Role of intravenous cloxacillin for inpatient infections

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www.sciencedirect.com Médecine et maladies infectieuses 42 (2012) 241–246

General review

Role of intravenous cloxacillin for inpatient infections Place de la cloxacilline intraveineuse chez les patients hospitalisés J.P. Bru a,∗ , R. Garraffo b a

Service des maladies infectieuses, centre hospitalier régional d’Annecy, 1, avenue de l’Hôpital, Metz-Tessy, BP 90074, 74374 Pringy cedex, France b Service de pharmacologie et toxicologie cliniques, faculté de médecine, hôpital Pasteur, CHU de Nice, 06002 Nice cedex 1, France Received 24 May 2011; accepted 20 October 2011 Available online 27 April 2012

Abstract One of the issues of antibiotic treatment is to warrant its optimal effectiveness while minimizing the risk for emergence of resistance. The time above minimal inhibiting concentration (MIC) (T > MIC) is the best predictive pharmacological parameter of effectiveness for antibiotics with timedependent activity, such as cloxacillin. Cloxacillin is the first line antibiotic in a great number of clinical situations generated by methicillin sensitive staphylococci, because of its intrinsic properties: bactericidal effect, tissue distribution and safety. The most recent anti-staphylococcal agents do not improve treatment of MSSA infections compared to penicillin M and especially cloxacillin. Cloxacillin has a narrow microbiological spectrum. This ecological feature is in line with the recommendation to use antibiotics with the narrowest spectrum to reduce the pressure of selection. The consensus is to have T > MIC for at least 40% of the dosing interval and is achieved by infusing 2 g of cloxacillin per day (T > MIC = 50%) or four infusions of 3 g per day (T > MIC = 42%) in adults. © 2012 Published by Elsevier Masson SAS. Keywords: Cloxacillin; MSSA; PK/PD relationship

Résumé Les préoccupations en matière de traitement antibiotique restent plus que jamais de garantir leur efficacité optimale tout en minimisant le risque d’apparition de résistance. Pour les antibiotiques dont l’activité est temps-dépendante comme la cloxacilline, le temps au-delà de la concentration minimale inhibitrice (CMI) (T > CMI) est le paramètre pharmacologique qui prédit le mieux l’efficacité. Les qualités intrinsèques de la cloxacilline — bactéricidie, diffusion tissulaire, tolérance — en font un antibiotique de choix dans un grand nombre de situations cliniques dues aux staphylocoques méticilline sensibles. Les molécules antistaphylococciques les plus récentes n’apportent rien par rapport aux pénicillines M et à la cloxacilline en particulier dans le traitement des infections dues à SAMS. La cloxacilline a un spectre microbiologique étroit. Cet avantage écologique lui permet de répondre à la recommandation d’utiliser les antibiotiques ayant le spectre le plus étroit possible pour réduire la pression de sélection. L’objectif consensuel d’un T > CMI d’au moins 40 % de la période entre deux doses est atteint avec l’administration de six perfusions de 2 g de cloxacilline par jour (T > CMI = 50 %) ou quatre perfusions de 3 g par jour (T > CMI = 42 %) chez l’adulte. © 2012 Publié par Elsevier Masson SAS. Mots clés : Cloxacilline ; Relation PK/PD ; SAMS

1. Introduction Staphylococcal infections are frequent and their implication in some diseases such as infective endocarditis is increasing

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Corresponding author. E-mail address: [email protected] (J.P. Bru).

0399-077X/$ – see front matter © 2012 Published by Elsevier Masson SAS. doi:10.1016/j.medmal.2011.10.015

[1,2]. Their management is, thus, a current issue, especially since some of these are associated to healthcare. Antibiotic stewardship seems to lead to encouraging results. A decreased prevalence of infections due to bacterial resistance has been reported, especially concerning Staphylococcus aureus. Antibiotic stewardship suggests using fewer antibiotics and when necessary with a narrower spectrum, while maintaining effectiveness and safety for patients.

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Cloxacillin (Orbenine® ) IV, studied in this review, is one of the most frequently used antibiotics, especially interesting for the treatment of S. aureus infections susceptible to methicillin (MSSA). Its characteristics correlate to the antibiotic stewardship policy. 2. Cloxacillin IV: pharmacological data 2.1. New pharmacological criteria The choice of an antibiotic used to be partly empirical, relying on the susceptibility of the strain measured by an antibiogram and the principle of a maximal well-tolerated dose. The physician’s personal experience was crucial. In the 1990s, a reasoned management of antibiotic use based on other criteria appeared to become necessary because of the increasing percentage of treatment failure and the decreasing availability of new antibiotics, especially with novel mechanisms of action. Animal models, especially those developed by Craig and his team, allowed documenting the pharmacological characteristics of antibiotics and determining a set of pharmacodynamic criteria (associating pharmacokinetics and assessment of antibacterial effectiveness of an antibiotic) (PK/PD criteria) to update prescription guidelines for rational dosage and administration mode of antibiotics (Fig. 1) [3]. The minimal inhibiting concentration (MIC) and the minimal bactericidal concentration (MBC) were, for a long time, the main parameters used to quantify the antibacterial activity of a treatment against a given bacterium. But, because they are measured at the end of the assay, they do not adequately reflect antibiotic/bacterium interaction, because they do not provide any information on the antibacterial activity of an antibiotic in the long run, activity that may greatly vary from one agent to the next [3,4]. Bactericidal antibiotics, such as cloxacillin, may be separated in two groups depending on whether their activity is concentration-dependent or time-dependent. In case of a concentration-dependent bactericidal activity, the higher the antibiotic concentration is, the faster and the stronger its bactericidal action will be (true for aminoglycosides and fluoroquinolones). Because of their mechanism of action (blocking of PK/PD criteria AUIC = ASC/CMI Cmax/MIC T>MIC QI (Cmax/MIC) PAE (post-antibiotic effect)

Concentration (Log)

Cmax

AUIC MIC T>MIC

PAE Time (T)

Fig. 1. PK/PD criteria for antibiotic use. Critères PK/PD pour l’utilisation des antibiotiques.

protein synthesis participating in key stages of the bacterium’s life), most of these antibiotics also present a significant postantibiotic effect with persistent inhibition of bacterial growth, even after antibiotic concentrations in the medium has become sub-inhibiting or even, undetectable. In this case, the inhibiting quotient (IQ = Cmax /MIC) and area under the inhibiting curve (AUIC = AUC/MIC) are the pharmacodynamic parameters used to predict the effectiveness and, in some case, the selection of resistant mutants, in vivo. Increasing the concentration beyond a given threshold does not significantly improve bactericidal activity in the case of antibiotics with a time-dependent bactericidal activity (such as beta-lactams). Nevertheless, because of their mechanism of action inhibiting bacterial wall construction, the effectiveness depends essentially on the bacteria’s time of exposure to antibiotic. In this case, the post-antibiotic effect is often weak or non-significant. Optimizing the therapeutic regimen for this antibiotic family can be done by maximizing the time of bacterial exposure to antibiotic. This is why the time during which the antibiotic serum concentration is higher than the MIC between two successive administrations (T > MIC) is the PK/PD parameter that best predicts the therapeutic effectiveness in vivo [3–5]. The current consensus is that this time should be at least 40% of the period between two successive doses and that it should be all the more extended that the infection is severe, so as to result in a maximum of bactericidal activity to reach a 100% spectrum. Increasing the dose at each injection to reach this level is not very effective for antibiotics with a very short elimination half life, such as most beta-lactams including cloxacillin. Indeed, the expected gain for T > MIC will be equal, in this case, to the value of a half life (inferior to one hour for cloxacillin), but increasing the frequency of administration should be more effective to reach T > MIC superior to 40% of time between two successive administrations [3]. Nevertheless, the antibacterial spectrum, from the bacteriological point of view and the extravascular and tissue diffusion profile of antibiotics in humans, from the pharmacokinetic point of view, remain essential parameters when choosing the treatment for an infection. They are a mandatory prerequisite to optimize antibiotic therapy. It is indeed crucial that the selected antibiotic reaches the infectious focus, in situ, in adequate quantity and duration to be effective. 2.2. Pharmacokinetic and pharmacodynamic characteristics of cloxacillin IV The antibiotic cloxacillin belongs to group M penicillins, which confers its resistance to penicillinases produced by S. aureus. The susceptible species are MSSA, S. pyogenes, and Clostridium perfringens [6]. The diseases, it is used for, may be severe, the most frequently used administration route in hospital is IV because of its fast action and because it prevents any potential problems of antibiotic resorption. The latter point is especially important for cloxacillin, the oral resorption of which varies from one patient to the next, with a mean value of 70% [6]. After a 20-minute IV infusion of 2 g of cloxacillin, the maximum serum concentration (Cmax ) reaches around 280 mg/L and

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100 mg/L if the infusion is 30 minutes long [7]. Its protein binding level in plasma reaches 90%. Cloxacillin diffuses in the skin and soft tissues all the way to bone tissue and synovial fluid even though its apparent volume of distribution is weak, close to 10 L [8]; it also diffuses to fetal blood and the amniotic fluid in the placenta [6]. After its IV administration, it is not metabolized and it is actively eliminated mostly via the urinary tract (70–80%) and in a lesser part via the biliary tract (20-30%). Its elimination half-life is short, from 30 to 40 minutes; this requires frequently renewing daily administrations according to PK/PD constraints and reaching a serum level beyond the MIC at least 40% of the time. According to recent data, the cloxacillin MIC for MSSA ranges between 0.125 and 0.5 mg/L [9]. Given its strong binding with plasmatic proteins (around 10% only of free fraction), the required percentage of time beyond the MIC (>40%) is obtained with six infusions of 2 g of cloxacillin per day (T > MIC = 50%) or four infusions of 3 g of cloxacillin per day (T > MIC = 42%) in adults [9]. This dose is recommended by experts for severe infections such as infective endocarditis (12 g/d in four to six injections [1]) and prosthetic bone and joint infections (100 to 200 mg/kg per day in four to six injections, [10]). 2.3. Potential value of continuous infusion administration Continuous infusion administration of ␤-lactams, and more specifically of cloxacillin, is logical from the pharmacodynamic point of view since it allows compensating the very short half life elimination of most of the agents in this family, thus facilitating keeping serum levels above the MIC, an essential parameter for the effectiveness of these antibiotics. Furthermore, from a practical point of view, it prevents renewing infusions at regular intervals. The frequent use of central catheters in the severe diseases mentioned in this review should facilitate its implementation. Nevertheless, experience shows that using this mode of administration is justified only for patients presenting with a severe infection considering the bacterium and/or the patient’s comorbidities. In other cases, the usual treatment regimen is well adapted. 3. Cloxacillin IV: microbiological features 3.1. Antimicrobial spectrum of cloxacillin Cloxacillin, active principle Orbenine® , has a narrow spectrum activity, coherent when considering clinical presentations, with some targeted species on which its bactericidal activity has been widely demonstrated for several years. It is active against most S. aureus and a large proportion of coagulase negative meti-S staphylococci (MSCNS) [11,12]. It is resistant to the hydrolysis of penicillinases produced by 90% of S. aureus and thus remains effective on this bacterium. It is also active on a S. pyogenes (especially on groups A, C, G causing skin infections), and on C. perfringens [11]. Its mechanism of action is based on its binding with enzymes implicated in the synthesis of peptidoglycan, main constituent of the bacterial wall [13].

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The stability of intrinsic cloxacillin activity in time should be noted. Indeed, no modification of MIC for MSSA is noted in time; it ranges between 0.125 and 0.5 mg/L, according to the most recent data. This parameter is reassuring and supports the favourable ecological considerations associated with this agent; but it is worrying to note the progressive increase of glycopeptide MICs, including vancomycin, for MRSA. 3.2. Methicillin resistance of staphylococci The emergence of resistance is a permanent concern for antibiotic prescription. Resistance may result either from chromosomal mutations (modification of genes already present), or from the integration of plasmids (small strands of circular DNA which are transmitted from bacterium to bacterium) [14]. Resistance is responsible for therapeutic failure and their impact on the management of infections is considerable. It is currently estimated that 25,000 patients die every year from an intractable nosocomial infection in Europe [15]. The yearly cost of infections due to resistant bacteria is estimated at 1.5 billion euros [15]. Staphylococci resistant to oxacillin have acquired the mec gene that allows synthesizing synthesis an enzyme (PLP2a or PLP2 ) with only a very low affinity for ␤-lactams, which can no longer use their inhibitory action. The risk factors for resistance are hospitalization, including in healthcare institutions for old people, age and exposure to an antibiotic in the four to six months before the infection [16]. The repeated administration of antibiotics creates a selection pressure which tends to promote plasmid exchanges and, thus, to eliminate susceptible bacteria and leave resistant bacteria [14]. 3.2.1. Epidemiology of Staphylococcus aureus resistance to methicillin in France Resistance to methicillin differs widely depending on hospital or community acquisition. 3.2.2. Staphylococci acquired in hospital environment The resistance of staphylococci acquired in hospital has greatly changed. In France, its prevalence has significantly decreased in the last 15 years, thanks to a better management of antibiotic therapy (national antibiotic plans 2001–2005 then 2007–2010) and to the effective implementation of measures to prevent healthcare associated infections [17]. In the Paris hospital short-stay units, the mean percentage of MRSA decreased from 39.4% in 1993 to 18.9% in 2009 [18]. In 1993, in the ICU, surgical and medical wards, the proportions of MRSA were respectively 55.1%, 36.7% and 33,1%; in 2009, they had decreased to 20%. But, in long stay and rehabilitation units, the prevalence of MRSA did not follow the same trend and remained present in 57.7% of samples in 2009 [18]. Thus the percentage of cloxacillin susceptible strains ranges between 75 and 80% of isolated strains, as described in the most recent data concerning the largest French hospitals. Of course, there are territorial heterogeneities and the local epidemiological data should be taken into account when choosing first line antibiotics.

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3.2.3. Community acquired staphylococci The prevalence of S. aureus resistance isolated from a community-acquired infection is currently rather low in France, even if it is difficult to find reliable data [18–21]. Community acquired MRSA have two origins: diffusion from the hospital reservoir and strictly community acquired MRSA. The North-American region is currently quite concerned by the diffusion of a methicillin resistant S. aureus clone (USA300) highly pathogenic because secreting Panton and Valentine leukocidin. This clone, or a similar clone, does not seem to be implanting in Europe, but reasons for this remain unclear [22,23]. A S. aureus responsible for a community acquired infection will probably be susceptible to methicillin, currently in France, if the patient does not present one or several of the previously mentioned risk factors. This is what was suggested in a French study in which only 36 patients (11%) of the 313, presenting with community-acquired MRSA infections, had not been exposed to hospital or individual risks [24].

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3.3. Ecological profile of cloxacillin • There is little published data on the ecological consequences of cloxacillin. Nevertheless, it is possible to refer to the risk presented by Clostridium difficile infection, a very informative model on the ecological consequences of antibiotics. Narrow spectrum penicillins seem to present a weak risk for diarrhea associated with C. difficile. A systematic literature review published in 1998 [25] evaluated the risk for diarrhea associated with C. difficile depending on the antibiotic used. Penicillins M seemed to present one of the weakest risks (OR 3.2; CI95% 1.7–6.2), close to that of vancomycin (3.1; 1.8–5.2), and much lower than broad spectrum antibiotics such as quinolones (8; 4.5–14.3), the amoxicillin/clavulanic acid combination (22.1; 6.5–75.4), or cefotaxim (36.2; 19.0–68.9). This data is convincing and using antibiotics with the narrowest possible spectrum is mentioned in all antibiotic stewardships. Cloxacillin and its narrow spectrum exert a lesser selection pressure on bacterial flora, especially on commensal ones.

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4. Cloxacillin IV: clinical use Cloxacillin and penicillins M are the reference treatment for staphylococcal infections susceptible to methicillin [13]. Besides the above-mentioned microbiological, pharmacokinetic and pharmacodynamic pre requisites, the clinical use of cloxacillin relies on the following considerations: • cloxacillin is currently the most effective treatment for infections due to susceptible staphylococci. Published clinical data brings convincing elements. Several authors report the superiority of penicillin M compared to glycopeptides in the treatment of severe MSSA infections; • a prospective randomized study of treatment for right heart infective endocarditis (IE) in drug-addicts mentions a significantly superior effectiveness of cloxacillin compared to a

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glycopeptide [26]. It should be noted that the vancomycin and teicoplanin regimen were not optimized according to published pharmacodynamic data. But they complied with international guidelines; failures and relapses in bacteremia associated or not to oxacillin susceptible S. aureus IE, were significantly associated to vancomycin use in several studies. Chambers reported that the cure rate for IE was 33% vs. 100% if patients were treated by vancomycin + tobramycin or penicillin M + tobramycin respectively [27]. Other authors also report an earlier negativity of hemocultures [28]. A slower bactericidal activity of vancomycin could be one of the reasons for more frequent failures associated to the use of glycopeptides compared to penicillins M [28]; the most recent anti-staphylococcal agents do not improve treatment of MSSA infections compared to penicillin M and cloxacillin, especially in the treatment of complicated or uncomplicated MSSA infections. The clinical trials comparing quinupristine dalfopristine, linezolide or daptomycin with penicillins M did not demonstrate any superiority of the newer agents [29–31]; cloxacillin is also active on streptococci and on C. perfringens, without being their referent antibiotic. This activity can allow its use in diseases due or supposedly due to bacterial associations of this type [32]; cloxacillin has a specific and narrow spectrum and the susceptibility of staphylococci varies according to strains and also with time. Prescriptions should be made after documented or having acquired a quasi certitude of the infection’s staphylococcal origin and of the strain’s oxacillin susceptibility. Cloxacillin is prescribed most often after microbiological documentation and antibiogram results. But it is not excluded, if the microbiological environment is documented and favorable, to consider its use in the first intention treatment of infections presumed to be of staphylococcal origin [32]. This may be applied to the French situation, because methicillin resistance of community-acquired S. aureus is currently very low, as specifically as mentioned above, if the patient does not present any risk factors [19,20,22]; the clinical regimen for cloxacillin is important to warrant its effectiveness. The importance to take into account pharmacodynamic datas has been confirmed during clinical use A dose of penicillin M inferior to 1 g every six hours was associated to over-mortality in a retrospective study of 186 MSSA bacteremia [33]. The pharmacodynamic data suggests that administration of betalactams in continuous infusion optimizes their effectiveness. In a recent retrospective study [34], the authors compared 78 patients presenting with MSSA IE and treated by a continuous infusion of oxacillin to 28 patients treated by repeated infusions. The death rate at D30 was identical (8% vs. 10% respectively), but the rate of microbiological eradication was significantly higher in the continuous infusion group (94% vs. 79%, p = 0.03). Data allowing the optimization of cloxacillin use would be useful and facilitate its use in ambulatory treatment; the recommended doses are 100 to 200 mg/kg per day. They depend on clinical, severity and especially diffusion

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parameters. The highest doses are recommended to treat endocarditis and bone and joint infections; • cloxacillin may be combined with several antibiotics, without drug interference. But the advantages of combinations in the treatment of staphylococcal infections should be assessed: ◦ combination with an aminoside should improve the bactericidal activity of an antibiotic therapy and improve the cure rate. But this has not been demonstrated. Ribera et al. [35] could not find any benefit with such a combination to treat right heart S. aureus endocarditis. Hughes et al. did not find any difference in cure or mortality rate between groups with gentamycin and without gentamycin in a series of S. aureus IE [34]. Nevertheless, apyrexia came in earlier in the group of patients with gentamycin (two days versus four days, p = 0.02). In every case, the duration of combination with an aminoside should remain short, except for infections on foreign material, ◦ combination with clindamycin or linezolide is recommended in some specific and severe situations, staphylococcal toxic shock syndromes, global exfoliation syndromes or severe infections with suspected secretion of Panton and Valentine leukocidin. The severity is related to the secretion of toxins by S. aureus. Clindamycin and linezolide, because of their mode of action inhibiting protein synthesis, decrease the production of toxins, contrary to beta-lactams. The clinical benefit of this regimen has not been demonstrated. It should be noted that the recommendations, in these settings, are to take advantage of cloxacillin bactericidal activity which is essential for antibiotic therapy; • there are alternatives to cloxacillin IV. Other agents have a good anti-staphylococcal activity, but none has demonstrated a superior effectiveness as injectable treatment. And their use as first intention is not recommended for various reasons. Using quinolones, rifampicin or fusidic acid may induce the emergence of a resistant mutant if the bacterial inoculum is important. They can be included in the regimen after decreasing this inoculum, especially with cloxacillin, more effective. Clindamycin is not more effective in its injectable formulation. Pristinamycin does not have any injectable formulation and clinical data is weak. The intrinsic qualities of cloxacillin — bactericidal activity, tissue diffusion, tolerance, low ecological cost — make it a choice antibiotic in a great number of cases due to oxacillin susceptible staphylococci. Its use is essential for therapeutic strategies. The other antibiotics are alternatives, the use of which is justified in case of intolerance or switch to oral administration. In an infection documented as due to an oxacillin susceptible staphylococcus, cloxacillin is recommended as first line treatment to treat most major severe infections due to this bacterium: • bacteremia whatever its origin. Infections on peripheral, central, or implanted catheters and devices are mostly dues to S. aureus or a coagulase negative staphylococcus; • infective endocarditis. A more and more important rate of native valve or prosthetic endocarditis is due to S. aureus

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[1]. It is usually responsible for acute and destructive infective endocarditis [1]. Cloxacillin is the reference treatment whatever the localization (aortic, mitral, or tricuspid) with a native or prosthetic valve. It should be administered for 4 to 6 weeks at 12 g/d in 4 to 6 injections. A short-term combination association with an aminoside is recommended, eventually complemented by rifampicin if there is any foreign material; staphylococci are major causes of bone and joint infections with or without foreign material. In 90% of case, these infections are mono-microbial. Cloxacillin IV, with good bone tissue diffusion, at doses leading to high plasma levels, is recommended by French experts (as well as oxacillin or cefazoline) combined with gentamycin or rifampicin [10]. The treatment should be a long term one, switch to the oral route may be justified; diabetic foot infections; severe skin infections and the cellulitis, including malignant staphylococcal infections of the face; staphylococcal infections, of various presentations, related to the secretion of toxins: exfoliatins, TSST-1, or Panton and Valentine leukocidin. The diseases associated to toxinogenic strains are: the disseminated exfoliation syndrome, especially the pediatric presentation, the staphylococcal toxic shock syndrome, and necrotic infections, especially cutaneous or pulmonary ones. It should be kept in mind that it is recommended to combine clindamycin or linezolide to cloxacillin; cloxacillin is recommended as surgical prophylaxis in neurosurgery, for internal CSF derivations [10].

Only some specific cases of MSSA infections justify prescribing an antibiotic other than cloxacillin or oxacillin: • in case of allergy to penicillins and only in this case, vancomycin may be used with the usual precautions for its prescription: regular control of serum levels because of its inter- and intra-individual variations, because of the risk for non-effectiveness and risk of nephrotoxicity [1,13]; • in case of meningitis, prostatitis or eye infection, an antibiotic with a better diffusion than cloxacillin in infected organs will be used. For example in meningitis, third generation cephalosporins combined to fosfomycin are recommended first-line treatments. 5. General conclusion The emergence of pathogenic bacteria resistant to antibiotics and their diffusion in human populations are one of the major infectious phenomena of the last twenty years, while the perspective of discovering new classes of antibiotics are reduced [36]. Cloxacillin IV, because of its solidly demonstrated clinical effectiveness in the treatment severe MSSA infections, its narrow spectrum, its positive pharmacodynamic characteristics and its good tolerance perfectly answers antibiotic stewardship requirements. Cloxacillin IV is recommended by the European and French experts with an administration regimen and doses taking into account the latest pharmacological criteria, for an optimal effectiveness.

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Disclosure of interest J.P. Bru is paid for conferences, clinical research activity and as expert for various laboratories (BMS, Janssen, Gilead, Astellas). R. Garaffo was given grants for giving conferences, expert advice, and performing pharmacological research for various laboratories (MSD, Gilead, Tibotec, Astellas, BMS). References [1] European Society of Cardiology (ESC). Guidelines on the prevention, diagnosis, and treatment of infective endocarditis (new version 2009). The task force on the prevention, diagnosis and treatment of infective endocarditis of the ESC. European Heart Journal. [2] Hoen B, Celard M, Alla F, LeMoing V, Doco-Lecompte T, Tattevin P, et al. Continuing changing profile of infective endocarditis. Results of a repeat one-year population based survey in France (IE2008). In: 50e ICAAC; Boston 2010; K-2166. [3] Craig WA. Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 1998;26:1–12. [4] Cars O. Efficacy of beta-lactam antibiotics: integration of pharmacokinetics and pharmacodynamics. Diagn Microbiol Infect Dis 1997;27:29–33. [5] Frimodt-Moller N. How predictive is PK/PD for antibacterial agents? Int J Antimicrob Agents 2002;19:333–9. [6] Mentions légales orbénine gélules, IV (ML amalgamées Orbénine® 2011-2/Mai 2011). http://www.afssaps.fr/content/search?SearchText= oxacilline&ok=Valider. [7] Bergan T, Oydvin B. Cross-over study of penicillin pharmacokinetics after intravenous infusions. Chemotherapy 1974;20:263–79. [8] Mattie H, De Marie S, Slaghuis G, Rozing PM, Van Strijen E. Diffusion of cloxacillin into synovial tissue. Br J Clin Pharmac 1992;34:275–7. [9] Odenholt I. Prediction of individual antibiotic dose in the clinic. www.worldpharma2010.org/pp/W29.2.pdf. [10] Société de pathologie infectieuse de langue franc¸aise (SPILF). Recommandations de pratique clinique. Infections ostéo-articulaires sur matériel (prothèse, implant, ostéosynthèse). Texte court. Version 6 définitive du 13 mai 2009. [11] Reverdy ME, Coignard S, Dubreuil L, Bouvet A, Fleurette J. Activité in vitro de la cloxacilline sur les staphylocoques, les streptocoques du groupe A et Clostridium perfringens. Index inhibiteurs sériques. Med Mal Infect 1994;24:898–905. [12] Reverdy ME, Fleurette J, Nervi C, Etienne J. Bactéricidie comparée de la cloxacilline seule et en association sur S. aureus. Med Mal Infect 1996;26:504–9. [13] Pilly E. Maladies infectieuses et tropicales. Ouvrage du collège des universitaires de maladies infectieuses et tropicales (CMIT), 2010, 22e édition–septembre 2009. [14] INVS. Résistance aux anti-infectieux. Rappel de la problématique. 23 octobre 2006 (mise à jour 9 juin 2010) www.invs.sante.fr/surveillance/ resistance/problematique.htm. [15] EMEA. The bacterial challenge: time to react. A call to narrow the gap between multidrug-resistant bacteria in the EU and the develpment of new antibacterial agents. Technical report, 2009, http://www.ecdc. europa.eu/en/publications/Publications/Forms/ECDC DispForm.aspx?ID =444. [16] Tacconelli E, De Angelis G, Cataldo MA, Pozzi E, Cauda R. Does antibiotic exposure increase the risk of methicillin-resistant S. aureus (MRSA) isolation? A systematic review and meta-analysis. J Antimicrob chemother 2008;61(1):26–38. [17] Anonymous Recent trends in antimicrobial resistance among streptococcus pneumoniae and Staphylococcus aureus isolates: the French experience EUROSURVEILLANCE, 2008; 13(40):51, 533-8, www.eurosurveillance.org.

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