sign in sign up
<<
Home , Cefaclor, Cefadroxil, Cefatrizine, Cefixime, Cefoperazone, Cefotetan

REVIEWS

Ref: Ro J Pharm Pract. 2020;13(3) DOI: 10.37897/RJPhP.2020.3.2 The new fifth-generation – a balance between safety and efficacy

Aura Rusu1, Ioana-Andreea Lungu2 1 Pharmaceutical and Therapeutical Chemistry Department, Faculty of Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania 2 Doctoral School of Medicine and Pharmacy, George Emil Palade University of Medicine, Pharmacy, Science and Technology, Targu Mures, Romania

Abstract Cephalosporins are beta-lactam classified into five generations. The newest generation has three representa- tives: ceftaroline fosamile, the combination ceftolozane/ (/beta-lactamase inhibitor), and ceftobi- prole medocaril. These new cephalosporins are valuable anti-infective agents, with potent activity against multidrug-re- sistant , and with a positive balance between benefits and . However, the fifth-generation cephalosporins should be judiciously used to prevent the occurrence of bacterial resistance phenomenon. Keywords: cephalosporins, ceftaroline, ceftolozane, , MRSA, community-acquired , complicated skin and soft tissue infections

INTRODUCTION emerged as a result of increased only, in the situation where other Cephalosporins (CFs) are beta- bacterial resistance to classical antibacterial drugs were not lactam antibiotics with numerous antibiotics. Based on the efficient. representatives widely used in the antimicrobial activity, the CFs are therapy of infectious diseases. Like classified into five generations REPRESENTATIVES other beta-lactam antibiotics, CFs (Table 1) [1]. Representatives of the inhibit the synthesis of the bacterial fifth-generation which are used in Ceftaroline fosamil (anatomical . The beta-lactam ring is therapy are comprised of: therapeutic chemical (ATC) code: essential in binding to the ceftaroline fosamil, ceftolozane/ J01DI02) is a relatively recent -binding proteins, crucial tazobactam, and ceftobiprole approved cephalosporin from the in the synthesis of the medocaril [1-3]. The clinical studies fifth-generation [1,4,5]. The U.S. bacterial cell wall. The high affinity conducted so far support the Food and Drug Administration of fifth-generation CFs for positive balance between benefits approved ceftaroline fosamil in penicillin-binding proteins leads to and side effects for these new CFs. 2010 and the European Medicine an efficient activity against clinically However, the fifth-generation CFs Agency, in 2011 (under trade name relevant pathogens. The new CFs should be judiciously used in Teflaro and Zinforo) [5-7]. (fourth and fifth generations) have difficult-to-treat bacterial infections Ceftaroline fosamil is active against

Corresponding author: Aura Rusu E-mail: [email protected]\

https://FARMA.com.ro | PHARMACEUTICAL PRACTICE | 121 REVIEWS

Gram-positive (G(+)) organisms, Safety of ceftaroline fosamil. including -resistant Ceftaroline fosamil is considered Staphylococcus aureus (MRSA) and effective in therapy, and well- pneumoniae, as well tolerated, with a good safety as common Gram-negative (G(-)) profile. However, ceftaroline organisms [6]. fosamil could be responsible for , , headache and Physical-chemical properties. pruritus as the most common side Ceftaroline is an oxyimino effects with similar rates compared compound based on the structure to other antibiotics [5,6,9-11]. of (a fourth-generation Precautions for use and special representative) [6]. Ceftaroline warnings are for fosamil is a prodrug that turns in reactions, Clostridium difficile- vivo into ceftaroline (the active associated diarrhea, superinfections metabolite). The name „fosamil” is with non-susceptible bacteria, and given by an extra phosphono group pre-existing seizure disorder. in the chemical structure Ceftaroline fosamil has a low comparative to ceftaroline. The potential for drug-drug interactions resulted compound has the [6,12]. Because the effects of the advantage that it is more water- compound in and soluble [6]. The oxime group in the lactation or on fertility are C7 acyl moiety and a 1,3-thiazole unknown, it is advisable to avoid ring attached to the central nucleus the treatment in these situations (C3 position) facilitate the increased activity against MRSA (Table 2) [5]. More studies are needed in the [6,8]. The parenteral formulation future to assess the safety profile of (600 mg powder for concentrate for ceftaroline fosamil [9]. solution for infusion) contains an equivalent amount of ceftoraline Ceftolozane/tazobactam fosamil acetic acid solvate combination monohydrate [5]. Ceftolozane is a new fifth- generation CF, a derivative of Indications, dosing and (third generation). administration. Ceftaroline fosamil Because it is not resistant to has been approved for beta-lactamases, ceftolozane was administration to children combined with an inhibitor of (neonates, infants, children, beta-lactamases, respectively adolescents) for the same tazobactam. The obtained indications as for adults: combination provides great activity complicated skin and soft tissue against extended-spectrum beta- infections and community-acquired lactamase-producing pneumonia [5]. Ceftaroline fosamil Enterobacteriaceae, is administrated intravenously (600 aeruginosa, and certain anaerobic mg every 12 hours over 1 hour in germs [2,13]. The combination of adults) during 5-14 days. Dosage ceftolozane with tazobactam (ATC adjustment is necessary for code: J01DI54) was approved in patients with moderate to severe 2014 by the FDA, and in 2015 by renal impairment [6]. Also, the EMA (under trade name ceftaroline fosamil is used off-label Zerbaxa). Recently, the FDA has in the treatment of bacteremia, approved Zerbaxa for the treatment endocarditis, osteoarticular of adults with hospital-acquired infections, hospital-acquired and ventilator-associated , and [9]. pneumonia [14-16].

122 | PHARMACEUTICAL PRACTICE | Vol. XIII, No. 3 (52), Year 2020 REVIEWS

TABLE 1. Classification of the most used CFs by generation and route of administration (G(+) = Gram positive, G(-) = Gram negative) [1,2,17,22,24]. Generations/Administration First Second Third Fourth Fifth Cefalotine parenteral Cefamandol parenteral parenteral parenteral Ceftaroline fosamil parenteral Ceftolozane/ parenteral Cefapirine parenteral parenteral Ceftazidime parenteral parenteral tazobactam Cefalexina oral parenteral parenteral Ceftobiprol medocaril parenteral oral parenteral parenteral oral oral parenteral oral oral oral Cefuroxime oral oral axetil Antibacterial spectrum G(+) cocci All have less activity All have extended activity Cefepime is active Ceftaroline is a broad- (staphylococci spp. and against G(+) cocci against G(-) bacteria against Streptococcus spectrum with great streptococci spp.) and increased activity (including those resistant pneumoniae, activity against MRSA, Listeria against G(-) bacilli to the frst and second methicillin-resistant monocytogenes, All have minimal compared to the frst- generation CFs or other Staphylococcus faecalis, and no activity against activity against G(-) generation. Cefuroxime beta-lactam antibiotics). aureus (MRSA), . bacteria. has increased activity Ceftriaxone is useful and Pseudomonas against Haemophilus in the treatment of aeruginosa. In Ceftolozane/tazobactam influenza. Cefotetan meningitis (caused by addition to the has activity against resistant and cefoxitin have Haemophilus influenza, activity of the third G(-) pathogens (including Pseudomonas aeruginosa increased activity Neisseria meningitidis, generation, cefepime ), Enterobacteriaceae, against Bacteroides spp. or Streptococcus has activity against and pneumoniae) beta-lactamase- some anaerobic pathogens and disseminated Lyme producing G(-) bacilli. (e.g., ). disease. Ceftazidime Ceftobiprole is active against Streptococcus presents activity Cefepime is reserved MRSA and pneumoniae against Pseudomonas for severe systemic resistant to third- aeruginosa. infections produced generation CFs and penicillin, by multi-resistant and G(-) bacteria associated with organisms. hospital-acquired pneumonia and community-acquired pneumonia.

Physical-chemical properties. The ceftolozane sulphate and Safety of ceftolozane/ chemical structure is based on the tazobactam sodium) [15]. tazobactame. Generally, therapy structure of ceftazidime (an with ceftolozane/tazobactam is well oxyimino-aminothiazolyl CF), Indications, dosing and tolerated. The reported common optimized to have activity on administration. Usually, the side effects such as nausea, Pseudomonas spp. The approved dose of ceftolozane/ vomiting, diarrhea, constipation, aminothiadiazole moiety (attached tazobactam is 1 g ceftolozane/0.5 g , hypotension, rash, to the side-chain from C7 position) tazobactam for the treatment of headache, , insomnia, confers increased activity against complicated intra-abdominal , hypokalemia, G(-) bacteria. Also, a pyrazole infections, urinary tract infections thrombocytosis, and Clostridioides difficile colitis were mild or moiety attached to the side-chain and acute . Hospital- from C3 position confers stability to moderate [16,20]. Although acquired pneumonia, including beta-lactamases and permeability contraindications for the use of ventilator-associated pneumonia, through the outer bacterial ceftolozane/tazobactam have not require a dose of 2 g ceftolozane/1 membrane. These properties of been identified, precautions for use ceftolozane lead to increased g tazobactam. It is administered and special warnings are activity against Pseudomonas intravenously, every 8 hours (1 hour hypersensitivity reactions (may aeruginosa. The parenteral infusion time) for 4 – 14 days. It can appear in patients allergic to formulation (1 g ceftolozane/0.5 g be associated with metronidazole beta-lactam antibiotics) and tazobactam powder for concentrate and other antibacterial agents for a impairment of renal function [15]. for solution for infusion) contains broader antimicrobial spectrum In ceftolozane/tazobactam an equivalent amount of [15,19]. administration, no significant

https://FARMA.com.ro | PHARMACEUTICAL PRACTICE | 123 REVIEWS

a)

b)

c)

FIGURE 1. Chemical structures of a) ceftaroline fosamil; b) ceftolozane/tazobactam; c) ceftobiprole medocaril [18] drug-drug or food-drug interactions licensed in some European and Physical-chemical properties. have been reported. There is no non-European countries (Zeftera or Structurally, this new cephalosporin data on ceftolozane/tazobactam Zevtera). However, ceftobiprole has is an yrrolidinone-3-ylidenemethyl effects in pregnancy, , not been approved by the FDA and [24]. The used or on fertility [15,20]. Unlike EMA [22,24]. Ceftobiprole presents pharmaceutical form is a water- ceftaroline fosamil, ceftolozane/ activity against MRSA, soluble monosodium salt [23,24]. tazobactam combination is under Streptococcus Indications, dosing and evaluation for use in children [21]. pneumoniae resistant to third- administration. Ceftobiprole Ceftobiprole medocaril generation CFs and penicillin, and medocaril is indicated for the Ceftobiprole medocaril (ATC code: G(-) bacteria associated with treatment of complicated skin and J01DI) is the prodrug form of hospital-acquired pneumonia and soft tissue infections and ceftobiprole [22,23]. This fifth- community-acquired pneumonia pneumonia [24]. Ceftobiprole generation cephalosporin has been [3,22,25]. medocaril is administrated

124 | PHARMACEUTICAL PRACTICE | Vol. XIII, No. 3 (52), Year 2020 REVIEWS intravenously (500 mg every 8 contribute to the list of approved hours over 2 hours in adults) during indications and will complete the 4 - 14 days. Dosage adjustment is knowledge on the use of necessary for patients with ceftobiprole medocaril [3]. moderate and severe renal impairment [23]. CONCLUSIONS Ceftaroline fosamile, the Safety of ceftobiprole medocaril. combination ceftolozane/ Ceftobiprole has a good safety tazobactame, and ceftobiprole profile [3]. Nausea, headache and medocaril are the first gastrointestinal disorders are the representatives of the fifth- most common side effects of generation of CFs used in therapy. ceftobiprole [3,22]. Besides the These new antibiotics are valuable broad spectrum of activity anti-infective agents with a positive (including MRSA), the excellent balance between benefits and safety profile of ceftobiprole side-effects. Nevertheless, the medocaril is a significant advantage fifth-generation CFs should be in comparison with other highly restricted to prevent the antimicrobial agents. However, occurrence of bacterial resistance. there are no published studies These new beta-lactam antibiotics regarding the usage of ceftobiprole must be judiciously used, only in medocaril in pregnancy, the situation where other breastfeeding, effects on fertility, antibacterial drugs were not and drug-drug interactions [23]. effective. The ongoing phase 3 studies will

references

1. Bui T, Preuss CV. Cephalosporins. [Updated Antimicrob. Chemother. 2011; 12. Teflaro, FDA, [Online]. Available at: https:// 2020 Mar 24]. In: StatPearls [Internet]. 66(3):iii11-iii18. www.accessdata.fda.gov/drugsatfda_docs/ Treasure Island (FL): StatPearls Publishing; 7. Drug Approval Package: Teflaro (ceftaroline label/2011/200327s001lbl.pdf (Accessed 2020 Jan-. Available from: https://www. fosamil) NDA #200327 https://www. 09/04/2020). ncbi.nlm.nih.gov/books/NBK551517/ accessdata.fda.gov/drugsatfda_docs/ 13. Xipell M, Paredes S, Fresco L et al. Clinical (Accessed 08/27/2020). nda/2010/200327orig1s000toc.cfm Experience with Ceftolozane/Tazobactam in 2. Cho JC, Fiorenza MA, Estrada SJ. (Accessed 09/01/2020). Patients with Serious Infections Due to Ceftolozane/Tazobactam: A Novel 8. Ceftaroline fosamil, PubChem, [Online]. Resistant Pseudomonas Aeruginosa. J Glob Cephalosporin/β-Lactamase Inhibitor Available: https://pubchem.ncbi.nlm.nih. Antimicrob Re. 2018;13:165-170. Combination. Pharmacotherapy 2015; gov/compound/9852981 (Accessed 14. Zerbaxa, FDA, [Online]. Available at: https:// 35(7):701-715. 09/01/2020). www.accessdata.fda.gov/drugsatfda_docs/ 3. Giacobbe DR, Rosa FGD, Bono VD et al. 9. Pani A, Colombo F, Agnelli F et al. Off-Label label/2014/206829lbl.pdf (Accessed Ceftobiprole: Drug Evaluation and Place in Use of Ceftaroline Fosamil: A Systematic 09/02/2020). Therapy. Expert Review of Anti-infective Review. Int. J. Antimicrob. Ag. 2019; 15. Zerbaxa, European Medicines Agency, Therapy 2019;17(9):689-698. 54(5):562-571. [Online]. Available at: https://www.ema. 4. Duplessis C, Crum-Cianflone NF. Ceftaroline: 10. Rosanova MT, Aguilar PS, Sberna N et al. europa.eu/en/medicines/human/EPAR/ A New Cephalosporin with Activity against Efficacy and Safety of Ceftaroline: zerbaxa (Accessed 09/02/2020). Methicillin-Resistant Staphylococcus Aureus Systematic Review and Meta-Analysis. Ther 16. FDA, FDA approves new treatment for (MRSA). Clin Med Rev Ther. 2011;3. Adv Infect Dis. 2018;6. hospital-acquired and ventilator-associated 5. Zinforo, European Medicines Agency, 11. Cheng K, Pypstra R, Yan JL et al. Summary of bacterial pneumonia, [Online]. Available at: [Online]. Available: https://www.ema. the Safety and Tolerability of Two Treatment https://www.fda.gov/news-events/ europa.eu/en/medicines/human/EPAR/ Regimens of Ceftaroline Fosamil: 600 Mg press-announcements/fda-approves-new- zinforo (Accessed 08/27/2020). Every 8 h versus 600 Mg Every 12 h. treatment-hospital-acquired-and-ventilator- 6. Laudano JB. Ceftaroline Fosamil: A New J. Antimicrob Chemother. 2019; associated-bacterial-pneumonia (Accessed Broad-Spectrum Cephalosporin. J. 74(4):1086-1091. 09/03/2020).

https://FARMA.com.ro | PHARMACEUTICAL PRACTICE | 125 REVIEWS

17. Cephalosporins - Infectious Diseases, Randomized, Double-Blind, Phase 3 Trial Pneumonia: A European Perspective. Drug Merck Manuals Professional Edition, (ASPECT-CIAI). Clin Infect Dis. 2015; Des Devel Ther. 2015;9:4565-4572. [Online]. Available: https://www. 60(10):1462-1471. 23. Zevtera - Product monograph, AVIR merckmanuals.com/professional/ 20. Sorbera M, Chung E, Ho CW et al. Pharma Inc., 2017. [Online]. Available at: infectious-diseases/bacteria-and- Ceftolozane/Tazobactam: A New Option in AVIR Pharma Inc. https://www.avirpharma. antibacterial-drugs/cephalosporins. the Treatment of Complicated Gram- com/pdf/Product-Monograph-Zevtera.pdf (Accessed 09/03/2020). Negative Infections. P&T. 2014; (Accessed 09/13/2020). 39(12):825-832. 24. Chahine EB, Nornoo AO. Ceftobiprole: The 18. PubChem, [Online]. Available at: https:// 21. Bradley JS, Ang JY, Arrieta AC et al. First Broad-Spectrum Anti-Methicillin- .ncbi.nlm.nih.gov/ (Accessed and Safety of Single Resistant Staphylococcus Aureus 09/03/2020). Intravenous Doses of Ceftolozane/ Beta-Lactam. Journal of Experimental & 19. Solomkin J, Hershberger E, Miller B et al. Tazobactam in Children With Proven or Clinical Medicine 2011;3(1):9-16. Ceftolozane/Tazobactam Plus Suspected Gram-Negative Infection. Pediatr 25. Grau S. Safety and Tolerability of Metronidazole for Complicated Intra- Infect Dis J. 2018;37(11):1130-1136. Ceftobiprole. Rev Esp Quimioter. 2019; Abdominal Infections in an Era of 22. Liapikou A, Cillóniz C, Torres A. 32(3):34-36. Multidrug Resistance: Results From a Ceftobiprole for the Treatment of

126 | PHARMACEUTICAL PRACTICE | Vol. XIII, No. 3 (52), Year 2020