Activity of linezolid and daptomycin against methicillin

Antimicrobial Original Research Paper

Activity of linezolid and daptomycin against methicillin-resistant coagulase-negative staphylococci with increased MIC for vancomycin isolated from blood cultures in pediatric patients Elio Castagnola1, Loredana Amoroso2, Laura Banov2, Maura Faraci2, Anna Loy1, Andrea Moscatelli3, Francesco Risso4, Paola Barabino5, Antonella Ciucci6, Roberto Bandettini7 1

Infectious Diseases Unit, Istituto Giannina Gaslini, Genoa, Italy, 2Hemato-Oncology and Bone Marrow Transplant Unit, Istituto Giannina Gaslini, Genoa, Italy, 3Pediatric Intensive Care Unit, Istituto Giannina Gaslini, Genoa, Italy, 4Neonatal Intensive Care Unit, Istituto Giannina Gaslini, Genoa, Italy, 5Service of Pharmacy, Istituto Giannina Gaslini, Genoa, Italy, 6Sanitary Directorate, Hospital Infection Control Team, Istituto Giannina Gaslini, Genoa, Italy, 7Laboratory of Microbiology, Istituto Giannina Gaslini, Genoa, Italy

We evaluated minimal inhibitory concentration (MIC) for vancomycin, daptomycin, and linezolid in methicillin-resistant coagulase-negative staphylococci (MR-CoNS). Minimal inhibitory concentration of 2– 4 mg/l for vancomycin was observed in 16% of strains, and among them 19% had MIC at breakpoint for daptomycin or linezolid. Among strains completely susceptible to vancomycin, 16% had MIC at breakpoint for daptomycin and 11% had for linezolid. This large proportion of pathogens with MIC around the breakpoint suggests a possible risk of treatment failure with these drugs. This phenomenon is worth further and constant monitoring. Keywords: Linezolid, Daptomycin, Vancomycin, Methicillin-resistant coagulase-negative staphylococci, Increased minimal inhibitory concentration, Pediatric patients

Coagulase-negative staphylococci (CoNS) are common colonizers of human skin and are among the most commonly isolated organisms from blood cultures in hemato-oncology and in patients admitted in intensive care units. In spite of their low pathogenicity, CoNS may cause severe infectious complications in low birth weight neonates or immunocompromised children with intravascular catheters or in presence of prosthetic devices, or other foreign bodies. Resistance to methicillin is widespread among CoNS, and there are recent reports of strains with an increase in values of minimal inhibitory concentration (MIC) for vancomycin.1–3 In the period 2007–2009, we observed an increase in treatment failures in central venous catheter-related bacteremias in children with cancer due to methicillinresistant CoNS (MR-CoNS) with increased MIC for vancomycin.4 Therefore, we decided to evaluate the

Correspondence to: Elio Castagnola, Infectious Diseases Unit, Istituto Giannina Gaslini, Largo G. Gaslini, 5, 16147 Genova, Italy. Email: [email protected]

! 2013 Edizioni Scientifiche per l’Informazione su Farmaci e Terapia DOI 10.1179/1973947813Y.0000000134

Journal of Chemotherapy joc358.3d 3/9/13 13:19:24 The Charlesworth Group, Wakefield +44(0)1924 369598 -

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MIC of linezolid and daptomycin in MR-CoNS with increased MIC for vancomycin isolated from blood cultures in children with cancer or admitted in the pediatric or neonatal intensive care unit of ‘Istituto Giannina Gaslini’, Genova, Italy.

Materials and Methods Data regarding all the CoNS strains isolated from blood cultures performed in children admitted in hemato-oncology, infectious disease, and pediatric and neonatal intensive care units from January 2010 to December 2012 were retrieved from the Laboratory of Microbiology database. All strains isolated from blood cultures during the study period were evaluated, independently from a clinical diagnosis of ‘true’ infection or blood culture contamination (i.e. isolation from multiple cultures or from a single one).5 Pathogen identification and antibiotic susceptibility were performed by the automated Phoenix system (Becton Dickinson, Sparks, MD). All cases of

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Table 1 Minimal inhibitory concentration (MIC) for vancomycin, daptomycin, and linezolid among 426 methicillin-resistant coagulase-negative staphylococci (MR-CoNS) MIC for vancomycin: no. of strains ,2 mg/l 2–4 mg/l *

Daptomycin MIC51 mg/l (*)

Linezolid MIC54 mg/l (*)

59 (16%) 13 (19%)

41 (11%) 13 (19%)

359 (84%) 67 (16%)

Percentages are referred to the number of strains with different MICs for vancomycin.

isolation of MR-CoNS data on MIC for vancomycin, daptomycin, and linezolid were sorted out, and results were interpreted according to the most recent European Committee on Antimicrobial Susceptibility Testing (EUCAST) recommendations.6 Minimal inhibitory concentration values§2 mg/l for vancomycin, as well as MIC values.1 mg/l and .4 mg/L for daptomycin and linezolid, respectively were confirmed with the E-test.

Results During the study period, 426 strains of MR-CoNS were isolated from blood cultures and tested for vancomycin susceptibility. No strain resulted resistant to vancomycin, but 67 (16%) showed increased MIC values (2–4 mg/l). Among the 348 strains tested for daptomycin, 1 (0.3%) resulted resistant and 72 (21%) had MIC values equal to the breakpoint (1 mg/ l). As for linezolid, among 424 strains tested, 2 (0.5%) resulted resistant and 54 (13%) had MIC values equal to the breakpoint (4 mg/l). Strains were then stratified by MIC for vancomycin, and the proportions of strains with concomitant MIC values at the breakpoint for daptomycin or linezolid were evaluated in these settings (Table 1). The proportion of MRCoNS with higher MIC for vancomycin and MIC at the breakpoint for linezolid and daptomycin was 19% for both drugs. Interestingly, among strains completely susceptible to vancomycin, the proportion of strains with higher MIC values was 16% for daptomycin and 11% for linezolid. Finally, in order to estimate the use of vancomycin, linezolid, and daptomycin in the hospital, considering an improper, excessive use as a possible cause of increase in MIC values, we evaluated the amount of the drugs delivered by the Pharmacy Service to all the hospital wards during the study period that resulted to be of 6597 g of vancomycin, 84 g of daptomycin, and 1067.7 g of linezolid (including both intravenous and oral formulations).

observed in other studies,1,2 but no strain resulted in vancomycin resistance. Complete resistance to linezolid and daptomycin was observed in less than 1% of strains, but 19% of MR-CoNS with higher MIC for vancomycin had MIC value equal to the breakpoint for both these drugs. Moreover, there were notnegligible proportions of MR-CoNS completely susceptible to vancomycin that showed higher MIC values for daptomycin (16%) and linezolid (11%). Increased MIC values or resistance to these drugs have been already reported,2,7,8 but our findings were quite surprising, especially considering the high restriction in the use of daptomycin and linezolid we adopted in our hospital, suggested by the amount of each drug delivered by the Pharmacy Service to all the hospital wards (and not only to those considered in the present study) during the study period. At present we have no explanation for this observation, which in any case results quite worrisome. Treatment of bacteremias due to methicillinresistant staphylococci with higher MIC values for vancomycin is frequently disappointing, as observed in our previous study.4 In the case of infection due to MRSA with higher MIC for vancomycin guidelines suggests the possibility of increasing doses or changing to an alternative agent, like daptomycin or linezolid, in patients who have not clinically or microbiologically responded.9,10 On the contrary, in the case of infections due to MR-CoNS with higher MIC values for vancomycin, the picture is more confused and no recommendations or guidelines are available. Even if pediatric data are quite scarce, linezolid and daptomycin could represent possible treatments of infections due to MR-CoNS with higher MIC for vancomycin also in children,11,12 but our data show that a not-negligible proportion of strains may present MIC values at breakpoint for daptomycin and linezolid, with an underlying risk of treatment failure. This phenomenon is worth further and constant monitoring.

Discussion In the present study, we evaluated the MIC values for vancomycin, linezolid, and daptomycin against MRCoNS isolated during a 3-year period in children admitted in hemato-oncologic, infectious disease, or intensive care units in a tertiary care pediatric hospital. The prevalence of MR-CoNS with higher MIC values for vancomycin was 16%, similar to that 2


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