Pharmacokinetic and dynamic study of levofloxacin and rifampicin in bone and joint infections

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www.sciencedirect.com Médecine et maladies infectieuses 42 (2012) 414–420

Original article

Pharmacokinetic and dynamic study of levofloxacin and rifampicin in bone and joint infections Étude pharmacocinétique et dynamique de la lévofloxacine et de la rifampicine dans les infections ostéoarticulaires M. Guillaume a,∗ , R. Garraffo b , M. Bensalem a , C. Janssen a , S. Bland c , J. Gaillat a , J.-P. Bru a a

Service de maladies infectieuses, centre hospitalier de la région d’Annecy, 1, avenue de l’Hôpital, Metz Tessy, BP 90074, 74374 Pringy cedex, France b Laboratoire de pharmacologie, CHU de Nice, 30, avenue de la Voie-Romaine, BP 69, 06002 Nice cedex 1, France c Laboratoire de bactériologie, centre hospitalier de la région d’Annecy, 1, avenue de l’Hôpital, Metz Tessy, BP 90074, 74374 Pringy cedex, France Received 4 October 2011; received in revised form 10 March 2012; accepted 29 July 2012 Available online 1 September 2012

Abstract Objective. – We studied the pharmacokinetic and pharmacodynamic parameters of levofloxacin and rifampicin in bone and joint infections. The optimal dose regimen of these two antibiotics has not been documented yet. Patients and method. – We performed plasma dosage for each antibiotic in patients with a bone and joint infection requiring treatment with a levofloxacin and rifampicin combination. We then computed the 6 hours post dose area under the concentration-time curve (AUC0-6h ), the peak plasma concentration (Cmax), the area under the inhibitory concentration curve (AUIC), and the peak-to-minimum-inhibitory-concentration ratio (Cmax/MIC). The pharmacodynamic results were then compared to the published thresholds of effectiveness. The doses used were levofloxacin 500 mg bid and rifampicin 20 mg/kg per day. Results. – The plasma of 17 patients was dosed. The average AUC0-6h for levofloxacin was 46.59 mg.h/l, the average Cmax 10.7 mg/l, the average AUIC 932, and the average Cmax/MIC 107.5. The averages for rifampicin were 42.2 mg.h/l, 11.8 mg/l, 11,125 and 1514. Given that bone concentration of levofloxacin is 30% that of the plasma concentration, that concentration was divided by three to estimate bone concentration. Conclusion. – The optimal thresholds of pharmacodynamic effectiveness were obtained for most patients with levofloxacin at 500 mg bid. Additional studies are still required to determine the optimal rifampicin dose. © 2012 Published by Elsevier Masson SAS. Keywords: Bone and joint infections; Pharmacokinetics; Pharmacodynamics; Levofloxacin; Rifampicin

Résumé Objectif. – Nous avons étudié les paramètres pharmacocinétiques et pharmacodynamiques de la lévofloxacine et de la rifampicine dans les infections ostéoarticulaires, les posologies optimales de ces deux antibiotiques n’étant pas connues. Patients et méthode. – Chez les patients ayant une infection ostéoarticulaire nécessitant un traitement par une association lévofloxacine–rifampicine, nous avons réalisé des dosages plasmatiques pour chaque antibiotique puis nous avons calculé le quotient inhibiteur et l’aire sous la courbe inhibitrice, que nous avons comparés aux seuils d’efficacité établis dans la littérature. Les posologies utilisées étaient de 500 mg × 2/j pour la lévofloxacine et 20 mg/kg par jour pour la rifampicine. Résultats. – Les dosages étaient réalisés chez 17 patients. Pour la lévofloxacine, la moyenne des aires sous la courbe sur six heures était de 46,59 mg.h/L, la concentration maximale moyenne de 10,7 mg/L, l’aire sous la courbe inhibitrice moyenne de 932 et le quotient inhibiteur moyen de 107,5. Pour la rifampicine, les moyennes étaient respectivement de 42,2 mg.h/L, 11,8 mg/L, 11 125 et 1514. Si l’on considère une pénétration osseuse de la lévofloxacine de 30 % dans l’os cortical, il faut diviser par trois ces valeurs plasmatiques obtenues po ur estimer l’efficacité au niveau osseux.

∗

Corresponding author. E-mail address: [email protected] (M. Guillaume).

0399-077X/$ – see front matter © 2012 Published by Elsevier Masson SAS. http://dx.doi.org/10.1016/j.medmal.2012.07.018

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Conclusions. – Avec une posologie de lévofloxacine de 500 mg × 2/j, les seuils d’efficacité pharmacodynamiques sont atteints pour la majorité des patients mais pas pour tous. Des études complémentaires sont nécessaires pour déterminer des seuils d’efficacité pour la rifampicine. © 2012 Publié par Elsevier Masson SAS. Mots clés : Infections ostéoarticulaires ; Pharmacocinétique ; Pharmacodynamie ; Lévofloxacine ; Rifampicine

Bone and joint infections currently remain difficult to treat and some aspects of management have not been standardized, especially concerning the antibiotic therapy protocol. The fluoroquinolone–rifampicin combination is one of the recommended treatments for bone and joint infections due to staphylococci [1,2] because of: the good bioavailability of these antibiotics allowing administration per os (po), their very good penetration in bone tissue [3,4], their possible long-term use, and the additional effectiveness of rifampicin for infections on material [4,5]. According to French recommendations issued by the Société de Pathologie Infectieuse de Langue Franc¸aise (SPILF) [1], the fluoroquinolones which may be used for this indication are ofloxacin, pefloxacin, ciprofloxacin, or levofloxacin, the latter having an active ingredient concentration two times higher than ofloxacin [6]. Nevertheless, the dose of levofloxacin and rifampicin to be used for this type of infection has not been determined; studies and recommendations are not consensual. For example, according to French recommendations [1], the recommended dose of levofloxacin is 500 to 750 mg/d in one intake, and that of rifampicin is 20 mg/kg/d in two or three intakes. Zimmerli et al. recommended levofloxacin doses of 750 mg/d to 500 mg 2×/d, and 450 mg 2×/d for rifampicin [2]. This antibiotic combination recently proved its effectiveness for prosthetic infections, with doses of 750 mg/d to 500 mg 2×/d for levofloxacin, and 20 mg/kg/d for rifampicin [7]. Studying the pharmacokinetics and pharmacodynamics (PK/PD) parameters of antibiotics allows optimizing the treatments, for clinical and microbiological effectiveness, and preventing the selection of resistant strains [8,9]. The authors of numerous studies focused on the PK/PD parameters of fluoroquinolones, the antibiotic activity of which is concentration-dependent, so as to determine the thresholds of therapeutic effectiveness, in in vitro and in vivo model in animals and humans [10,11]. We studied the pharmacological parameters of levofloxacin and rifampicin in our patients managed for a bone and joint infection requiring treatment with a rifampicin–levofloxacin combination.

The following therapeutic regimen was used: initial intravenous treatment (IV) in most cases, using a betalactam–aminoside combination according to the SPILF recommendations [1], then relay, after 7 to 15 days of betalactam IV, with a levofloxacin–rifampicin combination per os. The levofloxacin dose was 500 mg × 2/d, because of this agent’s short half-life (6–8 h) [6,12] and the unit’s habit, based on recommendations made by Zimmerli et al. among others [2]. We followed the SPILF recommendations for rifampicin [1], using a dose of 20 mg/kg/d in two daily intakes, with a minimal dose of 600 mg × 2/d. We measured the area under the curve for each patient every 6 hours (AUC0-6h ) for each antibiotic, with the assistance of the Nice teaching hospital. To this end, levofloxacin and rifampicin were dosed in patients at H0, H1, H2, H3, H6 (residual level, then level 1 hour, 2 hours, 3 hours, and 6 hours after intake), starting after the third treatment day so as to be in a steady state. We decided to assess the AUC over 6 hours because this dosage is easier to perform in clinical practice than AUC over 12 hours. The antibiotic dosage was performed using high-performance liquid chromatography (HPLC) [13,14]. We also collected data on the surgical management, the duration of antibiotic therapy, treatment adverse events, and follow-up. The statistical analyses were made with Epi Info version 2007. 2. Results 2.1. Patient data We dosed antibiotics in 17 patients, between October 2010 and April 2011. There were 11 male and 6 female patients, with an average age of 53.7 years (±21), an average weight of 67.5 kg (±14), an average BMI of 22.7 (±3.7), an average albuminemia of 33.9 g/l (±6.7), an average creatinine clearance according to the MDRD formula was 103.9 ml/min (±25). The clearance was superior or equal to 60 ml for all patients. 2.2. Characteristics of bone and joint infections

1. Patients and method Our study was prospective and observational. We included patients 18 years of age or more, managed in the Annecy Regional Hospital infectious diseases or orthopedic units, or in the orthopedic surgery units of the Annecy region. The inclusion criterion was a bone and joint infection due to a levofloxacin and rifampicin susceptible bacterium. The Annecy Regional Hospital bacteriology laboratory measured the levofloxacin and rifampicin MIC for each bacterium.

Eleven patients presented with an infection on material: two cases of prosthetic infections, two of spondylodiscitis on material, and seven of infections on osteosynthetic material. Seven patients presented with bone and joint infection without material: two with spondylodiscitis, two with arthritis, two with lower limb osteitis, one with sacroiliitis. The bacteriological data was obtained by hemoculture, puncture of the infected site, or peroperative sampling. Fourteen patients presented with a Staphylococcus aureus infection,

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Table 1 Average MICs obtained from patient samples. Moyenne des CMI obtenues sur les prélèvements des patients. Average MIC (mg/l)

Levofloxacin

Rifampicin

All bacteria S. aureus

0.164 ± 0.05 0.170 ± 0.05

0.012 ± 0.012 0.013 ± 0.012

MIC: minimal inhibitory concentration. MICs were determined for 14 patients. Eleven patients presented with S. aureus infections.

one patient with a Staphylococcus lugdunensis infection, one with a Propionibacterium acnes infection, and one with an Escherichia coli and Staphylococcus epidermidis combined infection. The MIC means are listed in Table 1. 2.3. Therapeutic management All patients were given 500 mg of levofloxacin × 2/d, corresponding to a dose below 15 mg/kg/d for seven patients, and superior to 15 mg/kg/d for 10 patients. Twelve patients were given 1200 mg of rifampicin, per day, two patients 1500 mg/d, and three patients 1800 mg/d, corresponding to 20 mg/kg/d for most patients. Seven patients did not require surgical management, four patients underwent surgical lavage, and seven patients material removal, either on management initiation, or secondarily (one patient first underwent lavage, then secondarily material removal). The average duration of antibiotherapy was 3.4 months (±2.3); the average duration of levofloxacin–rifampicin combination was shorter (3 months, ±2.4), because treatment was modified for four patients, because of adverse events, or to broaden the spectrum for other bacteria (super infections).

Fig. 1. Levofloxacin AUC0-6h (area under the concentration-time curve) according to the dose in mg/kg/d. AUC0-6h (aire sous la courbe) de lévofloxacine en fonction de la posologie exprimée en mg/kg par jour.

correlation between the AUC0-6h and creatinine clearance according to the MDRD formula (P = 0.056) and a significant association between the AUC0-6h and age (P = 0.023). Patient No. 14 had an especially high Cmax and an AUC0-6h , she was 90 years old, low weight (42 kg), and had a creatinine clearance according to the MDRD formula at 60.3 ml/min. Four patients had a low Cmax (< 7 mg/l) and/or a low AUC0-6h (< 30 mg.h/l); they were young (18 to 29 years), male, and had a creatinine clearance according to the MDRD formula superior to 119 ml/min. 2.5. Rifampicin dosage

2.4. Levofloxacin dosage

AUC0-6h , Cmax, estimated AUIC, and IQ data for rifampicin for each patient is listed in Table 3. The average Cmax was

The results for each patient are listed in Table 2. The area under the inhibitory curve (AUIC) usually corresponds to AUC0-24h /MIC. We estimated it in our study from the AUC0-6h : AUC0-6h × 2/MIC, because of the levofloxacin intake every 12 h (under-estimation). The inhibitory quotient (IQ) corresponds to the maximum concentration (Cmax)/MIC. The average Cmax was 10.7 (±6.4) mg/l and the average AUC0-6h was 46.59 (±34.5) mg.h/l. The Cmax was assessed at H1 for nine patients, H2 for five patients, and H3 for three patients. The average IQ for all bacterial species was 107.5 (±146) and that of estimated AUIC was 932 (±1,258). The average IQ was de 72.3 (±47.6) and that of estimated AUIC was 641 (±518) when S. aureus infections only were considered. We looked for association between pharmacokinetic parameters and the various variables. We identified a significant association and a linear relationship between the AUC0-6h and the levofloxacin dose in mg/kg/d (P = 0.0007), as well as between the Cmax and the levofloxacin dose in mg/kg/d (P = 0.0004), this was not adjusted to the creatinine clearance and age because of the small sample size (Figs. 1 and 2). The univariate analysis revealed a trend to

Fig. 2. Levofloxacin peak plasma concentration (Cmax) according to the dose in mg/kg/d. Cmax (concentration maximale) de lévofloxacine en fonction de la posologie exprimée en mg/kg par jour.

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Table 2 Results for levofloxacin dosages. Résultats par patient des dosages de lévofloxacine. Patients

AUC0-6h (mg.h/l)

Cmax (mg/l)

Estimated AUIC

IQ

Bacteria

MIC (mg/l)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Average

50 31 41 28 33 68 46 38 43 32 40 22 28 171 64 36 21 46.59 ± 34.5

10.7 7.1 9.1 7.9 8.6 13.2 12.1 8.2 9.6 6.8 9.5 5.4 6.2 33.7 15.9 8.5 8.8 10.7 ± 6.4

400 496 656 224 348 1446 736

43 57 73 32 45 140 97

0.25 0.125 0.125 0.25 0.19 0.094 0.125

688 336 5000 352 294 1800

76.8 35.8 594 43 33 177

280 932 ± 1258

59 107.5 ± 146

SA SA S. lugdu SA SA SA SA SA SA SA E. coli Propioni SA SA SA SA SA

0.125 0.19 0.016 0.125 0.19 0.19

0.15 0.164 ± 0.05

AUC0-6h : area under the curve measured for 6 hours; Cmax: maximum concentration; AUIC: area under the inhibitory curve; IQ: inhibitory quotient; MIC: minimal inhibitory concentration; SA: S. aureus; S. lugdu: S. lugdunensis; Propioni: Propionibacterium acnes.

de 11.8 (±5.6) mg/l and the average AUC0-6h was 42.2 (±27) mg.h/l. The Cmax was measured at H1 for three patients, H2 for seven patients, H3 for five patients, and at H2 and H32 for two patients. The global average estimated AUIC and IQ were respectively 11,125 (±8,006) and 1514 (±960); in the S. aureus infection sub-group it was 10,046 (±7,281) for the estimated AUIC and 1355 (±788) for the IQ. We found, in continuous variable analysis, that the AUC0-6h increased with age (P = 0.07) and when creatinine clearance according to the MDRD formula decreased (P = 0.047). We also determined a tendency for the

AUC0-6h to decrease when the delay between the onset of treatment and performing dosages increased (P = 0.125). But there was no significant linear relationship between the rifampicin AUC0-6h and the dose neither in mg/kg/d, nor between the Cmax and the dose in mg/kg/d (Fig. 3). Three patients had a low Cmax and a low AUC0-6h : patients No. 11 and 16 were given rifampicin doses inferior to 20 mg/kg/d, but patient No. 17 was given 30 mg of rifampicin/kg/d and had a creatinine clearance according to the MDRD formula at 165 ml/min. The Cmax was measured at H3 for these three patients.

Table 3 Results for rifampicin dosages. Résultats par patient des dosages de rifampicine. Patients

AUC0-6h (mg.h/l)

Cmax (mg/l)

Estimated AUIC

IQ

Bacteria

MIC (mg/l)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Average

35 71 37 45 49 70 77 19 36 38 11 24 20 56 106 14 10 42.2 ± 27

11 16.7 9.7 13.5 13 16.2 17.6 12.6 12.3 8.5 3.7 6.8 7.8 14 26.4 4.2 6.6 11.8 ± 5.6

3042 23,666 18,500 7500 8166 17,500 19,250

478 2783 2425 1125 1083 2025 2200

0.023 0.006 0.004 0.012 0.012 0.008 0.008

12,000 9500 2750 24,000 5000 2382

2050 1062 462 3400 975 298

2500 11,125 ± 8006

825 1514 ± 960

SA SA S. lugdu SA SA SA SA SA SA SA S. epi Propioni SA SA SA SA SA

0.006 0.008 0.008 0.002 0.008 0.047

0.008 0.012 ± 0.012

AUC0-6h : area under the curve measured for 6 hours; Cmax: maximum concentration; AUIC: area under the inhibitory curve; IQ: inhibitory quotient; MIC: minimal inhibitory concentration; SA: S. aureus; S. lugdu: S. lugdunensis; Propioni: propionibacterium acnes.

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Fig. 3. Rifampicin peak plasma concentration (Cmax) according to the dose in mg/kg/d. Cmax (concentration maximale) de rifampicine en fonction de la posologie exprimée en mg/kg par jour.

2.6. Searching for interactions between levofloxacin and rifampicin We checked if the levofloxacin AUC0-6h changed according to the rifampicin dose administrated whether in mg/kg/d or in mg/d. We did not find any significant relationship between these parameters. 2.7. Adverse effects of treatment and follow-up Our patients were treated on average 3 months (±2,4) with a levofloxacin-rifampicin combination. Three patients presented with adverse events due to rifampicin (nausea, loss of appetite, digestive intolerance), requiring treatment interruption in a patient after 15 days. Two patients presented with adverse events due to levofloxacin requiring treatment interruption: polyarthralgia after 3 months of treatment, and diffuse muscular and tendinous pain after 5 months of treatment. These patients were not given unusually high drug doses. In August 2011, two patients were still being treated with antibiotherapy. The 15 others were considered as cured when antibiotherapy was stopped. The average follow-up after stopping treatment was 5.4 months (±1.97), there was no relapse. 3. Discussion Our original approach was to study the PK/PD parameters of levofloxacin and rifampicin on a cohort of patients with bone and joint infection. There is some published pharmacological data on levofloxacin, but it only rarely concerns bone and joint infections. The PK/PD parameters of rifampicin we studied had, to our knowledge, never been described before. At the Annecy Regional Hospital, we chose to use levofloxacin, rather than ofloxacin, for staphylococcal bone and joint infections first because of pharmacokinetics parameters.

Ofloxacin is made of 2 enantiomers, of the isomer (R) and of the isomer (S), the latter being twice more bactericidal than the former [6,15]. With levofloxacin, which is made only of the more active isomer (S), lower MICs are obtained for Grampositive and Gram-negative bacteria than with ofloxacin [6]. The penetration rate of ofloxacin in cortical bone seems weaker than that of levofloxacin, but with different methods [3,16–19]. The ofloxacin dose per intake needs to be increased to obtain plasma levels of ofloxacin identical to those of levofloxacin in healthy volunteers; this cannot always be achieved because of a safety issue [6,16,17,20]. Furthermore, even if only a few studies have been published on the use of levofloxacin for bone and joint infections, they all concluded to its good effectiveness [7,21–24]. Some teams suggested using levofloxacin and not ofloxacin as antibiotherapy for staphylococcal bone and joint infections [2,25]. If we first consider the pharmacokinetics parameters of levofloxacin, its AUC0-6h and Cmax, we can note in our results a broad range of plasma concentrations, which was relatively variable from one patient to the next. The average Cmax was 10.7 (±6.4) mg/l, which is higher than published data for healthy volunteers (average 7.8 mg/l with the same dose) [6]. We assessed the Cmax between 1 and 3 hours after administration, which corresponds more or less to previously described data (between 0.8 and 2.4 hours) [6]. The AUC0-24h with 500 mg 1×/d of levofloxacin was 47.5 mg.h/l, the AUC0-24h with 750 mg 1×/d was 91 mg.h/l, and the AUC0-12h with 500 mg 2×/d was 59 mg.h/l in healthy volunteers [6]. We measured an AUC0-6h of 46.6 mg.h/l with a dose of 500 mg 2×/d in our patients. We identified a correlation between the levofloxacin AUC0-6h and the dose depending on weight. It seems that a minimum dose of 15 mg/kg/d is necessary to obtain an adequate Cmax and AUC0-6h for most patients (Fig. 1), but even at that dose, some patients still had low levels. This also suggests the need to adapt the dose for patients with a low weight (750 mg/d for example, for patients weighing less than 50 kg). The AUC0-6h was also correlated to clearance creatinine and age. Some young male patients with a high creatinine clearance had low pharmacokinetic parameters despite a high drug dose. Some teams studying the pharmacodynamics of levofloxacin investigated the target values of the AUIC and IQ allowing bacterial eradication and clinical success; but no study was made in humans for bone and joint infection. An AUIC greater than 125 is correlated to clinical success in respiratory infections, soft tissue infections, urinary infections, and bacteremia due to a Gram-negative bacillus [10,11,26,27]. The data is much more controversial for Gram-positive cocci infections, and studies were more often made on a pneumococcus than on a staphylococcus. For some authors, an AUIC superior to 30 to 50 in pneumococcal pneumonia is sufficient [11,28], whereas for the authors of other in vitro and in vivo animal studies, an AUIC greater than 100–115 would allow an adequate bactericidal effect and prevent the emergence of resistant mutants, especially in studies on the staphylococcus [9,10,29–32]. It is also currently admitted that IQ target should be superior or equal to 10 to 12 [29].

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But these pharmacodynamic thresholds of effectiveness have not been demonstrated for bone infections. The published data on bone penetration of levofloxacin is that penetration in cancellous bone ranges between 50 and 100%, and in cortical bone between 30 to 50% of the blood levels [3,18,19]. The results of plasma AUIC and IQ should a priori be divided by three to obtain effectiveness in the bone. If we consider our data for S. aureus infections only, this would give an average IQ of 24, and an average estimated AUIC of 214 in bone. We would thus obtain values superior to the target thresholds with 500 mg 2×/d de levofloxacin for most patients. Nevertheless, two patients had below-threshold values for two parameters (patients No. 4 and 13). It should be noted that these estimated values do not take into account the protein binding of levofloxacin, which ranges around 30%. The results of animal studies on a model of infected foreign material (cages) support the idea that high doses of levofloxacin (750 to 1000 mg/24 h) should be used to obtain an adequate bactericidal effect, but they do not demonstrate any difference of effectiveness between a single and double daily administration [23,24]. This raises another question: is it useful to reach the target IQ once or twice a day? Concerning the safety of these high levofloxacin doses, two patients stopped treatment because of adverse events, having occurred after 3 months and 5 months of treatment; the average levofloxacin course was 3 months (±2.4) for all patients. Published data on high levofloxacin doses show that they are rather well tolerated [33], even though for courses superior to 4 weeks with a dose of more than 750 mg/d, there were more adverse events (22%), the average onset of adverse events was 40 days [21]. It is interesting to note that in our study on a limited number of patients, we did not find any correlation between high levofloxacin doses and the occurrence of adverse effects. Performing dosage in clinical practice would thus be more contributive to check effectiveness than to prevent toxicity. As far as we know, there is very little data published on the PK/PD parameters of rifampicin, which is why our study is unique. In pharmacokinetic studies made on healthy volunteers [34,35], after ingestion of 600 mg po, the average Cmax was 10 mg/l and reached between 1- and 3-hour after intake, correlating with our data. The elimination half-life of the antibiotic is short (around 3 h), this half-life as well as the Cmax increase with higher doses and decrease in time until the sixth day [34,35], a trend which we also demonstrated on our small study sample. The variations of plasma dosage with the renal function have also been reported [34]. According to published data [34], the rifampicin concentration in the skin and muscles is the same as the plasma concentration, but as far as we know, there is no data on bone penetration for this agent. Nevertheless, its contribution for bone and joint infections was frequently reported, especially for infections on material [4,7]. Various doses have been reported to be used with success rates ranging from 75 to 100%: 300 mg 2×/d, 600 mg 1×/d, 900 mg 1×/d, 450 mg 2×/d [4,5,22,36], but it was not possible to determine an ideal dose. Rifampicin like levofloxacin is an antibiotic with concentration dependent bactericidal effect, but we could

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not find any published data concerning pharmacodynamic parameters such as the AUIC or the IQ. It would be interesting to compare our pharmacodynamic data to that of other studies and to clinical follow-up, so as to try to determine an optimal dose. As far as we know, no drug interactions has ever been reported between rifampicin and levofloxacin [37] and this was the case in our study. This should be compared to the absence of any significant hepatic metabolism for this fluoroquinolone (it is excreted mainly through the urinary tract in an unchanged form) [6]. Likewise, levofloxacin does not impact the pharmacokinetic of rifampicin because it does not have any inductive or inhibitory effect on metabolism. This study had some limitations: the study population was small, and this did not allow the adjusting pharmacokinetic parameters and taking bias into account; we measured the AUC0-6h , to facilitate clinical practice, which is difficult to compare to published data and from which we had to estimate the AUIC; the MIC was not available for three patients; the pharmacological study was mostly descriptive, because we did not have enough feedback to correlate these results to clinical data; the study was observational but we did not have any comparative arm. 4. Conclusion The effectiveness of the levofloxacin–rifampicin combination for bone and joint infections no longer needs to be proved, but optimal doses have yet to be determined. We showed that on a small series of 17 patients with 500 mg of levofloxacin/12 h, the pharmacological thresholds of effectiveness were not reached for all patients. Nevertheless, this dose seemed adapted for most patients. The pharmacological follow-up could be contributive for young heavyweight patients, with an elevated creatinine clearance, or when MICs are high. Performing an AUC seems more reliable than dosing the Cmax, since the delay between drug intake and the Cmax is variable from one patient to another. When considering adverse events reported for prolonged treatment, lower doses such as 750 mg/d may be considered for lightweight patients, with a therapeutic pharmacological follow-up. Complementary research is needed to study other doses, and correlate these results with clinical response. We were the first to study descriptively the pharmacodynamics parameters of rifampicin, but further research is necessary to correlate the PK/PD parameters to therapeutic success and determine the thresholds of effectiveness. We are currently continuing our study with the objective to determine the predictive value of a “mini” AUIC (0–6 h) and the IQ of levofloxacin and rifampicin for the bacteriological and clinical effectiveness of bone infection treatment. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.

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