The new fifth-generation cephalosporins – a balance between safety and efficacy

Cephalosporins are beta-lactam antibiotics classified into five generations. The newest generation has three representatives: ceftaroline fosamile, the combination ceftolozane/tazobactam (cephalosporin/beta-lactamase inhibitor), and ceftobiprole medocaril. These new cephalosporins are valuable anti-infective agents, with potent activity against multidrug-resistant bacteria, and with a positive balance between benefits and side effects. However, the fifth-generation cephalosporins should be judiciously used to prevent the occurrence of bacterial resistance phenomenon.


INTRODUCTION
Cephalosporins (CFs) are betalactam antibiotics with numerous representatives widely used in the therapy of infectious diseases. Like other beta-lactam antibiotics, CFs inhibit the synthesis of the bacterial cell wall. The beta-lactam ring is essential in binding to the penicillin-binding proteins, crucial enzymes in the synthesis of the bacterial cell wall. The high affinity of fifth-generation CFs for penicillin-binding proteins leads to an efficient activity against clinically relevant pathogens. The new CFs (fourth and fifth generations) have emerged as a result of increased bacterial resistance to classical antibiotics. Based on the antimicrobial activity, the CFs are classified into five generations (Table 1) [1]. Representatives of the fifth-generation which are used in therapy are comprised of: ceftaroline fosamil, ceftolozane/ tazobactam, and ceftobiprole medocaril [1][2][3]. The clinical studies conducted so far support the positive balance between benefits and side effects for these new CFs. However, the fifth-generation CFs should be judiciously used in difficult-to-treat bacterial infections only, in the situation where other antibacterial drugs were not efficient.

Physical-chemical properties.
Ceftaroline is an oxyimino compound based on the structure of cefozopran (a fourth-generation representative) [6]. Ceftaroline fosamil is a prodrug that turns in vivo into ceftaroline (the active metabolite). The name "fosamil" is given by an extra phosphono group in the chemical structure comparative to ceftaroline. The resulted compound has the advantage that it is more watersoluble [6]. The oxime group in the C7 acyl moiety and a 1,3-thiazole ring attached to the central nucleus (C3 position) facilitate the increased activity against MRSA (Table 2) [6,8]. The parenteral formulation (600 mg powder for concentrate for solution for infusion) contains an equivalent amount of ceftoraline fosamil acetic acid solvate monohydrate [5].
Indications, dosing and administration. Ceftaroline fosamil has been approved for administration to children (neonates, infants, children, adolescents) for the same indications as for adults: complicated skin and soft tissue infections and community-acquired pneumonia [5]. Ceftaroline fosamil is administrated intravenously (600 mg every 12 hours over 1 hour in adults) during 5-14 days. Dosage adjustment is necessary for patients with moderate to severe renal impairment [6]. Also, ceftaroline fosamil is used off-label in the treatment of bacteremia, endocarditis, osteoarticular infections, hospital-acquired pneumonia, and meningitis [9].

Safety of ceftaroline fosamil.
Ceftaroline fosamil is considered effective in therapy, and welltolerated, with a good safety profile. However, ceftaroline fosamil could be responsible for diarrhea, nausea, headache and pruritus as the most common side effects with similar rates compared to other antibiotics [5,6,[9][10][11]. Precautions for use and special warnings are for hypersensitivity reactions, Clostridium difficileassociated diarrhea, superinfections with non-susceptible bacteria, and pre-existing seizure disorder. Ceftaroline fosamil has a low potential for drug-drug interactions [6,12]. Because the effects of the compound in pregnancy and lactation or on fertility are unknown, it is advisable to avoid the treatment in these situations [5]. More studies are needed in the future to assess the safety profile of ceftaroline fosamil [9].

Ceftolozane/tazobactam combination
Ceftolozane is a new fifthgeneration CF, a derivative of ceftazidime (third generation). Because it is not resistant to beta-lactamases, ceftolozane was combined with an inhibitor of beta-lactamases, respectively tazobactam. The obtained combination provides great activity against extended-spectrum betalactamase-producing Enterobacteriaceae, Pseudomonas aeruginosa, and certain anaerobic germs [2,13]. The combination of ceftolozane with tazobactam (ATC code: J01DI54) was approved in 2014 by the FDA, and in 2015 by the EMA (under trade name Zerbaxa). Recently, the FDA has approved Zerbaxa for the treatment of adults with hospital-acquired and ventilator-associated bacterial pneumonia [14][15][16].

REVIEWS
Physical-chemical properties. The chemical structure is based on the structure of ceftazidime (an oxyimino-aminothiazolyl CF), optimized to have activity on Pseudomonas spp. The aminothiadiazole moiety (attached to the side-chain from C7 position) confers increased activity against G(-) bacteria. Also, a pyrazole moiety attached to the side-chain from C3 position confers stability to beta-lactamases and permeability through the outer bacterial membrane. These properties of ceftolozane lead to increased activity against Pseudomonas aeruginosa. The parenteral formulation (1 g ceftolozane/0.5 g tazobactam powder for concentrate for solution for infusion) contains an equivalent amount of  by generation and route of administration (G(+) = Gram positive, G(-) = Gram negative) [1,2,17,22,24]. ceftolozane sulphate and tazobactam sodium) [15].

Indications, dosing and administration.
Usually, the approved dose of ceftolozane/ tazobactam is 1 g ceftolozane/0.5 g tazobactam for the treatment of complicated intra-abdominal infections, urinary tract infections and acute pyelonephritis. Hospitalacquired pneumonia, including ventilator-associated pneumonia, require a dose of 2 g ceftolozane/1 g tazobactam. It is administered intravenously, every 8 hours (1 hour infusion time) for 4 -14 days. It can be associated with metronidazole and other antibacterial agents for a broader antimicrobial spectrum [15,19].

Safety of ceftolozane/
tazobactame. Generally, therapy with ceftolozane/tazobactam is well tolerated. The reported common side effects such as nausea, vomiting, diarrhea, constipation, abdominal pain, hypotension, rash, headache, dizziness, insomnia, anxiety, hypokalemia, thrombocytosis, and Clostridioides difficile colitis were mild or moderate [16,20]. Although contraindications for the use of ceftolozane/tazobactam have not been identified, precautions for use and special warnings are hypersensitivity reactions (may appear in patients allergic to beta-lactam antibiotics) and impairment of renal function [15]. In ceftolozane/tazobactam administration, no significant drug-drug or food-drug interactions have been reported. There is no data on ceftolozane/tazobactam effects in pregnancy, breastfeeding, or on fertility [15,20]. Unlike ceftaroline fosamil, ceftolozane/ tazobactam combination is under evaluation for use in children [21].

Indications, dosing and administration.
Ceftobiprole medocaril is indicated for the treatment of complicated skin and soft tissue infections and pneumonia [24]. Ceftobiprole medocaril is administrated intravenously (500 mg every 8 hours over 2 hours in adults) during 4 -14 days. Dosage adjustment is necessary for patients with moderate and severe renal impairment [23].

Safety of ceftobiprole medocaril.
Ceftobiprole has a good safety profile [3]. Nausea, headache and gastrointestinal disorders are the most common side effects of ceftobiprole [3,22]. Besides the broad spectrum of activity (including MRSA), the excellent safety profile of ceftobiprole medocaril is a significant advantage in comparison with other antimicrobial agents. However, there are no published studies regarding the usage of ceftobiprole medocaril in pregnancy, breastfeeding, effects on fertility, and drug-drug interactions [23]. The ongoing phase 3 studies will REVIEWS contribute to the list of approved indications and will complete the knowledge on the use of ceftobiprole medocaril [3].

CONCLUSIONS
Ceftaroline fosamile, the combination ceftolozane/ tazobactame, and ceftobiprole medocaril are the first representatives of the fifthgeneration of CFs used in therapy.
These new antibiotics are valuable anti-infective agents with a positive balance between benefits and side-effects. Nevertheless, the fifth-generation CFs should be highly restricted to prevent the occurrence of bacterial resistance. These new beta-lactam antibiotics must be judiciously used, only in the situation where other antibacterial drugs were not effective.