Abstract Objectives Daptomycin has become a first-line therapeutic option for vancomycin-resistant Enterococcus faecium infective endocarditis (IE). Although high doses (≥8 mg/kg) are often recommended, optimal doses, particularly for strains with MICs close to the susceptibility breakpoint (4 mg/L), are still debated. Methods Daptomycin efficacy at doses equivalent to 8 mg/kg daptomycin (DAP8) and 12 mg/kg daptomycin (DAP12) in humans was evaluated in a rabbit model of aortic valve IE induced by 108 cfu of E. faecium reference strain Aus0004 (daptomycin MIC = 2 mg/L) or its in vitro mutant strain Mut4 (daptomycin MIC = 4 mg/L). Treatment began 48 h post-inoculation and lasted 5 days. Results With Aus0004, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [6.05 (n = 12) and 2.15 (n = 10) versus 9.14 (n = 11), respectively; P < 0.001], with DAP12 being more effective than DAP8 concerning vegetation bacterial load (P < 0.001) and percentages of sterile vegetations (100% versus 0%, respectively; P < 0.001). Daptomycin-resistant Aus0004 mutants were detected in 8.3% of DAP8-treated vegetations. With Mut4, the median log10 cfu/g of vegetations was significantly lower after DAP8 and DAP12 versus controls [7.7 (n = 11) and 6.95 (n = 10) versus 9.59 (n = 11), respectively; P = 0.001 and P = 0.002], without any between-dose difference, but no vegetation was sterile. Moreover, 7 of 11 (63.6%) and 7 of 9 (77.8%) vegetations contained resistant mutants after DAP8 and DAP12, respectively. Conclusions DAP12 was the most successful strategy against IE due to a WT E. faecium strain (daptomycin MIC = 2 mg/L). To treat IE strains with MIC = 4 mg/L, DAP8 or DAP12 monotherapy was poorly effective with the risk of resistant mutant emergence. Reassessment of the daptomycin susceptibility breakpoint for enterococci seems necessary. Introduction Enterococci are ubiquitous Gram-positive cocci usually present among animal and human normal gut flora, and other natural and hospital environments. Two species are mainly responsible for human infections: Enterococcus faecalis (75%–85%) and Enterococcus faecium (15%–25%). After staphylococci and streptococci, enterococci are the third most common cause of infective endocarditis (IE).1 Enterococcal endocarditis most often occurs in elderly patients with native valves and comorbidities (diabetes, haemodialysis).2 Treatment of serious E. faecium infections is usually based on glycopeptides. However, in the USA, up to 80% of E. faecium clinical isolates are VRE, attributable to the worldwide dissemination of a subpopulation of E. faecium hospital-adapted clones that belong to the so-called clonal complex 17 (CC17).3 Only a few antibiotics are available to treat VRE infections: quinupristin/dalfopristin, linezolid and daptomycin. The quinupristin/dalfopristin combination lost FDA approval in 2010. Linezolid is bacteriostatic and results of a recent study put in doubt its efficacy against severe VRE infections.4 Daptomycin, a cyclic lipopeptide, bactericidal, concentration-dependent antibiotic has become the first-line therapy to treat those infections.5 International recommendations suggest using high daptomycin doses to treat VRE endocarditis, even without FDA approval.6,7 However, treatment failures due to high MICs and resistance emergence during treatment have been described.8–10 According to CLSI guidelines, enterococci are categorized as daptomycin susceptible when the MIC is ≤4 mg/L, but no resistance breakpoint has been established.5 Based on ex vivo and in vitro studies, high daptomycin doses (≥8 mg/kg) seem necessary, but no published in vivo data support using those doses, particularly for IE.11,12 As comparative clinical trials are difficult to design in the field of endocarditis we used an experimental model to determine the optimal daptomycin dose to treat experimental VRE endocarditis and evaluate the emergence of daptomycin-resistant mutants. This study was undertaken to determine the optimal daptomycin dose to treat experimental VRE endocarditis and evaluate the emergence of daptomycin-resistant mutants. Materials and methods Strains Two isogenic strains of vancomycin-resistant E. faecium were used: the vanB-positive Aus0004 reference strain, recovered from a bacteraemic patient, which belongs to CC17, frequently encountered in hospitals;13 and Mut4, an isogenic mutant obtained in vitro and derived from the parental strain Aus0004.14 The respective daptomycin MICs were 2 and 4 mg/L.14 Time–kill curves Daptomycin bactericidal activity was determined using time–kill assays run at least four times for each strain. Briefly, overnight cultures were diluted in 10 mL of fresh Mueller–Hinton (MH) broth, supplemented with calcium chloride (50 mg of Ca2+/L) to yield an inoculum of 105 cfu/mL. The antibiotic concentrations used were equivalent to 2× or 4× the daptomycin MIC. After 0, 3, 6, 9, 12 and 24 h of incubation at 35 ± 2 °C, serial 0.1 mL dilutions were subcultured on trypticase–soy (TS) agar and incubated at 35 ± 2 °C for 24 h before cfu were counted. The bactericidal effect was defined as a cfu count ≥3 log10 lower than that of the initial inoculum. Plasma daptomycin levels It was previously shown that a daily intravenous (iv) infusion of 8 mg/kg daptomycin (DAP8) into humans was equivalent to 22 mg/kg iv daily in rabbits.15 To determine the dose equivalent to 12 mg/kg daptomycin (DAP12), serum antibiotic levels were measured in four uninfected rabbits after an iv injection of daptomycin at different doses. Blood samples were collected 15 and 30 min, and 1, 3, 8 and 24 h post-injection and AUCs were calculated.16 Trough and peak plasma daptomycin concentrations before and 15 min after the last iv injection of five infected rabbits treated for 5 days were also determined by HPLC with a reversed-phase C18 column and UV detection (λ = 214 nm, concentration range: 3–500 mg/L).16 Experimental endocarditis White female New Zealand rabbits (Hypharm S.A.S, Sèvremoine, France), each weighing 2.5–3 kg, were used. They were housed in individual cages with a natural light–dark cycle and food and water ad libitum. The experimental protocol was in keeping with French legislation on animal experimentation and was approved by the Animal Use Committee of Maison Alfort Veterinary School, France. Left-sided IE was induced after the usual protocol of anaesthesia obtained with intramuscular injection of ketamine 1000 (Virbac, Carros, France) and xylazine (Rompun 2%; Bayer, Leverkusen, Germany) (25 mg/kg of body weight).17,18 After incising the neck, a polyethylene catheter was inserted through the right carotid artery and left in place throughout the experiment. On day 1 (D1), 24 h after catheter placement, the rabbits were inoculated via the marginal ear vein with 108 cfu of Aus0004 or Mut4 in 1 mL of saline. IE was confirmed by blood cultures on D3 and identification of infected valvular vegetations after animals were sacrificed. For each strain, rabbits were randomized to receive: no treatment (controls, n = 12) or daptomycin (Cubicin® 350 mg; Novartis, Basel, Switzerland) by once-daily iv injection into the marginal ear vein at doses equivalent to 8 mg/kg (DAP8, n = 12) and 12 mg/kg (DAP12, n = 12) iv in humans. Antibiotic therapy was started 48 h post-inoculation (D3) and lasted 5 days. Animals were sacrificed 24 h after the last daptomycin dose or on D9 for controls, after collecting blood samples for culture. The vegetations were differentiated from normal cardiac tissue, excised, weighed, homogenized in 1 mL of 0.9% saline and 100 μL volumes were quantitatively cultured on TS blood–agar plates incubated at 35 ± 2 °C for 24 h. Spleen samples were also collected, weighed, homogenized and quantitatively cultured on TS blood–agar plates. Positive blood cultures at sacrifice (D9) defined persistent bacteraemia. The bacterial load in vegetations and spleen from each rabbit were expressed as log10 cfu/g of tissue. Vegetation was considered sterile when the culture showed no growth after incubation for 48 h at 35 ± 2 °C and the number of cfu recorded was the lowest detectable bacterial count (1.88–2.57 log10 cfu/g of vegetation, depending on sample weight). Resistance analysis Before searching for resistant mutants, population analysis evaluated whether each of the initial strains harboured subpopulation(s) expressing a higher daptomycin resistance level(s). From an initial inoculum of 0.5 × 1010 cfu/mL, serial dilutions of each strain were spread on MH agar supplemented with calcium chloride (50 mg/L) and daptomycin (0.25, 0.5, 1, 2, 4 or 8 mg/L). Control plates contained no antibiotic. Plates were incubated for 48 h at 35 ± 2 °C and cfu were counted at 24 and 48 h. In vivo resistant mutants were sought in all control and treated rabbits with positive vegetation cultures at the end of treatment. Each undiluted vegetation homogenate (0.1 mL) was plated on MH agar supplemented with calcium chloride (as above) and daptomycin (concentrations equivalent to 2× or 4× MIC), and incubated for 48 h at 35 ± 2 °C. When bacterial growth was observed, colonies were counted and identified as E. faecium by MALDI-TOF MS (Microflex; Bruker Daltonics, Bremen, Germany). MICs of daptomycin were determined with the broth microdilution method according to EUCAST recommendations on five colonies per sample. Each MIC was determined at least three times and resistant mutants were defined as having MICs 2-fold higher than the initial strains. Statistical analyses Data were analysed using R software (R Development Core Team, 2012). Between-group cfu counts for vegetations and spleen were expressed by the minimum, maximum, median, IQR, mean and SD. Mortality, positive blood culture, sterile vegetation and resistance emergence were expressed as percentages. The group comparisons of the analysed distributions were carried out by appropriate statistical tests with a threshold of 5% bilateral. The χ2 test, Fisher’s exact test and the non-parametric Wilcoxon method were used. Results Time–kill curve studies For Aus0004 and Mut4 strains, only doses equivalent to 4× MIC (8 and 16 mg/L, respectively) achieved cfu/mL ≥3 log10 lower than that of the inoculum (Figure 1) after 9 h of daptomycin exposure. Figure 1. View largeDownload slide Killing curves of E. faecium Aus0004 (a) and Mut4 (b) strains by daptomycin at different concentrations. Figure 1. View largeDownload slide Killing curves of E. faecium Aus0004 (a) and Mut4 (b) strains by daptomycin at different concentrations. Serum daptomycin levels The mean AUC for uninfected rabbits given a single 30 mg/kg iv dose was 1459 mg·h/L, similar to steady-state rates in healthy humans given DAP12 (AUC = 1277 ± 253 mg·h/L).16 The uninfected rabbits’ Cmax, reached 15 min post-injection, was 241.3 ± 9.7 mg/L (Table S1, available as Supplementary data at JAC Online). The mean Cmax for infected rabbits was 316.4 ± 29.8 mg/L and the 24 h trough concentration was 3.4 ± 1.8 mg/L. Experimental endocarditis Among the 72 operated rabbits (36 per strain), five (6.9%) died before being inoculated; the remaining 67 rabbits were inoculated with 2.9–8.9 × 108 cfu/mL. All but one rabbit infected with each strain (excluded from the statistical analyses) had positive blood cultures on D3 and cardiac vegetations around the catheter, on the aortic or mitral valve, or more rarely on the ventricle wall at sacrifice. Mortality of Aus0004-infected control rabbits was 36.4%, while 6 of 7 (85.7%) rabbits sacrificed on D9 had positive blood cultures (Table 1) and spleen cultures contained a median of 4.55 log10 cfu/g (Figure 2b), and vegetations a median of 9.14 log10 cfu/g (Figure 2a). Comparing DAP8- and DAP12-treated rabbits with controls, no rabbits died [0% (P = 0.037) and 0% (P = 0.09), respectively]; 12 and 10 Aus0004-infected rabbits were sacrificed on D9, respectively. The two regimens achieved lower percentages of rabbits with persistent bacteraemia [8.3% (P = 0.002) and 10% (P = 0.004), respectively, versus controls] (Table 1). Notably, the two doses also obtained significantly lower bacterial loads in vegetations [6.05 log10 cfu/g (P < 0.001) and 2.15 log10 cfu/g (P < 0.001), respectively] and in spleens [1.7 log10 cfu/g (P < 0.001) and 1.74 log10 cfu/g (P < 0.001), respectively] versus controls (Figure 2a and b). Note that the bacterial load was significantly lower in DAP12- than DAP8-treated rabbits’ vegetations (P < 0.001) (Figure 2a). Moreover, vegetations in all Aus0004-infected DAP12-treated rabbits were sterile (P < 0.001 versus controls). Table 1. Mortality, persistent bacteraemia and sterile vegetations at sacrifice (D9) in infected rabbits according to the strain (Aus0004 and Mut4) Controls DAP8 DAP12 Pa Pb Pc Aus0004 n = 11 n = 12 n = 10 mortality 4 (36.4) 0 (0) 0 (0) 0.037 0.09 1 persistent bacteraemia 6/7 (85.7) 1/12 (8.3) 1/10 (10) 0.002 0.004 1 sterile vegetations 0/7 (0) 0/12 (0) 10/10 (100) 1 <0.001 <0.001 Mut4 n = 11 n = 11 n = 10 mortality 4 (36.4) 2 (18.2) 0 (0) 0.635 0.09 0.476 persistent bacteraemia 5/7 (71.4) 6/9 (66.7) 4/10 (40) 1 0.335 0.37 sterile vegetations 0/7 (0) 0/9 (0) 0/10 (0) 1 1 1 Controls DAP8 DAP12 Pa Pb Pc Aus0004 n = 11 n = 12 n = 10 mortality 4 (36.4) 0 (0) 0 (0) 0.037 0.09 1 persistent bacteraemia 6/7 (85.7) 1/12 (8.3) 1/10 (10) 0.002 0.004 1 sterile vegetations 0/7 (0) 0/12 (0) 10/10 (100) 1 <0.001 <0.001 Mut4 n = 11 n = 11 n = 10 mortality 4 (36.4) 2 (18.2) 0 (0) 0.635 0.09 0.476 persistent bacteraemia 5/7 (71.4) 6/9 (66.7) 4/10 (40) 1 0.335 0.37 sterile vegetations 0/7 (0) 0/9 (0) 0/10 (0) 1 1 1 a DAP8 versus controls. b DAP12 versus controls. c DAP12 versus DAP8. Figure 2. View largeDownload slide Bacterial loads in vegetations (a) and spleens (b) according to strain (Aus0004 or Mut4) and daptomycin dose [none (C), DAP8 or DAP12]. Box plot whiskers show the minimum and maximum values; the horizontal line in each box plot is the median, and the box covers the interquartile range. Figure 2. View largeDownload slide Bacterial loads in vegetations (a) and spleens (b) according to strain (Aus0004 or Mut4) and daptomycin dose [none (C), DAP8 or DAP12]. Box plot whiskers show the minimum and maximum values; the horizontal line in each box plot is the median, and the box covers the interquartile range. Mortality of Mut4-infected controls (n = 11) was 36.4% and 5 of 7 (71.4%) rabbits sacrificed on D9 had positive blood cultures (Table 1); their spleen cultures contained a median of 4.33 log10 cfu/g (Figure 2b) and the median count in vegetations was 9.59 log10 cfu/g (Figure 2a). DAP8 and DAP12 mortality rates were non-significantly lower [18.2% (P = 0.635) and 0% (P = 0.09), respectively] than that of the controls, and 66.7% of the 9 and 40% of the 10 rabbits sacrificed on D9 (P = 1.00 and P = 0.335, respectively, versus controls) had persistent bacteraemia (Table 1). By contrast, vegetation bacterial counts under both doses were significantly lower [7.7 log10 cfu/g (P = 0.002) and 6.95 log10 cfu/g (P = 0.001), respectively] than control counts. In the spleen, neither DAP8 nor DAP12 significantly reduced bacterial counts [2.56 log10 cfu/g (P = 0.065) and 2.15 log10 cfu/g (P = 0.061), respectively, versus controls] (Figure 2a and b). Neither DAP8 nor DAP12 sterilized Mut4 vegetations. Analysis of daptomycin resistance No subpopulation with a high level of daptomycin resistance was found in vitro for either the Aus0004 or Mut4 strain (Figure 3a), meaning the absence of heteroresistance. All infected rabbits were screened for the presence of daptomycin-resistant mutants in vegetations. No daptomycin-resistant mutant was found in the Aus0004 (n = 11) or Mut4 (n = 11) control groups (Figure 3b). Among the 12 Aus0004-infected DAP8-treated rabbits, only one (8.3%) had daptomycin-resistant mutants with MICs = 4 mg/L (Figure 3a). Because all vegetations were sterile, daptomycin-resistant mutants were not screened in Aus0004-infected DAP12-treated rabbits. Figure 3. View largeDownload slide (a) In vitro analysis: bacterial count of each strain (Aus0004 and Mut4) cultured with different doses of daptomycin. (b) In vivo emergence of daptomycin resistance according to strain (Aus0004 or Mut4) and daptomycin dose [none (C), DAP8 or DAP12]. Figure 3. View largeDownload slide (a) In vitro analysis: bacterial count of each strain (Aus0004 and Mut4) cultured with different doses of daptomycin. (b) In vivo emergence of daptomycin resistance according to strain (Aus0004 or Mut4) and daptomycin dose [none (C), DAP8 or DAP12]. Among the 11 Mut4-infected DAP8-treated rabbits tested, seven (63.6%) had daptomycin-resistant mutants with MICs of daptomycin ranging from 8 to 32 mg/L (Figure 3b). Finally, among the nine Mut4-infected DAP12-treated rabbits tested, seven (77.8%) had daptomycin-resistant mutants with MICs ranging from 8 to 16 mg/L (Figure 3b). Discussion Few data are available on therapeutic management of severe VRE infections, including E. faecium IE. Daptomycin is commonly used as a last-resort antibiotic to treat serious infections. Indeed, the European Society of Cardiology recommends combining daptomycin and ampicillin as a therapeutic alternative for VRE IE. That guideline is based on two studies that tested in vitro daptomycin efficacy against cardiac E. faecium-infected vegetations:11,12 Luther et al.11 recommended using daptomycin doses of 6 or 10 mg/kg, whereas Hall et al.12 observed that it was necessary to use doses of up to 10 mg/kg if the VRE strain’s daptomycin MIC was 2–4 mg/L. Recently, Senneville et al.19 also recommended that same dose. Until now, no in vivo experimental study had used high doses of daptomycin against VRE strains with MICs close to the clinical susceptibility breakpoint. Concentrations to be used in rabbits were determined using pharmacokinetics parameters and more specifically AUC values. Indeed, several reports of pharmacokinetic/pharmacodynamics analyses of daptomycin in in vivo infection models, have shown that daptomycin efficacy is correlated with the ratio of AUC to the MIC (AUC0–24/MIC).20,21 The mean AUC for uninfected rabbits given a single 30 mg/kg iv dose was 1459 mg·h/L, similar to steady-state rates in healthy humans given DAP12 (AUC = 1277 ± 253 mg·h/L).16 According to these results, we determined that a dose of 30 mg/kg in rabbits was equivalent to a dose of 12 mg/kg in humans. In our study, for the WT Aus0004 strain with a daptomycin MIC of 2 mg/L, DAP12 seemed to be more effective than DAP8. Indeed, after 5 days of administration, DAP12 sterilized all vegetations and prevented the in vivo emergence of resistant mutants. Those findings, and as suggested by some in vitro studies,11,12 indicate that higher doses of daptomycin (≥10 mg/kg) are needed to treat VRE IE when the MIC of daptomycin is equal to 2 mg/L. Results obtained with the Mut4 strain, with a daptomycin MIC of 4 mg/L, are more moderate. Neither dose sterilized vegetations nor obtained cfu counts reduced by ≥3 log10 compared with the initial inoculum. Moreover, we found no difference between treated groups and their controls concerning spleen bacterial load, persistence of post-treatment bacteraemia and mortality. Resistant mutants were also detected in treated rabbits, regardless of the dose. Those results suggest that daptomycin is poorly effective against an E. faecium strain with an MIC close to the clinical daptomycin susceptibility breakpoint, even when high doses are administered. Recently, Shukla et al.22 published a retrospective study on 62 patients with E. faecium bacteraemia treated with daptomycin. Isolates exhibiting daptomycin MICs of 3–4 mg/L were significantly associated with microbiological failure and the authors concluded that modification of the daptomycin susceptibility breakpoint (≤4 mg/L) for enterococci should be considered, a result consistent with our conclusion. In Aus0004-infected rabbits, resistance emerged with DAP8 and not DAP12. These findings and other observations obtained with this experimental in vivo model indicate that treatment failures are possible with DAP8, even when the daptomycin MIC is 2 mg/L. In Mut4-infected rabbits, resistance emergence was common, regardless of the dose studied. Resistant strain MICs were two to eight times the original MIC, suggesting that daptomycin should not be used alone, even at high doses, to treat IE caused by VRE with MIC ≥4 mg/L. Our experimental model did not evaluate risks of recurrence or mid-term mortality. Only daptomycin monotherapy was evaluated, although this antibiotic is recommended for use in combination with another antibiotic.7 It could be informative to assess the efficacy of daptomycin combined with another molecule, e.g. ampicillin. In conclusion, daptomycin alone was poorly effective against IE due to E. faecium strains with an MIC of 4 mg/L and resistant mutants emerged. Hence, reassessment of the daptomycin-susceptibility breakpoint for enterococci seems to be necessary. Acknowledgements We warmly thank Dr Christophe Isnard, Michel Auzou and Omar Aimer for their excellent assistance. Funding This work was supported by grants from the Ministère de l’Enseignement Supérieur et de la Recherche to EA4655, Université de Caen Normandie, France. Transparency declarations None to declare. Supplementary data Table S1 is available as Supplementary data at JAC Online. 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Journal of Antimicrobial Chemotherapy – Oxford University Press
Published: Apr 1, 2018
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