9 The Role of Suppressive Surgery
E. Concia, A. Tedesco
Department of Infective Disease, University of Verona, Italy
Introduction
The main aim of treating joint prosthesis infections is to eradicate the infection in order to obtain a functional and non-painful joint. Generally, infections are eradi- cated with a combined surgical and pharmacological treatment, removing the for- eign body and prescribing an appropriate antibiotic therapy.
In managing post-prosthetic infections the main treatment options include debridement without removal of the prosthesis, one-stage or two-stage replacement of the prosthesis, permanent removal of the implant, arthrodesis and finally a sole long-term antibiotic therapy.
Main
The sole long-term antibiotic therapy (named suppressive therapy), without the combined surgical intervention in the implant site, is able to control the clinical symptoms but it rarely eradicates the infection. Indeed, in most patients clinical symptoms of infection reoccur after the suspension of the antibiotic therapy [12].
Suppressive antibiotic therapy is considered when the surgical treatment is not advised. This occurs for example if the patient has an intolerance to anaesthesia, if the removal of the prosthesis is technically too difficult, if there is a high morbidity or there are unacceptable risks for the patient or surgeon, if there is no need for the pros- thesis to be functional (i.e. the patient is confined to bed or is very old), if the patient refuses the operation, if there are difficulties in removing non-mobile and well- placed prostheses and when the infection is not very virulent and is sensitive to the oral antibiotic therapy [10, 12, 15].
In general, the suppressive antibiotic therapy should be ideally conducted with antibiotics that have a bactericidal action, an antimicrobic activity spectrum against microorganisms that adhere to surfaces, a slow growth and produce biofilm. How- ever, for infections associated to joint prostheses, standard antimicrobial sensitivity tests cannot be used to predict the result in a reliable way [16].
From an etiological point of view, post-prosthetic infections are mainly caused by staphylococci (45 – 55 %), particularly S. aureus (33 – 43 %) and coagulase-negative staphylococci (17 – 21 %). However, other microorganisms can be involved such as streptococci (11 – 12 %) and more rarely Gram-negative bacteria (5 – 14 %), entero-
cocci and anaerobes. In 5 – 13 % of cases mixed flora is found, while in 5 % of infec- tions no microorganism is isolated [6, 7].
From a pathogenic point of view, the bacterial situation (due to their chronic characteristics and the difficulty of eradication with antibiotic therapies) are similar to typical diseases caused by the local biofilm production. In the biofilm, germs become capable of producing great quantities of polysaccharide polymers (glicoca- lyx). They reproduce into microcolonies at a very low speed and are aware of their density, triggering off (at very high concentration levels) a synthesis of various viru- lent factors. For this reason, biofilm is a survival mechanism with which microbes are able to resist the host’s internal and external environmental factors, such as anti- biotic agents and the immunity system. Due to these physiological situations, which are very different from those that dominate bacterial multiplication in biological liq- uids and in culture media, sensitivity to antibiotics is very limited thus creating some inconsistencies between the antibiogram data and the real in vivo situation [3].
In studies performed on animal infection models in which prosthetic infection was caused by S. epidermidis it was analysed the efficacy of different antibiotics. It was noted that fluoroquinolones monotherapy (like Ciprofloxacin) has a low efficacy, but this rises to 90% if combined with rifampicin. It was also noted that during high-dose monotherapy, rifampicin has a high efficacy. Good results were also obtained by the combination of daptomycin and netilmicin, as opposed to daptomycin monotherapy.
Poor results were, instead, achieved using glycopeptide monotherapy: however, if vancomycin is combined with netilmicin it becomes more effective [13].
Therefore, among the antibiotics indicated for implant-releated staphylococcal infections, rifampicin not only has a good bioavailability and an excellent anti-staph- ylococcal activity but it also has an excellent penetration of soft tissues, bone, abscesses and polymorphonucleates. It also succeeds in eradicating organisms that adhere to prosthetic surfaces during a steady growth stage. However, the use of rifam- picin is limited both by the rapid development of resistance (therefore it must always be combined with another antibiotic) and by patients’ poor tolerability to the antibi- otic’s toxic effects (such as nausea, hepatic disorder) and to the various other phar- maceutical interactions [4].
Last generation fluoroquinolones (such as moxifloxacin and levofloxacin) that have recently been introduced in clinical practice present lower MICs in vitro than ciprofloxacin in the presence of Gram-positive microorganisms. However, data regarding their penetration and efficacy in bone infections are still not available. Fur- thermore, the resistance of nosocomial staphylococci to quinolones has dramatically increased. At the moment, 90% of nosocomial methicillin-resistant S. aureus (MRSA) are also resistant to quinolones [4, 12].
Clinical studies show that the use of rifampicin and fluoroquinolones as a mono- therapy cure orthopaedic implant infections associated to staphylococci, but most of the treatments fail due to the emergence of antibiotic-resistant isolates. The associa- tion of fluoroquinolones and rifampicin is a highly effective in eradicating implant- associated staphylococci and in preventing the emergence of ciprofloxacin-resistant starins. This association has also the advantage of an excellent oral bioavailability of both active principles, which reach serum concentrations comparable to those obtained during intravenous therapy. High levels of intracellular penetration and activity against intracellular staphylococci are also obtained [2, 17].
74 Orthopaedic Device-related Infections
Fusidic acid is another oral antibiotic used in association with rifampicin, even though It is less effective against oxacillin-resistant and quinolones-resistant staphy- lococci, but reaches high intracellular concentrations. Bactericidal concentrations have also been obtained in bone infections. However, if used as a monotherapy it rap- idly selects resistant bacteria. On the other hand, as shown by in vitro studies, the association of fusidic acid and rifampicin seems to prevent the selection of staphylo- cocci resistant to other antibiotics [5].
In case of outpatient treatment of prosthetic infections caused by multi-resistant staphylococci and susceptible only to cotrimoxazole and glycopeptides, high doses of cotrimoxazole were used (trimethoprim 20 mg/Kg/day, sulphamethoxazole 100 mg/Kg/
day), obtaining an overall success rate of 66.7% (26 patients out of 39): in knee prosthesis infections the percentage was 62.5 %; in hip prosthesis infections 50 %; 60.7% of patients were treated only with suppressive antibiotic therapy without implant removal. How- ever, home oral treatment with cotrimoxazole is limited to the occurrence of side effects, such as rashes, vomit, diarrhoea, anaemia, thrombocytopenia and neutropenia [11].
Minocycline is another antimicrobial agent that can be used for the treatment of post-prosthetic infections. However, at the moment data regarding the use of this drug in implant-related infections are not available in literature.
Glycopeptides (vancomycin and teicoplanin) are the first choice antibiotics against MRSA. Vancomycin has an antibacterial activity against Gram-positive microorganisms lower than beta-lactam drugs. Furthermore, studies suggest that the administration of vancomycin by continuous i.v. infusion may be more efficient than by intermittent mode. Finally, its use is limited due higher association with nephro- toxicity, lack of oral formulas and cannot be given by bolus injection: all this discour- ages its use in suppressive therapy. Teicoplanin, instead, has a long half-life that enables its once-a-day administration, with the possibility of discharging the patient from hospital while continuing the parenteral antibiotic therapy at home, with high doses (12 mg/Kg/day). However, its use is limited by the occurrence of toxic effects such as thrombocytopenia, neutropenia, rash and fever [4, 12].
As a consequence of the above considerations, in empirical suppressive therapies of post-prosthetic infections, the association of rifampicin with a fluoroquinolone, or with fusidic acid, or with cotrimoxazole, or a monotherapy with fluoroquinolone could be an optimal solution. The possibility of a monotherapy with cotrimoxazole or minocycline has also been suggested [12].
Conclusion
In conclusion, new antibiotics that could reveal to be effective in the suppressive ther- apy of these infections are currently being studied. These are quinupristin-dalfopris- tin, linezolid, daptomycin, tigecycline, dalbavancin, RWJ-416457 (a new oxazolidi- none), BP-102 (a new carbapenemic) and new by-products of rifampicin (ABI-0043, ABI-0363, ABI-0699) [1, 12].
Instead, as far as regards infections caused by Gram-negative microorganisms, very few studies are available in literature. Some trials conducted on animal models and in vitro have shown that ciprofloxacin is more effective against Gram-negative bacilli with respect to other antibiotics [14].
9 The Role of Suppressive Surgery 75
Finally, the optimal duration of suppressive antibiotic therapies in joint prosthesis infections is still not known [8]. Long-term oral therapy can cause benefits to old- aged patients, where a surgical therapy is not recommended [9, 10]. Important crite- ria to decide the suppressive therapy must be entrusted to clinical judgement, taking into consideration risk factors, microbiological isolations, drug tolerability, clinical conditions and preferences.
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