Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC Bacteraemia Surveillance Programme, 2013–2015

Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC... Coagulase-negative staphylococci (CoNS) are a significant cause of bacteraemia, the treatment of which is becoming increas- ingly complex due to the emergence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of ceftobiprole, an advanced-generation cephalosporin, as compared with other antimicrobial agents against CoNS from patients with bacteraemia. As part of the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme, 650 blood isolates of CoNS were obtained from patients with bacteraemia at 74 centres throughout the UK and Ireland for the years 2013–2015. Minimum inhibitory concentrations (MICs) of ceftobiprole and other antimicrobial agents were determined using the BSAC agar dilution method. Susceptibility was assessed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The majority of the isolates (63.2%) were Staphylococcus epidermidis. Overall, methicillin resis- tance, as determined by oxacillin susceptibility testing, was observed in 64.2% of isolates. The MIC of ceftobiprole was 1/ 50/90 2 mg/L, and 100% of CoNS isolates were inhibited at the EUCAST ceftobiprole non-species-specific pharmacokinetic/ pharmacodynamic breakpoint of 4 mg/L. Only one isolate was resistant to vancomycin. Overall rates of resistance to ciproflox- acin, clindamycin, erythromycin and teicoplanin were 50.5, 25.1, 68.2 and 20.9%, respectively. In S. epidermidis, resistance to oxacillin was associated with increased resistance to other antimicrobials. Ceftobiprole demonstrated in vitro activity against all CoNS species isolated from patients with bacteraemia and was active against species resistant to other antistaphylococcal antimicrobials. The collection of clinical data regarding the efficacy of ceftobiprole in treating CoNS bacteraemia is warranted. . . . Keywords Antimicrobial resistance Bacteraemia Surveillance Programme British Society for Antimicrobial Chemotherapy . . Ceftobiprole Coagulase-negative staphylococci Susceptibility testing Introduction and systemic infections [1]. These include catheter-related bloodstream infections (CRBSIs) and infections of implants, Coagulase-negative staphylococci (CoNS) are ubiquitous such as prosthetic heart valves and orthopaedic devices [1]. colonisers of human skin and mucous membranes that have Device-related infections are particularly difficult to treat, and the potential to cause clinically significant infections [1]. removal of the device may be required [1, 4]. Developments in CoNS are a major cause of nosocomial infection, with a par- healthcare, including higher proportions of elderly and comor- ticular risk in premature newborns, patients with neutropenia bid patients and more frequent use of medical/surgical proce- and patients undergoing invasive procedures [1–3]. Due in dures involving insertion or implantation of synthetic devices, part to their affinity for synthetic substrates and ability to form have increased the rate of infections with CoNS [1, 4]. The biofilms, CoNS are a frequent cause of device-related local incidence of resistance to methicillin (as determined by oxa- cillin susceptibility testing), as well as to other classes of an- timicrobial agents, is high among CoNS [1]. Emergence of these multidrug-resistant strains has further complicated the * Kamal Hamed treatment of CoNS infections. kamal.hamed@basilea.com Ceftobiprole is an advanced-generation, broad-spectrum 1 cephalosporin that binds to several penicillin-binding proteins Basilea Pharmaceutica International Ltd., Grenzacherstrasse 487, (PBPs), including PBP2a, and is therefore active against 4005 Basel, Switzerland 1654 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 methicillin-resistant (MR) staphylococci [5]. Ceftobiprole resistance [7, 11]. Resistance to the other antimicrobial agents medocaril, the prodrug form of ceftobiprole, has been ap- (ciprofloxacin, clindamycin, erythromycin, teicoplanin and proved in several European and non-European countries for vancomycin) was determined based on EUCAST breakpoints the treatment of hospital-acquired pneumonia, excluding [11]. MIC and MIC were determined for the entire collec- 50 90 ventilator-associated pneumonia, and for community- tion of isolates and for individual species with at least ten acquired pneumonia caused by susceptible Gram-positive isolates collected. and Gram-negative pathogens including MR Staphylococcus aureus [6, 7]. Ceftobiprole has demonstrated in vitro potency Data availability The datasets generated and/or analysed dur- and bactericidal activity against methicillin-susceptible (MS) ing the current study are available from the corresponding and MR strains of S. aureus, as well as against CoNS [8]. This author on reasonable request. study was conducted in order to determine the activity of ceftobiprole against a total of 650 isolates of several different CoNS species collected between 2013 and 2015 from patients Results with bacteraemia in the UK and Ireland. A total of 650 CoNS isolates were collected, with consistent numbers obtained in each year of the study. The isolates were Materials and methods collected from inpatients and outpatients at both university and community hospitals. CRBSIs were the source of a large Bacterial isolates proportion of the isolates (46%; n = 299). The majority of isolates (63.2%; n =411) were Staphylococcus epidermidis; A total of 74 centres from across the UK and Ireland partici- other CoNS species occurring relatively frequently included pated in the British Society for Antimicrobial Chemotherapy Staphylococcus hominis (12.6%; n = 82), Staphylococcus (BSAC) Bacteraemia Surveillance Programme. Up to seven haemolyticus (9.8%; n =64) and Staphylococcus capitis CoNS isolates per centre per year were obtained from the (7.2%; n =47). blood of patients with clinically significant bacteraemia. The ceftobiprole MIC and MIC values across all 650 50 90 Repeat isolates from the same clinical episode were excluded. isolates were 1 and 2 mg/L, respectively, and no isolate had a The isolates were sent to the central testing laboratory (Public ceftobiprole MIC > 4 mg/L (Table 1). Therefore, based on the Health London, Colindale, London), along with relevant pa- EUCAST PK/PD non-species-specific breakpoint for tient demographic information. At the central testing labora- ceftobiprole (4 mg/L), resistance to ceftobiprole was not de- tory, the isolates were identified to the species level using the tected in any of the 650 CoNS isolates. Furthermore, the ma- matrix-assisted laser desorption ionisation-time of flight jority of isolates (91.6%; n =596) had a ceftobiprole MIC of (MALDI-TOF) mass spectrometry. For the surveillance year < 4 mg/L. Of the 54 isolates with a ceftobiprole MIC of 4 2013, the isolates were identified by MALDI-TOF mass spec- mg/L, all were classified as MR and 79.6% (n = 43) were trometry in conjunction with ChromAgar (Becton Dickinson) S. haemolyticus (Table 1). The ceftobiprole MIC was ≤ and the coagulase tube test. 1 mg/L for all MS isolates. Among the 650 isolates, 471 (72.5%) were MR based on Antimicrobial susceptibility testing oxacillin MICs (Table 2). Methicillin resistance was common in all species where more than ten isolates were collected, with Minimum inhibitory concentrations (MICs) of ceftobiprole rates ranging from 46.8% in S. capitis to 96.9% in and comparators were determined by the BSAC agar dilution S. haemolyticus. Of the ten S. lugdunensis isolates, only one method [9, 10]. Briefly, when testing staphylococci, 10 was MR. Across the entire collection, vancomycin resistance colony-forming units per spot are applied to Iso-Sensitest agar was only observed in a single isolate of S. capitis (Table 2). containing doubling dilutions of antimicrobial agents, except Overall, considerable resistance to ciprofloxacin (50.5%) and for oxacillin where Columbia agar plus 2% NaCl is used. erythromycin (68.2%) was observed, while there was a lower Determination of methicillin resistance was based on the level of resistance to clindamycin (25.1%) and teicoplanin European Committee on Antimicrobial Susceptibility (20.9%). Testing (EUCAST) oxacillin breakpoints: > 2 mg/L for Oxacillin-resistant S. epidermidis displayed high rates of Staphylococcus lugdunensis and Staphylococcus resistance to erythromycin (79.0%) and ciprofloxacin saprophyticus and > 0.25 mg/L for other CoNS species [11]. (75.2%) and moderate rates of resistance to clindamycin As there are currently no species-specific breakpoints for (35.8%) and teicoplanin (31.6%). Oxacillin-susceptible ceftobiprole against CoNS, the ceftobiprole non-species- S. epidermidis exhibited lower levels of cross-resistance to specific pharmacokinetic/pharmacodynamic (PK/PD) the other antibiotics tested compared with oxacillin-resistant breakpoint of 4 mg/L was used to determine ceftobiprole S. epidermidis. The largest difference observed between the Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1655 Table 1 MIC distribution of ceftobiprole against CoNS isolated from bacteraemias at centres in the UK and Ireland in 2013–2015 Organism (no. tested) No. of isolates (cumulative %) inhibited at MIC (mg/L) of MIC (mg/L) 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 50% 90% S. capitis (47) 2 (4.3) 7 (19.1) 7 (34.0) 8 (51.1) 2 (55.3) 9 (74.5) 10 (95.7) 2 (100) 0.125 1 S. epidermidis (411) 3 (0.7) 35 (9.2) 62 (24.3) 96 (47.7) 171 (89.3) 39 (98.9) 5 (100) 1 2 S. haemolyticus (64) 1 (1.6) 0 (1.6) 6 (10.9) 3 (15.6) 11 (32.8) 43 (100) 4 4 S. hominis (82) 1 (1.2) 6 (8.5) 17 (29.3) 13 (45.1) 12 (59.8) 28 (93.9) 5 (100) 1 2 S. lugdunensis (10) 1 (10.0) 8 (90.0) 0 (90.0) 1 (100) 0.5 0.5 S. warneri (20) 2 (10.0) 5 (35.0) 5 (60.0) 7 (95.0) 1 (100) 0.5 1 Other species (16) 2 (12.5) 3 (31.3) 2 (43.8) 6 (81.3) 1 (87.5) 1 (93.8) 1 (100) 0.5 2 All isolates (650) 2 (0.3) 7 (1.4) 13 (3.4) 55 (11.8) 89 (25.5) 143 (47.5) 204 (78.9) 83 (91.7) 54 (100) 1 2 Organisms include Staphylococcus cohnii (1), Staphylococcus pasteuri (3), Staphylococcus pettenkoferi (6), Staphylococcus saprophyticus (1), Staphylococcus simulans (4) and unspeciated Staphylococcus (1) CoNS coagulase-negative staphylococci, MIC minimum inhibitory concentration two groups was with ciprofloxacin; only 11.1% of the significantly lower among most other CoNS strains, in this oxacillin-susceptible S. epidermidis isolates were resistant to analysis, methicillin resistance rates for S. capitis and ciprofloxacin, while 75.2% of the oxacillin-resistant S. warneri were similar to that observed for S. epidermidis, S. epidermidis isolates were resistant. No S. epidermidis iso- suggesting that methicillin resistance may be increasing lates were resistant to vancomycin, regardless of their suscep- among these species. tibility to oxacillin or teicoplanin. S. lugdunensis has a unique microbiological and clinical profile compared to other CoNS species [1]. While commonly found as a skin commensal in healthy individuals, Discussion S. lugdunensis can cause an acute and highly aggressive form of infectious endocarditis, as well as abscesses and wound This study investigated the in vitro activity of ceftobiprole and infections, urinary tract infections, and infections of intravas- other relevant antimicrobial agents against recently isolated cular catheters and other implanted medical devices [1]. For CoNS collected from patients with bacteraemia. S. lugdunensis, methicillin resistance rates of 10.0% were ob- Ceftobiprole demonstrated excellent in vitro activity across served in the present study, comparable with the 7.9% rate the different species, including against isolates with methicil- observed in a previous international surveillance study [1, 15]. lin resistance. In previous research, CoNS, and particularly MR CoNS, The majority of cases of nosocomial bacteraemia are have demonstrated a high rate of resistance to multiple classes caused by CRBSIs, with CoNS being one of the most com- of antibiotics, including fluoroquinolones (ciprofloxacin), monly involved pathogens [1, 12]. Indeed, in the current lincosamides (clindamycin) and macrolides (erythromycin) study, the underlying source of bacteraemia was a CRBSI in [16]. This is supported by the results presented here, where 46% of cases. CRBSIs have a significant impact on patients erythromycin and/or ciprofloxacin resistance was observed in and healthcare systems, with mortality rates and duration of all species, and clindamycin resistance was observed in all admission to intensive care units significantly increased in species apart from the clinically distinct S. lugdunensis. patients with a CRBSI, compared with uninfected patients As resistance to vancomycin is rare in CoNS isolates, and [13]. because the majority of isolates are MR, vancomycin is often Methicillin resistance is widespread among CoNS isolates the first-choice antimicrobial in the treatment of CoNS infec- [1]. Recent surveillance studies have found overall antibiotic tions [1, 17]. The current findings are in agreement with the resistance rates of approximately 80% for CoNS, with meth- previous studies, with only 1 out of 460 isolates (an S. capitis icillin resistance particularly frequent in S. haemolyticus and isolate without methicillin resistance) displaying resistance to S. epidermidis [14]. The findings presented here are consistent vancomycin. Vancomycin MIC creep, where increasing num- with these data, with 72.5% of the CoNS isolates found to be bers of isolates are observed with high vancomycin MICs that MR, and the highest methicillin resistance rates are observed nevertheless remain within the susceptible range, has been for S. haemolyticus (96.9%) and S. epidermidis (75.4%). frequently reported in S. aureus, but has not yet been observed in CoNS [1]. However, the occurrence of vancomycin- While methicillin resistance is generally reported to be 1656 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 Table 2 Comparative in vitro activity of ceftobiprole against 650 CoNS from bacteraemias Organism (n) Antimicrobial agent MIC determination EUCAST MIC interpretation MIC MIC MIC range Percentage Percentage 50 90 (mg/L) (mg/L) (mg/L) susceptible resistant a a All (650) Ceftobiprole 1 2 0.015–4100 0.0 Oxacillin 16 > 128 ≤ 0.03–> 128 27.5 72.5 Ciprofloxacin 2 64 0.06–> 128 49.5 50.5 Clindamycin 0.125 > 128 ≤ 0.03–> 128 74.9 25.1 Erythromycin 64 > 128 0.125–> 128 31.8 68.2 Teicoplanin 4 8 0.25–> 16 79.1 20.9 Vancomycin 2 4 0.5–899.8 0.2 a a S. capitis (47) Ceftobiprole 0.125 1 0.015–2100 0.0 Oxacillin 0.25 > 128 0.06–> 128 53.2 46.8 Ciprofloxacin 0.25 4 0.125–8 89.4 10.6 Clindamycin 0.125 0.25 0.06–> 128 95.7 4.3 Erythromycin 0.5 > 128 0.125–> 128 70.2 29.8 Teicoplanin 1 8 0.5–> 16 89.4 10.6 Vancomycin 2 2 1–897.9 2.1 a a S. epidermidis (411) Ceftobiprole 1 2 0.06–4100 0.0 Oxacillin 8 128 ≤ 0.03–> 128 24.6 75.4 Ciprofloxacin 4 64 0.125–128 40.4 59.6 Clindamycin 0.125 > 128 0.06–> 128 68.6 29.0 Erythromycin 64 > 128 0.125–> 128 28.7 71.3 Teicoplanin 4 8 0.5–16 73.2 26.8 Vancomycin 2 4 1–4 100 0.0 a a Oxacillin-susceptible S. epidermidis (101) Ceftobiprole 0.25 0.25 0.06–0.25 100 0.0 Ciprofloxacin 0.25 8 0.125–128 88.1 11.9 Clindamycin 0.125 0.125 0.06–> 128 92.1 7.9 Erythromycin 0.5 > 128 0.125–> 128 52.5 47.5 Teicoplanin 4 8 0.5–16 88.1 11.9 Vancomycin 2 2 1–4 100 0.0 a a Oxacillin-resistant S. epidermidis (310) Ceftobiprole 1 2 0.125–4100 0.0 Ciprofloxacin 8 64 0.125–128 24.8 75.2 Clindamycin 0.125 > 128 0.06–> 128 61.0 35.8 Erythromycin > 128 > 128 0.125–> 128 21.0 79.0 Teicoplanin 4 8 1–16 68.4 31.6 Vancomycin 2 4 1–4 100 0.0 a a S. haemolyticus (64) Ceftobiprole 4 4 0.125–4100 0.0 Oxacillin > 128 > 128 0.125–> 128 3.1 96.9 Ciprofloxacin 16 128 0.125–> 128 23.4 76.6 Clindamycin 0.125 > 128 0.06–> 128 73.4 26.6 Erythromycin > 128 > 128 0.25–> 128 3.1 96.9 Teicoplanin 4 8 1–> 16 78.1 21.9 Vancomycin 2 4 1–4 100 0.0 a a S. hominis (82) Ceftobiprole 1 2 0.06–4100 0.0 Oxacillin 8 128 0.06–> 128 35.4 64.6 Ciprofloxacin 0.25 64 0.06–> 128 69.5 30.5 Clindamycin 0.125 > 128 0.06–> 128 85.4 13.4 Erythromycin > 128 > 128 0.25–> 128 24.4 75.6 Teicoplanin 0.5 4 0.25–891.5 8.5 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1657 Table 2 (continued) Organism (n) Antimicrobial agent MIC determination EUCAST MIC interpretation MIC MIC MIC range Percentage Percentage 50 90 (mg/L) (mg/L) (mg/L) susceptible resistant Vancomycin 1 2 0.5–4 100 0.0 a a S. lugdunensis (10) Ceftobiprole 0.5 0.5 0.25–2100 0.0 Oxacillin 0.5 0.5 0.25–128 90.0 10.0 Ciprofloxacin 0.25 0.25 0.125–2 90.0 10.0 Clindamycin 0.06 0.125 0.06–0.125 100 0.0 Erythromycin 0.125 0.25 0.125–> 128 90.0 10.0 Teicoplanin 1 1 1–1 100 0.0 Vancomycin 1 1 1–2 100 0.0 a a S. warneri (20) Ceftobiprole 0.5 1 0.125–2100 0.0 Oxacillin 64 > 128 0.125–> 128 30.0 70.0 Ciprofloxacin 0.5 0.5 0.25–64 95.0 5.0 Clindamycin 0.06 0.125 0.06–> 128 95.0 5.0 Erythromycin 0.25 > 128 0.125–> 128 70.0 30.0 Teicoplanin 2 4 1–4 100 0.0 Vancomycin 2 2 1–4 100 0.0 b a a Other species (16) Ceftobiprole 0.5 2 0.06–4100 0.0 Oxacillin 0.5 > 128 ≤ 0.03–> 128 43.8 56.2 Ciprofloxacin 0.25 4 0.125–8 87.5 12.5 Clindamycin 0.125 0.5 ≤ 0.03–> 128 87.5 6.3 Erythromycin 0.25 > 128 0.125–> 128 68.8 31.3 Teicoplanin 2 4 0.5–4 100 0.0 Vancomycin 2 2 1–2 100 0.0 The non-species-specific PK/PD breakpoint was used to determine ceftobiprole resistance Organisms included Staphylococcus cohnii (1), Staphylococcus pasteuri (3), Staphylococcus pettenkoferi (6), Staphylococcus saprophyticus (1), Staphylococcus simulans (4) and unspeciated Staphylococcus (1) CoNS coagulase-negative staphylococci, EUCAST the European Committee on Antimicrobial Susceptibility Testing, MIC minimum inhibitory concentration intermediate heteroresistant S. epidermidis has been reported decade, and there is no evidence of cross-resistance between in the last 5 years in several locations [18]. In one such out- teicoplanin and vancomycin. break in a neonatal intensive care unit, several of the isolates In general, resistance to all antibiotics except vancomycin collected were also non-susceptible to daptomycin [18]. was strongly associated with methicillin resistance. Among Therefore, the potential for CoNS strains to develop reduced MR S. epidermidis, a particularly high rate of ciprofloxacin susceptibility to vancomycin should not be ignored. resistance was observed, and this rate was markedly higher This study found an overall rate of resistance of 20.9% for than that observed in MS S. epidermidis. Previous studies teicoplanin, with teicoplanin-resistant strains observed (in or- have also observed high rates of ciprofloxacin resistance in der of highest to lowest resistance) for S. epidermidis, MR CoNS species [16]. While there may be a molecular link S. haemolyticus, S. capitis and S. hominis. These results are between methicillin resistance and resistance to other antibi- highly comparable to those observed in a previous study of otics, it has been hypothesised that this cross-resistance is CoNS strains isolated from the UK and Ireland from 2001 to more likely due to the overall prevalence of antibiotic resis- 2006, where an overall resistance rate of 20.8% to teicoplanin tance among CoNS species in the nosocomial setting [19]. was observed [16]. The similarities between these studies sug- Rifampicin has recently been reintroduced as an adjunctive gest that teicoplanin resistance in CoNS species has not treatment to vancomycin for the treatment of CoNS infections; changed significantly in the UK and Ireland in more than a however, rifampicin data were not included in this comparison as rifampicin monotherapy is not advised for the treatment of 1658 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 CoNS infections due to the rapid emergence of spontaneous A further factor complicating the treatment of CoNS infec- resistance [1, 20]. Furthermore, robust evidence demonstrat- tions is the tendency of the causative bacteria to form biofilms ing the efficacy of rifampicin against staphylococci is lacking, on the surface of implanted or inserted devices [1]. Biofilm- with a recent phase III study in adult patients with S. aureus associated bacteria often display greater resistance to antimi- infections failing to demonstrate clinical benefit from the ad- crobial therapy and frequently act as a source of reinfection, dition of rifampicin to conventional antibiotic regimens [21]. resulting in the need for removal and replacement of the de- The frequent occurrence of multidrug resistance in CoNS vice. Ceftobiprole has demonstrated in vitro activity against infections, together with the frequently chronic nature of the both MR and MS isolates in a biofilm model, which may be an infections [1], represents a major clinical challenge. Novel important attribute for potential clinical use in CoNS-related antimicrobial agents with activity against multidrug-resistant infections [25]. CoNS are therefore required to more effectively treat these A limitation of this analysis is that it does not report sus- infections. Ceftobiprole, an advanced-generation cephalospo- ceptibility data for linezolid, which is often used in the treat- rin, has previously demonstrated in vitro bactericidal activity ment of CoNS infections, as this antibacterial agent was not against staphylococci, including against CoNS. In an in vitro included in the testing panel for the period considered. time-kill model examining ceftobiprole activity against 6 In conclusion, as antibiotic resistance continues to evolve CoNS strains, including 4 MR CoNS strains, there was at least in CoNS species, new antibacterial agents are required, pref- a 3-log (99.9%) reduction in viable bacteria after 24-h expo- erably with differentiated mechanisms of action that have sure to a concentration of ceftobiprole equal to twice the MIC wide coverage of the different species in the CoNS group. [8]. In this study, all 650 isolates were found to be susceptible Ceftobiprole exhibited in vitro activity against all CoNS spe- to ceftobiprole; 91.7% were inhibited by a ceftobiprole con- cies tested, including S. capitis and MR isolates, but may have centration of 2 mg/L and the remainder inhibited by a somewhat lower activity against S. haemolyticus than against ceftobiprole concentration of 4 mg/L, corresponding to the other CoNS species. Based on the in vitro activity observed, EUCAST PK/PD non-species-specific susceptibility the collection of clinical data regarding the efficacy of breakpoint for ceftobiprole [11]. The three most common spe- ceftobiprole in CoNS infections is warranted. cies observed in this analysis were S. epidermidis, S. hominis Acknowledgements Medical writing assistance was provided by and S. haemolyticus, of which 98.9, 93.9 and 32.8% of Stephen Hawser of IHMA Europe Sàrl and Eve Blumson of Spirit and isolates, respectively, were inhibited by ceftobiprole concen- was funded by Basilea Pharmaceutica International Ltd. trations of 2 mg/L. The lower rate of inhibition in Data were collected by BSAC as part of their Bacteraemia Resistance S. haemolyticus suggests that ceftobiprole may be less Surveillance Programme and are available online at www.bsacsurv.org. effective against infections caused by this strain, compared Funding information This work was supported by Basilea with S. epidermidis and S. hominis. Previous research has Pharmaceutica International Ltd., Basel, Switzerland. shown that S. haemolyticus may be particularly predisposed to acquiring antibiotic resistance, as its genome has high Compliance with ethical standards plasticity due to a high number of insertion sequences [22]. S. haemolyticus may thereby act as a reservoir for resistance Conflict of interest Anne Santerre Henriksen is a former employee of genes that can be transferred to other staphylococci and there- Basilea Pharmaceutica International Ltd. Jennifer Smart and Kamal fore may be an important factor contributing to the develop- Hamed are employees of Basilea Pharmaceutica International Ltd. ment of antibiotic resistance in other CoNS species [22]. Ethical approval This article is based on bacteraemia surveillance data S. capitis was found to be the only species to demonstrate and does not involve any studies of human or animal subjects performed vancomycin resistance. S. capitis infection has been observed by any of the authors. in neonates and adults with infective endocarditis or bone infections and has historically been viewed as susceptible to Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// a broad range of antibiotics [1]. However, data have suggested creativecommons.org/licenses/by/4.0/), which permits unrestricted use, the emergence of multidrug-resistant S. capitis in hospitals distribution, and reproduction in any medium, provided you give appro- across Europe [23]. A recent study also identified S. capitis priate credit to the original author(s) and the source, provide a link to the as a likely causative agent in nosocomial prosthetic joint in- Creative Commons license, and indicate if changes were made. fections, with multidrug-resistant S. capitis detected in ap- proximately 28% of isolates [24]. S. capitis may be an emerg- ing nosocomial pathogen and therefore further surveillance of this species is warranted. Ceftobiprole demonstrated activity References against S. capitis in this study and should be investigated further as a potential treatment for these infections. 1. Becker K, Heilmann C, Peters G (2014) Coagulase-negative staph- ylococci. Clin Microbiol Rev 27:870–926 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1659 2. Rosa RG, dos Santos RP, Goldani LZ (2014) Mortality related to 14. May L, Klein EY, Rothman RE et al (2014) Trends in antibiotic resistance in coagulase-negative staphylococci in the United States. coagulase-negative staphylococcal bacteremia in febrile neutrope- nia: a cohort study. Can J Infect Dis Med Microbiol 25:e14–e17 1999 to 2012 Antimicrob Agents Chemother 58:1404–1409 15. Sader HS, Jones RN (2012) Antimicrobial activity of daptomycin in 3. de Oliveria A, Sanches P, Lyra JC et al (2012) Risk factors for comparison to glycopeptides and other antimicrobials when tested infection with coagulase-negative staphylococci in newborns from against numerous species of coagulase-negative Staphylococcus. the neonatal unit of a Brazilian university hospital. Clin Med Diagn Microbiol Infect Dis 73:212–214 Insights Pediatr 6:1–9 16. Hope R, Livermore DM, Brick G et al (2008) Non-susceptibility 4. Sabate Bresco M, Harris LG, Thompson K et al (2017) Pathogenic trends among staphylococci from bacteraemias in the UK and mechanisms and host interactions in Staphylococcus epidermidis Ireland, 2001–06. J Antimicrob Chemother 62(Suppl 2):ii65–ii74 device-related infection. Front Microbiol 8:1401 17. Farrell DJ, Flamm RK, Sader HS et al (2014) Ceftobiprole activity 5. Hebeisen P, Heinze-Krauss I, Angehrn P et al (2001) In vitro and in against over 60,000 clinical bacterial pathogens isolated in Europe, vivo properties of Ro 63-9141, a novel broad-spectrum cephalospo- Turkey and Israel from 2005 to 2010. Antimicrob Agents rin with activity against methicillin-resistant staphylococci. Chemother 58:3882–3888 Antimicrob Agents Chemother 45:825–835 18. Chong J, Quach C, Blanchard AC et al (2016) Molecular epidemi- 6. Syed YY (2014) Ceftobiprole medocaril: a review of its use in ology of a vancomycin-intermediate heteroresistant Staphylococcus patients with hospital- or community-acquired pneumonia. Drugs epidermidis outbreak in a neonatal intensive care unit. Antimicrob 74:1523–1542 Agents Chemother 60:5673–5681 7. Medicines and Healthcare products Regulatory Agency (2017) 19. Otto M (2019) Staphylococcus epidermidis—the Baccidental^ Summary of product characteristics for Zevtera (ceftobiprole pathogen. Nat Rev Microbiol 7:555–567 medocaril). http://www.mhra.gov.uk/home/groups/par/documents/ 20. van der Lugt NM, Steggerda SJ, Walther FJ (2010) Use of rifampin websiteresources/con369256.pdf. Accessed 25 April 2018 in persistent coagulase negative staphylococcal bacteremia in neo- 8. Bogdanovich T, Ednie LM, Shapiro S et al (2005) nates. BMC Pediatr 10:84 Antistaphylococcal activity of ceftobiprole, a new broad- 21. Thwaites GE, Scarborough M, Szubert A et al (2017) Adjunctive spectrum cephalosporin. Antimicrob Agents Chemother 49: rifampicin for Staphylococcus aureus bacteraemia (ARREST): a 4210–4219 multicentre, randomised, double-blind, placebo-controlled trial. 9. Andrews JM (2001) Determination of minimum inhibitory concen- Lancet 391:668–678 trations. J Antimicrob Chemother 48 Suppl 1:5–16 22. Czekaj T, Ciszewski M, Szewczyk EM (2015) Staphylococcus 10. Andrews JM (2009) Errata: Determination of minimum inhibitory haemolyticus - an emerging threat in the twilight of the antibiotics concentrations. J Antimicrob Chemother 49:1049–1050 age. Microbiology 161:2061–2068 11. The European Committee on Antimicrobial Susceptibility Testing 23. Butin M, Martins-Simões P, Pichon B et al (2017) Emergence and (2017) Breakpoint tables for interpretation of MICs and zone diam- dissemination of a linezolid-resistant Staphylococcus capitis clone eters. Version 7.0. www.eucast.org. Accessed 25 April 2018 in Europe. J Antimicrob Chemother 72:1014–1020 12. Fletcher S (2005) Catheter-related bloodstream infection. Contin 24. Tevell S, Hellmark B, Nilsdotter-Augustinsson A et al (2017) Educ Anaesth Crit Care Pain 5:49–51 Staphylococcus capitis isolated from prosthetic joint infections. Eur J Clin Microbiol Infect Dis 36:115–122 13. Warren DK, Quadir WW, Hollenbeak CS et al (2006) Attributable 25. Abbanat D, Shang W, Amsler K et al (2014) Evaluation of the in cost of catheter-associated bloodstream infections among intensive vitro activities of ceftobiprole and comparators in staphylococcal care patients in a nonteaching hospital. Crit Care Med 34:2084– colony or microtitre plate biofilm assays. Int J Antimicrob Agents 43:32–39 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Clinical Microbiology Infectious Diseases Springer Journals

Comparative activity of ceftobiprole against coagulase-negative staphylococci from the BSAC Bacteraemia Surveillance Programme, 2013–2015

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Springer Journals
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Copyright © 2018 by The Author(s)
Subject
Biomedicine; Medical Microbiology; Internal Medicine
ISSN
0934-9723
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1435-4373
D.O.I.
10.1007/s10096-018-3295-6
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Abstract

Coagulase-negative staphylococci (CoNS) are a significant cause of bacteraemia, the treatment of which is becoming increas- ingly complex due to the emergence of multidrug-resistant strains. This study aimed to evaluate the in vitro activity of ceftobiprole, an advanced-generation cephalosporin, as compared with other antimicrobial agents against CoNS from patients with bacteraemia. As part of the British Society for Antimicrobial Chemotherapy (BSAC) Bacteraemia Surveillance Programme, 650 blood isolates of CoNS were obtained from patients with bacteraemia at 74 centres throughout the UK and Ireland for the years 2013–2015. Minimum inhibitory concentrations (MICs) of ceftobiprole and other antimicrobial agents were determined using the BSAC agar dilution method. Susceptibility was assessed by European Committee on Antimicrobial Susceptibility Testing (EUCAST) criteria. The majority of the isolates (63.2%) were Staphylococcus epidermidis. Overall, methicillin resis- tance, as determined by oxacillin susceptibility testing, was observed in 64.2% of isolates. The MIC of ceftobiprole was 1/ 50/90 2 mg/L, and 100% of CoNS isolates were inhibited at the EUCAST ceftobiprole non-species-specific pharmacokinetic/ pharmacodynamic breakpoint of 4 mg/L. Only one isolate was resistant to vancomycin. Overall rates of resistance to ciproflox- acin, clindamycin, erythromycin and teicoplanin were 50.5, 25.1, 68.2 and 20.9%, respectively. In S. epidermidis, resistance to oxacillin was associated with increased resistance to other antimicrobials. Ceftobiprole demonstrated in vitro activity against all CoNS species isolated from patients with bacteraemia and was active against species resistant to other antistaphylococcal antimicrobials. The collection of clinical data regarding the efficacy of ceftobiprole in treating CoNS bacteraemia is warranted. . . . Keywords Antimicrobial resistance Bacteraemia Surveillance Programme British Society for Antimicrobial Chemotherapy . . Ceftobiprole Coagulase-negative staphylococci Susceptibility testing Introduction and systemic infections [1]. These include catheter-related bloodstream infections (CRBSIs) and infections of implants, Coagulase-negative staphylococci (CoNS) are ubiquitous such as prosthetic heart valves and orthopaedic devices [1]. colonisers of human skin and mucous membranes that have Device-related infections are particularly difficult to treat, and the potential to cause clinically significant infections [1]. removal of the device may be required [1, 4]. Developments in CoNS are a major cause of nosocomial infection, with a par- healthcare, including higher proportions of elderly and comor- ticular risk in premature newborns, patients with neutropenia bid patients and more frequent use of medical/surgical proce- and patients undergoing invasive procedures [1–3]. Due in dures involving insertion or implantation of synthetic devices, part to their affinity for synthetic substrates and ability to form have increased the rate of infections with CoNS [1, 4]. The biofilms, CoNS are a frequent cause of device-related local incidence of resistance to methicillin (as determined by oxa- cillin susceptibility testing), as well as to other classes of an- timicrobial agents, is high among CoNS [1]. Emergence of these multidrug-resistant strains has further complicated the * Kamal Hamed treatment of CoNS infections. kamal.hamed@basilea.com Ceftobiprole is an advanced-generation, broad-spectrum 1 cephalosporin that binds to several penicillin-binding proteins Basilea Pharmaceutica International Ltd., Grenzacherstrasse 487, (PBPs), including PBP2a, and is therefore active against 4005 Basel, Switzerland 1654 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 methicillin-resistant (MR) staphylococci [5]. Ceftobiprole resistance [7, 11]. Resistance to the other antimicrobial agents medocaril, the prodrug form of ceftobiprole, has been ap- (ciprofloxacin, clindamycin, erythromycin, teicoplanin and proved in several European and non-European countries for vancomycin) was determined based on EUCAST breakpoints the treatment of hospital-acquired pneumonia, excluding [11]. MIC and MIC were determined for the entire collec- 50 90 ventilator-associated pneumonia, and for community- tion of isolates and for individual species with at least ten acquired pneumonia caused by susceptible Gram-positive isolates collected. and Gram-negative pathogens including MR Staphylococcus aureus [6, 7]. Ceftobiprole has demonstrated in vitro potency Data availability The datasets generated and/or analysed dur- and bactericidal activity against methicillin-susceptible (MS) ing the current study are available from the corresponding and MR strains of S. aureus, as well as against CoNS [8]. This author on reasonable request. study was conducted in order to determine the activity of ceftobiprole against a total of 650 isolates of several different CoNS species collected between 2013 and 2015 from patients Results with bacteraemia in the UK and Ireland. A total of 650 CoNS isolates were collected, with consistent numbers obtained in each year of the study. The isolates were Materials and methods collected from inpatients and outpatients at both university and community hospitals. CRBSIs were the source of a large Bacterial isolates proportion of the isolates (46%; n = 299). The majority of isolates (63.2%; n =411) were Staphylococcus epidermidis; A total of 74 centres from across the UK and Ireland partici- other CoNS species occurring relatively frequently included pated in the British Society for Antimicrobial Chemotherapy Staphylococcus hominis (12.6%; n = 82), Staphylococcus (BSAC) Bacteraemia Surveillance Programme. Up to seven haemolyticus (9.8%; n =64) and Staphylococcus capitis CoNS isolates per centre per year were obtained from the (7.2%; n =47). blood of patients with clinically significant bacteraemia. The ceftobiprole MIC and MIC values across all 650 50 90 Repeat isolates from the same clinical episode were excluded. isolates were 1 and 2 mg/L, respectively, and no isolate had a The isolates were sent to the central testing laboratory (Public ceftobiprole MIC > 4 mg/L (Table 1). Therefore, based on the Health London, Colindale, London), along with relevant pa- EUCAST PK/PD non-species-specific breakpoint for tient demographic information. At the central testing labora- ceftobiprole (4 mg/L), resistance to ceftobiprole was not de- tory, the isolates were identified to the species level using the tected in any of the 650 CoNS isolates. Furthermore, the ma- matrix-assisted laser desorption ionisation-time of flight jority of isolates (91.6%; n =596) had a ceftobiprole MIC of (MALDI-TOF) mass spectrometry. For the surveillance year < 4 mg/L. Of the 54 isolates with a ceftobiprole MIC of 4 2013, the isolates were identified by MALDI-TOF mass spec- mg/L, all were classified as MR and 79.6% (n = 43) were trometry in conjunction with ChromAgar (Becton Dickinson) S. haemolyticus (Table 1). The ceftobiprole MIC was ≤ and the coagulase tube test. 1 mg/L for all MS isolates. Among the 650 isolates, 471 (72.5%) were MR based on Antimicrobial susceptibility testing oxacillin MICs (Table 2). Methicillin resistance was common in all species where more than ten isolates were collected, with Minimum inhibitory concentrations (MICs) of ceftobiprole rates ranging from 46.8% in S. capitis to 96.9% in and comparators were determined by the BSAC agar dilution S. haemolyticus. Of the ten S. lugdunensis isolates, only one method [9, 10]. Briefly, when testing staphylococci, 10 was MR. Across the entire collection, vancomycin resistance colony-forming units per spot are applied to Iso-Sensitest agar was only observed in a single isolate of S. capitis (Table 2). containing doubling dilutions of antimicrobial agents, except Overall, considerable resistance to ciprofloxacin (50.5%) and for oxacillin where Columbia agar plus 2% NaCl is used. erythromycin (68.2%) was observed, while there was a lower Determination of methicillin resistance was based on the level of resistance to clindamycin (25.1%) and teicoplanin European Committee on Antimicrobial Susceptibility (20.9%). Testing (EUCAST) oxacillin breakpoints: > 2 mg/L for Oxacillin-resistant S. epidermidis displayed high rates of Staphylococcus lugdunensis and Staphylococcus resistance to erythromycin (79.0%) and ciprofloxacin saprophyticus and > 0.25 mg/L for other CoNS species [11]. (75.2%) and moderate rates of resistance to clindamycin As there are currently no species-specific breakpoints for (35.8%) and teicoplanin (31.6%). Oxacillin-susceptible ceftobiprole against CoNS, the ceftobiprole non-species- S. epidermidis exhibited lower levels of cross-resistance to specific pharmacokinetic/pharmacodynamic (PK/PD) the other antibiotics tested compared with oxacillin-resistant breakpoint of 4 mg/L was used to determine ceftobiprole S. epidermidis. The largest difference observed between the Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1655 Table 1 MIC distribution of ceftobiprole against CoNS isolated from bacteraemias at centres in the UK and Ireland in 2013–2015 Organism (no. tested) No. of isolates (cumulative %) inhibited at MIC (mg/L) of MIC (mg/L) 0.015 0.03 0.06 0.125 0.25 0.5 1 2 4 50% 90% S. capitis (47) 2 (4.3) 7 (19.1) 7 (34.0) 8 (51.1) 2 (55.3) 9 (74.5) 10 (95.7) 2 (100) 0.125 1 S. epidermidis (411) 3 (0.7) 35 (9.2) 62 (24.3) 96 (47.7) 171 (89.3) 39 (98.9) 5 (100) 1 2 S. haemolyticus (64) 1 (1.6) 0 (1.6) 6 (10.9) 3 (15.6) 11 (32.8) 43 (100) 4 4 S. hominis (82) 1 (1.2) 6 (8.5) 17 (29.3) 13 (45.1) 12 (59.8) 28 (93.9) 5 (100) 1 2 S. lugdunensis (10) 1 (10.0) 8 (90.0) 0 (90.0) 1 (100) 0.5 0.5 S. warneri (20) 2 (10.0) 5 (35.0) 5 (60.0) 7 (95.0) 1 (100) 0.5 1 Other species (16) 2 (12.5) 3 (31.3) 2 (43.8) 6 (81.3) 1 (87.5) 1 (93.8) 1 (100) 0.5 2 All isolates (650) 2 (0.3) 7 (1.4) 13 (3.4) 55 (11.8) 89 (25.5) 143 (47.5) 204 (78.9) 83 (91.7) 54 (100) 1 2 Organisms include Staphylococcus cohnii (1), Staphylococcus pasteuri (3), Staphylococcus pettenkoferi (6), Staphylococcus saprophyticus (1), Staphylococcus simulans (4) and unspeciated Staphylococcus (1) CoNS coagulase-negative staphylococci, MIC minimum inhibitory concentration two groups was with ciprofloxacin; only 11.1% of the significantly lower among most other CoNS strains, in this oxacillin-susceptible S. epidermidis isolates were resistant to analysis, methicillin resistance rates for S. capitis and ciprofloxacin, while 75.2% of the oxacillin-resistant S. warneri were similar to that observed for S. epidermidis, S. epidermidis isolates were resistant. No S. epidermidis iso- suggesting that methicillin resistance may be increasing lates were resistant to vancomycin, regardless of their suscep- among these species. tibility to oxacillin or teicoplanin. S. lugdunensis has a unique microbiological and clinical profile compared to other CoNS species [1]. While commonly found as a skin commensal in healthy individuals, Discussion S. lugdunensis can cause an acute and highly aggressive form of infectious endocarditis, as well as abscesses and wound This study investigated the in vitro activity of ceftobiprole and infections, urinary tract infections, and infections of intravas- other relevant antimicrobial agents against recently isolated cular catheters and other implanted medical devices [1]. For CoNS collected from patients with bacteraemia. S. lugdunensis, methicillin resistance rates of 10.0% were ob- Ceftobiprole demonstrated excellent in vitro activity across served in the present study, comparable with the 7.9% rate the different species, including against isolates with methicil- observed in a previous international surveillance study [1, 15]. lin resistance. In previous research, CoNS, and particularly MR CoNS, The majority of cases of nosocomial bacteraemia are have demonstrated a high rate of resistance to multiple classes caused by CRBSIs, with CoNS being one of the most com- of antibiotics, including fluoroquinolones (ciprofloxacin), monly involved pathogens [1, 12]. Indeed, in the current lincosamides (clindamycin) and macrolides (erythromycin) study, the underlying source of bacteraemia was a CRBSI in [16]. This is supported by the results presented here, where 46% of cases. CRBSIs have a significant impact on patients erythromycin and/or ciprofloxacin resistance was observed in and healthcare systems, with mortality rates and duration of all species, and clindamycin resistance was observed in all admission to intensive care units significantly increased in species apart from the clinically distinct S. lugdunensis. patients with a CRBSI, compared with uninfected patients As resistance to vancomycin is rare in CoNS isolates, and [13]. because the majority of isolates are MR, vancomycin is often Methicillin resistance is widespread among CoNS isolates the first-choice antimicrobial in the treatment of CoNS infec- [1]. Recent surveillance studies have found overall antibiotic tions [1, 17]. The current findings are in agreement with the resistance rates of approximately 80% for CoNS, with meth- previous studies, with only 1 out of 460 isolates (an S. capitis icillin resistance particularly frequent in S. haemolyticus and isolate without methicillin resistance) displaying resistance to S. epidermidis [14]. The findings presented here are consistent vancomycin. Vancomycin MIC creep, where increasing num- with these data, with 72.5% of the CoNS isolates found to be bers of isolates are observed with high vancomycin MICs that MR, and the highest methicillin resistance rates are observed nevertheless remain within the susceptible range, has been for S. haemolyticus (96.9%) and S. epidermidis (75.4%). frequently reported in S. aureus, but has not yet been observed in CoNS [1]. However, the occurrence of vancomycin- While methicillin resistance is generally reported to be 1656 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 Table 2 Comparative in vitro activity of ceftobiprole against 650 CoNS from bacteraemias Organism (n) Antimicrobial agent MIC determination EUCAST MIC interpretation MIC MIC MIC range Percentage Percentage 50 90 (mg/L) (mg/L) (mg/L) susceptible resistant a a All (650) Ceftobiprole 1 2 0.015–4100 0.0 Oxacillin 16 > 128 ≤ 0.03–> 128 27.5 72.5 Ciprofloxacin 2 64 0.06–> 128 49.5 50.5 Clindamycin 0.125 > 128 ≤ 0.03–> 128 74.9 25.1 Erythromycin 64 > 128 0.125–> 128 31.8 68.2 Teicoplanin 4 8 0.25–> 16 79.1 20.9 Vancomycin 2 4 0.5–899.8 0.2 a a S. capitis (47) Ceftobiprole 0.125 1 0.015–2100 0.0 Oxacillin 0.25 > 128 0.06–> 128 53.2 46.8 Ciprofloxacin 0.25 4 0.125–8 89.4 10.6 Clindamycin 0.125 0.25 0.06–> 128 95.7 4.3 Erythromycin 0.5 > 128 0.125–> 128 70.2 29.8 Teicoplanin 1 8 0.5–> 16 89.4 10.6 Vancomycin 2 2 1–897.9 2.1 a a S. epidermidis (411) Ceftobiprole 1 2 0.06–4100 0.0 Oxacillin 8 128 ≤ 0.03–> 128 24.6 75.4 Ciprofloxacin 4 64 0.125–128 40.4 59.6 Clindamycin 0.125 > 128 0.06–> 128 68.6 29.0 Erythromycin 64 > 128 0.125–> 128 28.7 71.3 Teicoplanin 4 8 0.5–16 73.2 26.8 Vancomycin 2 4 1–4 100 0.0 a a Oxacillin-susceptible S. epidermidis (101) Ceftobiprole 0.25 0.25 0.06–0.25 100 0.0 Ciprofloxacin 0.25 8 0.125–128 88.1 11.9 Clindamycin 0.125 0.125 0.06–> 128 92.1 7.9 Erythromycin 0.5 > 128 0.125–> 128 52.5 47.5 Teicoplanin 4 8 0.5–16 88.1 11.9 Vancomycin 2 2 1–4 100 0.0 a a Oxacillin-resistant S. epidermidis (310) Ceftobiprole 1 2 0.125–4100 0.0 Ciprofloxacin 8 64 0.125–128 24.8 75.2 Clindamycin 0.125 > 128 0.06–> 128 61.0 35.8 Erythromycin > 128 > 128 0.125–> 128 21.0 79.0 Teicoplanin 4 8 1–16 68.4 31.6 Vancomycin 2 4 1–4 100 0.0 a a S. haemolyticus (64) Ceftobiprole 4 4 0.125–4100 0.0 Oxacillin > 128 > 128 0.125–> 128 3.1 96.9 Ciprofloxacin 16 128 0.125–> 128 23.4 76.6 Clindamycin 0.125 > 128 0.06–> 128 73.4 26.6 Erythromycin > 128 > 128 0.25–> 128 3.1 96.9 Teicoplanin 4 8 1–> 16 78.1 21.9 Vancomycin 2 4 1–4 100 0.0 a a S. hominis (82) Ceftobiprole 1 2 0.06–4100 0.0 Oxacillin 8 128 0.06–> 128 35.4 64.6 Ciprofloxacin 0.25 64 0.06–> 128 69.5 30.5 Clindamycin 0.125 > 128 0.06–> 128 85.4 13.4 Erythromycin > 128 > 128 0.25–> 128 24.4 75.6 Teicoplanin 0.5 4 0.25–891.5 8.5 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1657 Table 2 (continued) Organism (n) Antimicrobial agent MIC determination EUCAST MIC interpretation MIC MIC MIC range Percentage Percentage 50 90 (mg/L) (mg/L) (mg/L) susceptible resistant Vancomycin 1 2 0.5–4 100 0.0 a a S. lugdunensis (10) Ceftobiprole 0.5 0.5 0.25–2100 0.0 Oxacillin 0.5 0.5 0.25–128 90.0 10.0 Ciprofloxacin 0.25 0.25 0.125–2 90.0 10.0 Clindamycin 0.06 0.125 0.06–0.125 100 0.0 Erythromycin 0.125 0.25 0.125–> 128 90.0 10.0 Teicoplanin 1 1 1–1 100 0.0 Vancomycin 1 1 1–2 100 0.0 a a S. warneri (20) Ceftobiprole 0.5 1 0.125–2100 0.0 Oxacillin 64 > 128 0.125–> 128 30.0 70.0 Ciprofloxacin 0.5 0.5 0.25–64 95.0 5.0 Clindamycin 0.06 0.125 0.06–> 128 95.0 5.0 Erythromycin 0.25 > 128 0.125–> 128 70.0 30.0 Teicoplanin 2 4 1–4 100 0.0 Vancomycin 2 2 1–4 100 0.0 b a a Other species (16) Ceftobiprole 0.5 2 0.06–4100 0.0 Oxacillin 0.5 > 128 ≤ 0.03–> 128 43.8 56.2 Ciprofloxacin 0.25 4 0.125–8 87.5 12.5 Clindamycin 0.125 0.5 ≤ 0.03–> 128 87.5 6.3 Erythromycin 0.25 > 128 0.125–> 128 68.8 31.3 Teicoplanin 2 4 0.5–4 100 0.0 Vancomycin 2 2 1–2 100 0.0 The non-species-specific PK/PD breakpoint was used to determine ceftobiprole resistance Organisms included Staphylococcus cohnii (1), Staphylococcus pasteuri (3), Staphylococcus pettenkoferi (6), Staphylococcus saprophyticus (1), Staphylococcus simulans (4) and unspeciated Staphylococcus (1) CoNS coagulase-negative staphylococci, EUCAST the European Committee on Antimicrobial Susceptibility Testing, MIC minimum inhibitory concentration intermediate heteroresistant S. epidermidis has been reported decade, and there is no evidence of cross-resistance between in the last 5 years in several locations [18]. In one such out- teicoplanin and vancomycin. break in a neonatal intensive care unit, several of the isolates In general, resistance to all antibiotics except vancomycin collected were also non-susceptible to daptomycin [18]. was strongly associated with methicillin resistance. Among Therefore, the potential for CoNS strains to develop reduced MR S. epidermidis, a particularly high rate of ciprofloxacin susceptibility to vancomycin should not be ignored. resistance was observed, and this rate was markedly higher This study found an overall rate of resistance of 20.9% for than that observed in MS S. epidermidis. Previous studies teicoplanin, with teicoplanin-resistant strains observed (in or- have also observed high rates of ciprofloxacin resistance in der of highest to lowest resistance) for S. epidermidis, MR CoNS species [16]. While there may be a molecular link S. haemolyticus, S. capitis and S. hominis. These results are between methicillin resistance and resistance to other antibi- highly comparable to those observed in a previous study of otics, it has been hypothesised that this cross-resistance is CoNS strains isolated from the UK and Ireland from 2001 to more likely due to the overall prevalence of antibiotic resis- 2006, where an overall resistance rate of 20.8% to teicoplanin tance among CoNS species in the nosocomial setting [19]. was observed [16]. The similarities between these studies sug- Rifampicin has recently been reintroduced as an adjunctive gest that teicoplanin resistance in CoNS species has not treatment to vancomycin for the treatment of CoNS infections; changed significantly in the UK and Ireland in more than a however, rifampicin data were not included in this comparison as rifampicin monotherapy is not advised for the treatment of 1658 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 CoNS infections due to the rapid emergence of spontaneous A further factor complicating the treatment of CoNS infec- resistance [1, 20]. Furthermore, robust evidence demonstrat- tions is the tendency of the causative bacteria to form biofilms ing the efficacy of rifampicin against staphylococci is lacking, on the surface of implanted or inserted devices [1]. Biofilm- with a recent phase III study in adult patients with S. aureus associated bacteria often display greater resistance to antimi- infections failing to demonstrate clinical benefit from the ad- crobial therapy and frequently act as a source of reinfection, dition of rifampicin to conventional antibiotic regimens [21]. resulting in the need for removal and replacement of the de- The frequent occurrence of multidrug resistance in CoNS vice. Ceftobiprole has demonstrated in vitro activity against infections, together with the frequently chronic nature of the both MR and MS isolates in a biofilm model, which may be an infections [1], represents a major clinical challenge. Novel important attribute for potential clinical use in CoNS-related antimicrobial agents with activity against multidrug-resistant infections [25]. CoNS are therefore required to more effectively treat these A limitation of this analysis is that it does not report sus- infections. Ceftobiprole, an advanced-generation cephalospo- ceptibility data for linezolid, which is often used in the treat- rin, has previously demonstrated in vitro bactericidal activity ment of CoNS infections, as this antibacterial agent was not against staphylococci, including against CoNS. In an in vitro included in the testing panel for the period considered. time-kill model examining ceftobiprole activity against 6 In conclusion, as antibiotic resistance continues to evolve CoNS strains, including 4 MR CoNS strains, there was at least in CoNS species, new antibacterial agents are required, pref- a 3-log (99.9%) reduction in viable bacteria after 24-h expo- erably with differentiated mechanisms of action that have sure to a concentration of ceftobiprole equal to twice the MIC wide coverage of the different species in the CoNS group. [8]. In this study, all 650 isolates were found to be susceptible Ceftobiprole exhibited in vitro activity against all CoNS spe- to ceftobiprole; 91.7% were inhibited by a ceftobiprole con- cies tested, including S. capitis and MR isolates, but may have centration of 2 mg/L and the remainder inhibited by a somewhat lower activity against S. haemolyticus than against ceftobiprole concentration of 4 mg/L, corresponding to the other CoNS species. Based on the in vitro activity observed, EUCAST PK/PD non-species-specific susceptibility the collection of clinical data regarding the efficacy of breakpoint for ceftobiprole [11]. The three most common spe- ceftobiprole in CoNS infections is warranted. cies observed in this analysis were S. epidermidis, S. hominis Acknowledgements Medical writing assistance was provided by and S. haemolyticus, of which 98.9, 93.9 and 32.8% of Stephen Hawser of IHMA Europe Sàrl and Eve Blumson of Spirit and isolates, respectively, were inhibited by ceftobiprole concen- was funded by Basilea Pharmaceutica International Ltd. trations of 2 mg/L. The lower rate of inhibition in Data were collected by BSAC as part of their Bacteraemia Resistance S. haemolyticus suggests that ceftobiprole may be less Surveillance Programme and are available online at www.bsacsurv.org. effective against infections caused by this strain, compared Funding information This work was supported by Basilea with S. epidermidis and S. hominis. Previous research has Pharmaceutica International Ltd., Basel, Switzerland. shown that S. haemolyticus may be particularly predisposed to acquiring antibiotic resistance, as its genome has high Compliance with ethical standards plasticity due to a high number of insertion sequences [22]. S. haemolyticus may thereby act as a reservoir for resistance Conflict of interest Anne Santerre Henriksen is a former employee of genes that can be transferred to other staphylococci and there- Basilea Pharmaceutica International Ltd. Jennifer Smart and Kamal fore may be an important factor contributing to the develop- Hamed are employees of Basilea Pharmaceutica International Ltd. ment of antibiotic resistance in other CoNS species [22]. Ethical approval This article is based on bacteraemia surveillance data S. capitis was found to be the only species to demonstrate and does not involve any studies of human or animal subjects performed vancomycin resistance. S. capitis infection has been observed by any of the authors. in neonates and adults with infective endocarditis or bone infections and has historically been viewed as susceptible to Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// a broad range of antibiotics [1]. However, data have suggested creativecommons.org/licenses/by/4.0/), which permits unrestricted use, the emergence of multidrug-resistant S. capitis in hospitals distribution, and reproduction in any medium, provided you give appro- across Europe [23]. A recent study also identified S. capitis priate credit to the original author(s) and the source, provide a link to the as a likely causative agent in nosocomial prosthetic joint in- Creative Commons license, and indicate if changes were made. fections, with multidrug-resistant S. capitis detected in ap- proximately 28% of isolates [24]. S. capitis may be an emerg- ing nosocomial pathogen and therefore further surveillance of this species is warranted. Ceftobiprole demonstrated activity References against S. capitis in this study and should be investigated further as a potential treatment for these infections. 1. Becker K, Heilmann C, Peters G (2014) Coagulase-negative staph- ylococci. Clin Microbiol Rev 27:870–926 Eur J Clin Microbiol Infect Dis (2018) 37:1653–1659 1659 2. Rosa RG, dos Santos RP, Goldani LZ (2014) Mortality related to 14. May L, Klein EY, Rothman RE et al (2014) Trends in antibiotic resistance in coagulase-negative staphylococci in the United States. coagulase-negative staphylococcal bacteremia in febrile neutrope- nia: a cohort study. Can J Infect Dis Med Microbiol 25:e14–e17 1999 to 2012 Antimicrob Agents Chemother 58:1404–1409 15. Sader HS, Jones RN (2012) Antimicrobial activity of daptomycin in 3. de Oliveria A, Sanches P, Lyra JC et al (2012) Risk factors for comparison to glycopeptides and other antimicrobials when tested infection with coagulase-negative staphylococci in newborns from against numerous species of coagulase-negative Staphylococcus. the neonatal unit of a Brazilian university hospital. Clin Med Diagn Microbiol Infect Dis 73:212–214 Insights Pediatr 6:1–9 16. Hope R, Livermore DM, Brick G et al (2008) Non-susceptibility 4. Sabate Bresco M, Harris LG, Thompson K et al (2017) Pathogenic trends among staphylococci from bacteraemias in the UK and mechanisms and host interactions in Staphylococcus epidermidis Ireland, 2001–06. J Antimicrob Chemother 62(Suppl 2):ii65–ii74 device-related infection. Front Microbiol 8:1401 17. Farrell DJ, Flamm RK, Sader HS et al (2014) Ceftobiprole activity 5. Hebeisen P, Heinze-Krauss I, Angehrn P et al (2001) In vitro and in against over 60,000 clinical bacterial pathogens isolated in Europe, vivo properties of Ro 63-9141, a novel broad-spectrum cephalospo- Turkey and Israel from 2005 to 2010. Antimicrob Agents rin with activity against methicillin-resistant staphylococci. Chemother 58:3882–3888 Antimicrob Agents Chemother 45:825–835 18. Chong J, Quach C, Blanchard AC et al (2016) Molecular epidemi- 6. Syed YY (2014) Ceftobiprole medocaril: a review of its use in ology of a vancomycin-intermediate heteroresistant Staphylococcus patients with hospital- or community-acquired pneumonia. Drugs epidermidis outbreak in a neonatal intensive care unit. Antimicrob 74:1523–1542 Agents Chemother 60:5673–5681 7. Medicines and Healthcare products Regulatory Agency (2017) 19. Otto M (2019) Staphylococcus epidermidis—the Baccidental^ Summary of product characteristics for Zevtera (ceftobiprole pathogen. Nat Rev Microbiol 7:555–567 medocaril). http://www.mhra.gov.uk/home/groups/par/documents/ 20. van der Lugt NM, Steggerda SJ, Walther FJ (2010) Use of rifampin websiteresources/con369256.pdf. Accessed 25 April 2018 in persistent coagulase negative staphylococcal bacteremia in neo- 8. Bogdanovich T, Ednie LM, Shapiro S et al (2005) nates. BMC Pediatr 10:84 Antistaphylococcal activity of ceftobiprole, a new broad- 21. Thwaites GE, Scarborough M, Szubert A et al (2017) Adjunctive spectrum cephalosporin. Antimicrob Agents Chemother 49: rifampicin for Staphylococcus aureus bacteraemia (ARREST): a 4210–4219 multicentre, randomised, double-blind, placebo-controlled trial. 9. Andrews JM (2001) Determination of minimum inhibitory concen- Lancet 391:668–678 trations. J Antimicrob Chemother 48 Suppl 1:5–16 22. Czekaj T, Ciszewski M, Szewczyk EM (2015) Staphylococcus 10. Andrews JM (2009) Errata: Determination of minimum inhibitory haemolyticus - an emerging threat in the twilight of the antibiotics concentrations. J Antimicrob Chemother 49:1049–1050 age. Microbiology 161:2061–2068 11. The European Committee on Antimicrobial Susceptibility Testing 23. Butin M, Martins-Simões P, Pichon B et al (2017) Emergence and (2017) Breakpoint tables for interpretation of MICs and zone diam- dissemination of a linezolid-resistant Staphylococcus capitis clone eters. Version 7.0. www.eucast.org. Accessed 25 April 2018 in Europe. J Antimicrob Chemother 72:1014–1020 12. Fletcher S (2005) Catheter-related bloodstream infection. Contin 24. Tevell S, Hellmark B, Nilsdotter-Augustinsson A et al (2017) Educ Anaesth Crit Care Pain 5:49–51 Staphylococcus capitis isolated from prosthetic joint infections. Eur J Clin Microbiol Infect Dis 36:115–122 13. Warren DK, Quadir WW, Hollenbeak CS et al (2006) Attributable 25. Abbanat D, Shang W, Amsler K et al (2014) Evaluation of the in cost of catheter-associated bloodstream infections among intensive vitro activities of ceftobiprole and comparators in staphylococcal care patients in a nonteaching hospital. Crit Care Med 34:2084– colony or microtitre plate biofilm assays. Int J Antimicrob Agents 43:32–39

Journal

European Journal of Clinical Microbiology Infectious DiseasesSpringer Journals

Published: Jun 6, 2018

References

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