EJBR2018v8i3art112 ISSN 2449-8955 European Journal of Biological Research Review Article European Journal of Biological Research 2018; 8 (3): 112-120 Resistance to ceftaroline - 2018 review Rafał Ślusarczyk 1 *, Ada Bielejewska 1 , Arkadiusz Bociek 1 , Martyna Bociek 2 1 Faculty of Medicine and Health Science, Jan Kochanowski University, Kielce, Poland 2 Faculty of Medical Science, Higher School of Economics, Law and Medical Science of Professor Edward Lipiński, Kielce, Poland *Corresponding author: Rafał Ślusarczyk; Tel: +48 666 176 345; E-mail: kazzerr@gmail.com ABSTRACT Ceftaroline is a new fifth generation cephalosporin, active mostly against Gram-positive cocci, e.g. Staphylococcus aureus (including methicillin- resistant Staphylococcus aureus). It is used in treating acute bacterial skin and skin structure infections, community acquired respiratory tract infections and methicillin-resistant S. aureus bacteremia. The main resistance mechanisms of bacteria to β-lactam antibiotics, including ceftaroline, are mutations in PBP2a, PBP3 and PBP4. Clinically significant resistance has been noted among both archived and newly-isolated strains in a laboratory test using serial passages. Ceftaroline-resistant strains have also been found in patients suffering from cystic fibrosis, ventilator- associated pneumonia and infectious endocarditis. Irresponsible antibiotic treatment using ceftaroline or other antibiotics (due to a possibility of a cross- resistance) can lead to the spread of ceftaroline resistance and, consequently, its loss of value. Keywords: Antibiotic; Antibiotic resistance; MRSA; Resistant strains; Ceftaroline-resistant. 1. INTRODUCTION Ceftaroline, a fifth generation cephalosporin, has been approved by the FDA (Food and Drug Administration) as a therapeutic option for both adult (in 2010) and pediatric (in 2016) patients suffering from acute bacterial skin and skin structure infections (ABSSSI) (including infections caused by MRSA), as well as community-acquired respiratory tract infections (CARTI), including community acquired bacterial pneumonia (CABP).The antibiotic has also been approved for treating patients with methicillin-resistant S. aureus bacteremia (MRSAB) and endocarditis. Despite being a new drug, on which many people has pinned their hopes, there are more and more reports of bacterial strains resistant to it. THE USE OF CEFTAROLINE Ceftaroline is a broad-spectrum antibiotic [1], active against methicillin-susceptible and methi- cillin-resistant Staphylococcus aureus (MSSA and MRSA), daptomycin-nonsusceptible (DNS) S. aureus, vancomycin-intermediate (VISA and hetero-VISA) and vancomycin-resistant (VRSA) S. aureus, methicillin-susceptible and methicillin- resistant coagulase-negative streptococci (MSCoNS and MRCoNS), multidrug resistant Streptococcus pneumoniae, as well as many genera of Entero- bacteriaceae (Escherichia coli, Klebsiella pneumo- niae and K. oxytoca, Enterobacter aerogenes and E. cloacae, Citrobacter koseri and C. freundii, Proteus mirabilis, Serratia spp., Moraxella Received: 22 May 2018; Revised submission: 19 June 2018; Accepted: 01 July 2018 Copyright: © The Author(s) 2018. European Journal of Biological Research © T.M.Karpiński 2018. This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited. DOI: http://dx.doi.org/10.5281/zenodo.1304435 113 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 catarrhalis, Haemophilus influenzae, Morganella morganii) [2-4]. Ceftaroline is ineffective against Pseudomonas spp., Enterococcus spp., Bacteroides fragilis and atypical bacteria (Mycoplasma pneu- moniae, Chlamydia pneumoniae and Legionella pneumophila) [2]. In the USA, ceftaroline was put into use in October 2010 and in Europe - two years later. At first, it was used in treating ABSSSI and CARTI [5]. In vitro studies conducted by Gaikwead et al. show high effectiveness of the drug - among 30 MRSA strains sampled from different clinical materials, 2 (6,67%) were resistant to it [6]. Moreover, clinical trials showed that it is well-tolerated by patients [2, 5, 7] (most common side effects were: diarrhea, nausea, headache, pruritus [5]), leaving other antibiotics, with potentially severe side effects, such as nephrotoxicity, ototoxicity [8, 9] (vancomycin) or thrombocytopenia [9] (linezolid), as drugs of last resort [5]. A decreased percentage of patients having to stop therapy due to the side effects was noted - 2,7% compared to 3,7% when treating with ceftriaxone or vancomycin with aztreonam [2]. Another in vitro study showed that when it comes to eradication of MRSA, ceftaroline is as effective as vancomycin, daptomycin and linezolid (when minimal inhibitory concentration for ceftaroline, MIC, ≤ 2 mg/l). It doesn’t matter then, whether the strain has developed mechanisms of resistance to linezolid or vancomycin [10]. Among adults with CABP, ceftaroline treatment was more effective than a ceftriaxone one [7, 11, 12]. Moreover, the difference between therapeutic effect of both drugs was less significant if in 96 hours prior to their usage no other antimicrobial drug had been used [11]. Ceftaroline is the first intravenous antibiotic used among children over two months old to be approved by the FDA in over a decade [13]. Between 2012-2014 Pfaller et al. analyzed 3141 samples (1681 associated with ABSSSI, 1460 with CARTI) coming from pediatric patients from 29 different centers. The strains of S. aureus, S. pneumoniae, H. influenzae, P. aeruginosa, beta- hemolytic streptococci, Enterobacteriaceae (inclu- ding E. coli and Klebsiella spp.) and others were isolated. 99-100% of the Gram-positive bacteria, as well as H. influenzae strains, were ceftaroline- susceptible. Also, the antibiotic was active against MRSA strains associated with ABSSSI and ceftriaxone-resistant S pneumoniae associated with CARTI [14]. The percentage of cured complicated ABSSSI and CABP in population of patients aged 2 months to 17 years old was high [7]. There’s also a known case of a ten year old girl who had had an accident and developed a MRSA sepsis (the bacteria were previously isolated from many of her wounds), which was fought off with relatively low dose of ceftaroline (2 x 9 mg/kg/d) - even though MIC of 1,5-4 mg/l suggested decreased susceptibility to it [15]. A therapeutic success in treating MRSAB was also stated among adults in a study conducted by Zasowski et al. [16]. White et al. proved that ceftaroline is effective at treating patients with MRSAB who haven’t responded to other drugs [17]. There are also reports stating that ceftaroline combined with daptomycin can be effective in treating daptomycin-resistant or vancomycin- intermediate resistant MRSA infectious endocarditis (IE) [18-20]. RESISTANCE MECHANISMS Microorganisms for which the MIC value for ceftaroline is equal or less than 1 mg/l (1 μg/ml) are considered susceptible to this antibiotic. When the MIC ranges from 1 to 8 mg/l the microorganism is considered nonsusceptible and when the MIC exceeds 32 mg/l, the microorganism is resistant to ceftaroline [21-24]. Mechanisms of microbial resistance to ceftaroline are based on mutations within the penicillin binding protein (PBP) group, and are primarily observed in S. aureus [20-31]. Among the mutations present in PBP proteins, mutations were observed predominantly within the PBP2a protein [25] both inside the penicillin-binding domain (PBD) and outside the penicillin-binding domain (nPBD) [21, 29]. Mutations in PBD seem to correlate more frequently with nonsusceptibility, and mutations in nPBD with resistance to cefta- roline. PBP3 and PBP4 were other mutated PBP to be proved to correlate with ceftaroline resistance. This type of resistance has been overcome by the combination of ceftaroline with very low methicillin or meropenem doses [24, 26]. The PBP2a is a mutated variant of the PBP2 114 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 responsible for bacterial cell wall biosynthesis, providing microbial resistance to β-lactam antibio- tics. Changes in the staphylococcal mecA gene result in conformational changes of the finished PBP2, which reduces its affinity to all β-lactam antibiotics [27]. It can be suspected that further mutations induced by environmental factors (ceftaroline therapy) within or outside the SCCmecA gene (Staphylococcal Cassette Chromosome mec) may result in resistance to fifth generation of cephalo- sporins [25, 28], which seemed to be completely effective in the treatment of MRSA infections so far. However, studies conducted by Kelley WL et al. show that during the introduction of ceftaroline to use, variants of the PBP2a providing ceftaroline resistance to hospital-acquired MRSA (HA-MRSA) have already existed (Table 1) [29]. Other factors leading to the increase of total resistance level in bacteria, include genes taking part in cell wall precursor formation and turnover, such as femA and femB genes, encoding proteins that take part in forming correct peptidoglycan pentaglycine interpeptide bridge, as well as fmhA, fmhB and fmhC genes, which encode proteins participating in forming peptidoglycan pentaglycine interpeptide. It was also noted that genes engaged in glutamine’s and glucosamine’s metabolism, such as femC and femD, can also cause the increase of bacterial resistance [32, 33]. Greninger A et al. suggested that mutations within genes such as clpX endopeptidase, pp2c protein phosphatase and transcription terminator rho can influence resistance to ceftaroline of MRSA in mechanisms different than the one involving mecA [34]. Chan LC et al. noted the significance of gdpP mutation, often identified within MRSA strains resistant to both ceftaroline and ceftobiprole. However, it’s role is yet to be discovered [26, 31]. Table 1. HA-MRSA strains isolated from University Hospital of Geneva’s patients’ blood between 1998-2003, showing primary resistance to ceftaroline (MIC > 1mg/l) [29]. Strain (GenBank no.) Molecular type SCCmec Mutations Year MIC (broth) (mg/l) 12 ST228 I E239K 1998 2 14 ST228 I E239K 1998 2 13 ST247 I N146K, E150K, G246E 1998 4 16 ST247 I N146K, E150K, G246E 1998 4 56 ST228 I N146K 1999 2 17 ST228 I N146K 1999 2 21 ST228 I N146K 1999 2 57 ST228 I N146K 2000 2 25 ST228 I N146K 2000 2 28 ST228 I N146K 2000 2 30 ST228 I N146K 2000 4 42 ST228 I N146K 2002 2 48 ST228 I N146K 2003 2 52 ST228 I N146K 2003 2 Chan LC et al. used the method of serial passages and the method of plasmid transduction to estimate the possibility of emergence of ceftaroline resistance and the potential consequences of its transmission in two strains of ceftaroline-passaged mutants: SF8300 and COL. In this way, mutants with MIC greater than 32 mg/l were obtained [26]. Lahiri SD et al. proved, using the method of serial 115 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 passages, that induction of ceftaroline-resistance (MIC ranging from 2 to 64 mg/l) is possible among strains ATCC 29213 (MIC: 0.25-4 mg/l), USA300 (MIC: 1-8 mg/l) and ARC3824 (MIC: 8-64 mg/l). Clinical strains of MRSA, investigated by Lahiri SD et al., have also shown the ability to rapid resistance development (manifesting itself as significant increase of MIC), as presented in Table 2 [30]. It is a discovery of great importance, since passing bacteria imitates the situation in human organism when, due to incorrect dosage, too long therapy or insufficient penetration of the antibiotic to the tissue, in vivo MIC has not been achieved. Besides the mutation within PBP2A, strains with point mutation within PBP4, providing them cefta- roline-resistance, were observed (strains TRN5426 and TRN5549) [25]. Table 2. Clinical MRSA strains with significantly increased (compared to parental strains) MIC due to serial passages. Descendant strains are marked by adding (after the dash) following letters of the alphabet to the name of a parental strain [30]. Strain Molecular type SCC mec Mutations of parental strain Additional mutations after passage Year Country MIC (broth) of parental strain (mg/l) MIC (broth) after passage (mg/l) ARC3824 ST228 I E239K, E447K 2010 Spain 8 ARC3824-A ST228 I E239K, E447K Y446N 2010 Spain 8 64 ARC3824-B ST228 I E239K, E447K A601S 2010 Spain 8 16 ARC3824-C ST228 I E239K, E447K A601S 2010 Spain 8 16 ARC3827 ST228 I E239K 2010 Thailand 2 ARC3827-A ST228 I E239K - 2010 Thailand 2 4 ARC3827-B ST228 I E239K - 2010 Thailand 2 4 TRN5426 ST22 IV WT 2012 Portugal 2 TRN5426-A ST22 IV WT - 2012 Portugal 2 8 TRN5467 ST5 II N146K, L357I, I563T 2012 South Korea 4 TRN5467-A ST5 II N146K, L357I, I563T Y446N 2012 South Korea 4 32 TRN5467-B ST5 II N146K, L357I, I563T Y446N 2012 South Korea 4 32 TRN5549 ST22 IV E150K 2012 Portugal 2 TRN5549-A ST22 IV E150K - 2012 Portugal 2 8 Moreover, there are more and more reports from all over the world, describing isolating from different clinical samples another MRSA strains capable of developing mechanisms of resistance to ceftaroline (Table 3). Laboratory results are also confirmed by reported clinical cases. This problem is seen (among others) in patients with cystic fibrosis (CF), 116 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 probably due to the multitude of therapeutic cycles using the same antibiotic - in this case - ceftaroline. Such cases, as presented in Table 4, prove that increasing resistance to antibiotics observed in microbiological laboratories while passing bacteria, is also reflected in clinical environment. In these patients, resistance to ceftaroline and its limited clinical effectiveness were observed [22, 31]. The case of ceftaroline resistance was also reported for a strain isolated from the blood of a patient suffering from IE, as well as from the broncho- alveolar lavage fluid (BALF) of a patient suffering from ventilation associated pneumonia (VAP) [35]. Molecular studies conducted on isolated MRSA strains revealed mutations in PBP2a [22, 30, 31]. Table 3. MRSA strains with potential of clinical resistance to ceftaroline [25, 30]. Strain Molecular type SCCmec Mutations Country MIC (broth) (mg/l) TRN5420 ST239 III E239K Hungary 2 TRN5427 ST36 II WT Greece 2 TRN5428 ST239 III N146K, E150K, N204K, G246E Greece 4 TRN5433 ST5 II K290Q Japan 4 TRN5444 ST5 II K281R China 2 TRN5454 ST5 II WT Japan 2 TRN5458 ST239 III N146K Philippines 2 TRN5471 ST228 I N146K, I563T Italy 4 TRN5474 ST5 II N236K Taiwan 2 TRN5475 ST239 III E239K China 2 TRN0478 ST228 I N146K Hungary 2 TRN5507 ST239 III N146K Russia 4 TRN5521 ST228 I E239K, E447K Thailand 8 TRN5536 ST239 III WT Turkey 2 TRN5539 ST5 II E170K, N236K Taiwan 2 TRN5552 ST239 III N146K, N204K, G246E South Africa 2 TRN5562 ST22 IV E239K, G246E France 2 TRN5563 ST239 with tpi-107 III N204K, T235I France 2 TRN5572 ST5 II WT Italy 2 ARC3824 ST228 I E239K, E447K Spain 8 ARC3828 ST228 I E239K, E447K Thailand 8 ARC3830 ST228 I E239K, E447K Thailand 8 TRN5474 ST228 I N236K Taiwan 2 TRN5472 ST228 I WT Italy 2 TRN5545 ST239 III N146K Turkey 2 TRN5418 ST5 I M122I, E150K Chile 2 TRN5350 ST8 II N236K USA 2 117 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 Table 4. Summary of clinical cases [22, 30, 31]. Strain Disease Sample Mutation MIC (mg/l) THMS-4519 Cystic fibrosis Sputum Y446N 1,5 THMS-3125 Cystic fibrosis Sputum Y446N, E447K >32 THMS-5007 Cystic fibrosis Sputum E239K, Y446N, E447K >32 THMS-5006 Cystic fibrosis Blood E239K, Y446N, E447K >32 USA100 Infectious endocarditis Blood E447K 4 USA100 Ventilation associated pneumonia BALF E447K 6 Pfaller MA et al. observed ceftaroline resi- stance in one multi-drug resistant S pneumoniae strain. Molecular analysis revealed 31 altered aminoacids within the MurM relative to the standard R6 strain. Changes in PBPs, mainly PBP2x, were also detected [36]. EPIDEMIOLOGY Despite being put into use only a few years ago, ceftaroline-resistant strains are detected in more and more countries. Moreover, it was proved that resistant strains have been existing for at least over a dozen years prior to introducing ceftaroline. In 2015 Kelley et al. published the results of a study concerning 60 archival MRSA strains (collected between 1994-2003 in Geneva, Switzerland), 40 out of which (66%), dated 1998-2003, turned out to be ceftaroline-resistant [29]. In 2016, in the same center, another study was conducted - this time on MRSA strains collected in 2013 and 2014. 23 out of 96 strains (24%) were ceftaroline-resistant [37]. The AWARE report from 2012 informed that among 2583 S. aureus strains collected in Europe, Russia and Turkey, 2 (0.08%) were cefta- roline-resistant (MIC, ≥4 mg/l) and 114 (4.4%) were ceftaroline-intermediate (MIC, 2 mg/l). Given EUCAST (European Committee on Antimicrobial Susceptibility Testing) criteria, 116 strains (4.5%) were ceftaroline-resistant (MIC, >1 mg/l), 94 (81%) out of which came from Russia, Turkey, Italy and Hungary [38]. In the USA the first ceftaroline- resistant MRSA strain was described in 2014 by Long et al. and it was isolated from a twenty-year- old CF patient treated with ceftaroline due to recurring respiratory tract infections caused by multi- drug resistant bacteria (including MRSA) [23]. In 2015 in China, Zhang et al. examined 251 hospital acquired MRSA strains from ABSSSI patients. None of the analyzed strains showed resistance to ceftaroline, but 84 of them (33.5%) showed intermediate resistance (MIC, 2 mg/l) [39]. In the same year, Abbott et al. tested 421 MRSA strains collected in Australia (270 from 2017, the rest from 2013). 71 (16.9%) out of them were nonsusceptible to ceftaroline (MIC, >1.0 mg/l) and most of them had MDR phenotype [40]. In Africa, 37 MRSA strains colonizing patients and 23 infectious MRSA strains were collected. 10 (16.7%) out of them were resistant to ceftaroline [28]. CONCLUSIONS Ceftaroline as a new antibiotic, in most cases allows to reach therapeutic effect provided in the Summary of Product Characteristics (SPC). However, it is very disturbing that in the moment of being introduced to market, there have already been existing ceftaroline-resistant strains, which may indicate that there's a possibility of obtaining cross-resistance to ceftaroline while using other β-lactam antibiotics in insufficient doses (which can be verified by testing archived MRSA strains). Laboratory tests prove that resistance to ceftaroline may be induced by selecting strains by increasing doses of the antibiotic. It shows rather clearly that bacteria can survive therapeutic concentration of ceftaroline if they have previously been exposed to it. Moreover, ceftaroline-resistant strains are isolated from patients with clinical symptoms of infections. Thus, ceftaroline, just like any other anti- biotic, may lose its clinical value if it's overused, its dosage is incorrect or the rest of β-lactams are 118 | Ślusarczyk et al. Resistance to ceftaroline - 2018 review European Journal of Biological Research 2018; 8 (3): 112-120 overused or dosed incorrectly. Reasonable antibiotic therapy is probably the only hope for effective use of ceftaroline in the future. However, it is impossible to estimate how fast will the resistance- gaining process progress or what percentage of bacteria will it concern. AUTHORS’ CONTRIBUTIONS ABo: Paper conception and design. RŚ, ABi, ABo, MB: Acquisition of literature, Analysis and interpretation of literature, Drefting of manuscript. MB, ABo: Drafting of tables. ABi, RŚ: Translation of manuscript. ABo: Adaptation to editorial guidelines. All authors read and approved the final manuscript. TRANSPARENCY DECLARATION Authors have declared that no competing interests exist. REFERENCES 1. 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