved prosthetic material (Table 1). Only one of these (case 26) underwent a two stage joint revision as part of therapy whereas the remainder (cases 1, 21, 22, 27) were treated with no surgical intervention. Of the 15 osteomyelitis infections without prosthetic devices, four (cases 5, 8, 10, 12) had surgical debridement with one of these (case 8) undergoing four operative procedures. All patients had received initial antibiotic therapy with either vancomycin or teicoplanin (mean duration 33 days; range 24–56 days).


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Table 1. Details of infections, treatment durations and outcomes

 
Twenty-one of 27 cases (78%) were due to multiresistant MRSA susceptible to vancomycin, linezolid and quinupristin/dalfopristin but resistant to macrolides, tetracyclines, clindamycin, aminoglycosides, quinolones and sulfamethoxazole/trimethoprim. Most multiresistant MRSA isolates were also susceptible to rifampicin and fusidic acid but as indicated in Table 1, some isolates were resistant to one or both antibiotics. In the six patients who did not have infection with multiresistant MRSA, one (case 1) had a non-multiresistant MRSA that was susceptible to vancomycin, quinupristin/dalfopristin, erythromycin, clindamycin, tetracycline, gentamicin, sulfamethoxazole/trimethoprim, rifampicin and fusidic acid but resistant to ciprofloxacin. There were three prosthetic, osteoarticular infections due to Staphylococcus epidermidis (cases 25, 26, 27). The isolate in case 25 was susceptible to vancomycin, rifampicin and fusidic acid but resistant to flucloxacillin, erythromycin, clindamycin, gentamicin and ciprofloxacin. The isolate in case 26 was susceptible to vancomycin, quinupristin/dalfopristin, pristinamycin, linezolid, rifampicin and fusidic acid but resistant to flucloxacillin, erythromycin, tetracycline and gentamicin. The isolate in case 27 was susceptible to vancomycin, pristinamycin, linezolid, erythromycin and fusidic acid but resistant to flucloxacillin and rifampicin. The two isolates of methicillin-susceptible S. aureus were both resistant to penicillin alone. Four patients had infection due to multiple microorganisms including Pseudomonas aeruginosa, Escherichia coli, Corynebacterium jeikeium and mixed anaerobes.

In seven cases (26%), pristinamycin was prescribed because of a microbiological isolate resistant to other available oral antibiotics (resistant to rifampicin, fusidic acid or both). In 20 instances (74%), pristinamycin was prescribed as a result of side effects to other antibiotics. These included eight patients with gastrointestinal disturbances due to fusidic acid; five allergic rashes from rifampicin; Stevens Johnson syndrome from clindamycin given to patient 23 because of known ß-lactam anaphylaxis; two cases of rifampicin-induced hepatitis; two rifampicin interactions with warfarin; one behavioural disturbance attributed to combined rifampicin plus fusidic acid; a single instance of peripheral neuropathy due to linezolid. The dose of pristinamycin given in each individual was either 0.5 g or 1.0 g three times per day by mouth.

Pristinamycin side effects (Table 1) occurred in 8/27 (30%) cases. Seven of these side effects were gastrointestinal disturbances (26%) with but one instance of allergic rash (4%). The latter resulted in cessation of the drug. With respect to gastrointestinal disturbance, a dose reduction of 1 g to 500 mg three times a day by mouth in 4/7 cases enabled the pristinamycin to be continued. In total, 4/27 patients (15%) were intolerant of pristinamycin and were therefore not included in the assessment of clinical outcomes. Cure was achieved in 9/23 (39%) cases and a further seven patients were probably cured of their infections but were not followed after pristinamycin cessation to confirm a sustained clinical response; 5/16 (31%) instances of cure or probable cure had concurrent therapy with other antimicrobial agents as indicated in Table 1. Polymicrobial infection was the reason for multiple antibiotics in one case. Where cure was successful, mean follow-up was 7 months after stopping all antibiotics (range 3–13 months). Another five infections were adequately suppressed on pristinamycin therapy only at the time of this study (mean 6 months duration) with no evidence of active infection (Table 1). In only 2/23 (9%) cases did infection progress on pristinamycin treatment resulting in clinical failure. There were no deaths in this study.


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The majority of microbiological isolates in this article, including all the multiresistant MRSA infections, were resistant to erythromycin plus clindamycin and hence possibly of the macrolide/lincosamide/streptogramin group B (MLSB) resistance phenotype. In studies of quinupristin/dalfopristin, resistance to quinupristin (but not dalfopristin) with the MLSB phenotype does not affect the minimal inhibitory concentration (MIC) although bactericidal activity appears to be diminished.10,11 In the present series, this did not translate into clinical resistance towards pristinamycin. Although > 95% of European erythromycin-resistant MRSA strains were of the MLSB phenotype,12 only 35 of 3052 European S. aureus strains collected by European SENTRY surveillance were resistant to quinupristin/dalfopristin.13 Likewise, MRSA resistance to pristinamycin has remained surprisingly low. In France, where pristinamycin has been administered therapeutically for over four decades, recent susceptibility rates are 98% in the community,14 and 93% in hospitals15 for MRSA isolates. In contrast, an older study from the 1980s that included 106 strains of MRSA from 21 different countries, reported that 100% of isolates were susceptible to pristinamycin.16

In this case series, the rate for gastrointestinal side effects was 26%, the rate for rash was 4% and there were no examples of glossitis. Moreover, 15% had to stop taking pristinamycin due to these side effects. These figures are higher than the 14% gastrointestinal side effects, 2% rash and 3.6% discontinuation rates described in the one, recent, published, clinical report of MRSA infections managed using pristinamycin.17 These differences may be explained by the observation that 74% of the patients in this study had already exhibited antibiotic intolerance to other agents prior to commencing pristinamycin. Moreover, prolonged therapy with pristinamycin was required to treat these osteoarticular infections resulting in a longer period for side effects to develop. In this report, gastrointestinal disturbance was dose-dependent and 85% of cases were tolerant of pristinamycin therapy.

This study found a total, combined cure plus probable cure rate of 70% (16/23) for pristinamycin therapy with an equivalent value of 59% (13/22) for pristinamycin management of MRSA infections specifically. This contrasts with the recent figure of 87% in a published report of 56 soft tissue infections with MRSA treated using a combination of pristinamycin and doxycycline (if the MRSA isolate was susceptible).17 Although most patients in the current review received pristinamycin alone, variation in antibiotic regimen cannot account for discrepancies in cure rate since in the cited report, there were similar outcomes for those receiving pristinamycin with or without doxycycline. Different definitions of the various outcomes (cure, failure, etc.) were used. However, the dissimilarities in cure rate are most probably related to disparate study populations. In the present case series, almost all the examined patients had osteoarticular infections, some involving prosthetic material. Figures for failure of pristinamycin treatment are low in both studies with a value of 9% from the Liverpool case series versus 6% in the published paper.17 In our series, pristinamycin monotherapy was used in the majority of cases rather than combination therapy with doxycycline/pristinamycin,17 with success and without development of resistance. We treated osteoarticular infections, many involving prosthetic material that can be notoriously difficult to treat, with a satisfactory cure rate. Only 1/56 cases in the Dancer et al.17 series was a bone or joint infection.

The paucity of effective antimicrobial agents to treat multiresistant MRSA infections has generated the need for alternative therapeutic options. Yet despite its availability since the 1950s, there are few data regarding the use of pristinamycin outside the French literature.18 This study outlines the experience of treating infections using the unlicensed antibiotic pristinamycin at the Liverpool Hospital. This observational case series is retrospective in nature and lacks controls. Consequently, clinical follow-up was incomplete, follow-up specimens to test for microbiological cure were not available and clinical information could not be standardized. However, one can conclude that pristinamycin is a viable option to treat multiresistant MRSA osteoarticular infections including those that involve prosthetic material. In addition, pristinamycin was well tolerated, unlike combination rifampicin/fusidic acid—in fact most of our patients were on pristinamycin due to intolerance of these agents. Although the oxazolidinones offer comparable efficacy to vancomycin,19 these agents are expensive. At the Liverpool Hospital, the acquisition cost of linezolid is $A122 per 600 mg tablet versus $A4 per 500 mg tablet for pristinamycin. Apart from being expensive, linezolid also has significant issues with myelosuppression and peripheral neuropathy, especially if used for prolonged periods, such as is required for osteoarticular infections. Although further prospective studies comparing the use of pristinamycin with other agents for the treatment of MRSA should be performed, we recommend pristinamycin as a treatment option for staphylococcal osteoarticular infections.


    Acknowledgements
 
This research was unfunded.


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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
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8 . Brumfitt, W., Hamilton-Miller, J. M. T. & Shah, S. (1992). In-vitro activity of RP 59500, a new semisynthetic streptogramin antibiotic against Gram positive bacteria. J Antimicrob Chemother 30, Suppl A, 29–37.[ISI][Medline]

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11 . Fantin, B., Leclercq, R., Merle, Y. et al. (1995). Critical influence of resistance to streptogramin B-type antibiotics on activity of RP 59500 (quinupristin-dalfopristin) in experimental endocarditis due to Staphylococcus aureus. Antimicrob Agents Chemother 39, 400–5.[Abstract]

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