New-Generation Cephalosporins

JULY 17, 2017
Marilyn N. Bulloch, PharmD, BCPS
Since their discovery in the 1950s, cephalosporins have become one of the largest classes of antibiotics. The class is divided into generations or subclasses, which are grouped by chemical properties and subsequent generalized microbiologic spectra.

Cephalosporins have been used to treat a variety of infections, from mild to life-threatening; however, like all antibiotics, resistance has been identified in bacteria. This typically occurs when the medications bind to an active site serine that is located on all functional penicillin-binding proteins (PBPs). The resulting inactive enzyme slowly hydrolyzes the antibiotic so that it forms an inactive entity compared with the bacteria.1

To address antibacterial resistance, the Generating Antibiotic Incentives Now provision of the FDA Safety and Innovation Act (FDASIA; Public Law 112-144) created the designation of “qualified infectious disease products” (QIDPs).2 This status is granted to agents that are intended to treat dangerous or life-threatening infections caused by resistant, novel, or emerging pathogens or those listed within the FDASIA. The agents receive an additional 5 years of patent exclusivity and priority and fast-track FDA review. In 2015, ceftolozane/tazobactam (Zerbaxa) became the fourth and ceftazidime/avibactam (Avycaz) became the fifth QIDP to receive FDA approval.3,4 Together, these new cephalosporins have been referred to as fifth-generation cephalosporins, or new-generation cephalosporins (NGCs).

PHARMACOLOGY
Both NGCs are bactericidal agents that bind to PBPs, the essential enzymes involved in the final step of cell wall biosynthesis in both Gram-positive and Gram-negative organisms. 1,3,4 Each is attached to a beta-lactamase inhibitor that does not possess clinically relevant in vitro activity against bacteria but does serve to protect the cephalosporin from degradation. Tazobactam, combined with the novel cephalosporin ceftolozane, is an irreversible inhibitor of class A penicillinases and class C cephalosporinases and forms covalent bonds to some chromosomal and plasma-mediated beta-lactamases. 2,6 Avibactam, a novel beta-lactamase inhibitor combined with ceftazidime, the established third-generation cephalosporin, inhibits class A penicillinases, extended-spectrum beta-lactamases (ESβLs), class C cephalosporinases, class D oxacillinases, and serine carbapenemases.1,5,7

MICROBIOLOGY
Ceftolozane/tazobactam and ceftazidime/avibactam have shown efficacy against a large number of pathogens. Both NGCs demonstrate in vitro activity against enterobacteriaceae in the presence of certain beta-lactamases and ES Ls and are effective against Pseudomonas aeruginosa, including some resistant isolates.6,7 Only ceftazidime/avibactam, however, is effective against Klebsiella pneumoniae carbapenemases. 7 Ceftolozane/tazobactam also has shown efficacy against Streptococcus species and the anaerobic pathogens Bacteroides fragilis and Fusobacterium species.6 Neither NGC is effective against the Enterococcus species and therefore may not provide adequate empiric coverage for all patients with a nitrate-negative urinalysis.

THERAPEUTIC USE
The NGCs are FDA approved for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis, and complicated intraabdominal infections (cIAIs).6,7 cIAIs include intraabdominal abscesses, peritonitis, gastric or duodenal perforation, intestinal perforation, appendicitis, cholecystitis, and diverticulitis. When treating cIAIs, metronidazole must be used with the NGCs to provide coverage against anaerobic organisms. The NGCs should be used only in patients 18 years old or older, when treating infections known or strongly suspected to be caused by susceptible organisms, and reserved for patients with no or limited antibacterial alternatives.

DOSING AND ADMINISTRATION
NGCs are parenteral antibiotics that are administered every 8 hours to adult patients with a creatinine clearance >50 mL/min.6,7 Dosing for each antibiotic is the same for the 2 approved indications. Ceftazidime/avibactam 2.5 g (2 g/0.5 g) should be infused during a 2-hour period, whereas ceftolozane/tazobactam 1.5 g (1 g/0.5 g) only requires a 1-hour infusion. The dose of ceftolozane/tazobactam is reduced with declining kidney function (creatinine clearance ≤50 mL/min), but the 8-hour frequency is unchanged. In contrast, decreased dosing and extended interval frequency are required for ceftazidime/avibactam when the creatinine clearance is ≤50 mL/min.

The duration of therapy differs between the 2 agents and by indication. A cUTI should be treated for at least 7 dayswith either NGC, although it may require up to 14 days with ceftazidime/avibactam.6,7 Patients with a cIAI should receive ceftolozane/tazobactam for 4 to 14 days or ceftazidime/ avibactam for 5 to 14 days. When used to treat cIAI, intravenous metronidazole 500 mg every 8 hours also should be administered.

COMPARATIVE EFFICACY
To the author’s knowledge, no head-to-head studies between the 2 NGCs have been conducted. The approvals of both NGCs for cIAIs were based on the results of similar large clinical trials of hospitalized patients in which the NGC plus metronidazole was compared with meropenem.6,7

Ceftolozane/tazobactam was evaluated in a multinational noninferiority study of 979 patients that assessed clinical response, defined as complete resolution or significant improvement in signs and symptoms of the infection 24 to 32 days after the first dose of the study drug.6 Ceftolozane/ tazobactam plus metronidazole was shown to be noninferior to meropenem in clinical response (83% vs 87.3%; observed difference, −4.3% [95% CI, −9.2% to 0.7%]). A subanalysis of Escherichia coli and K pneumoniae isolates used genotypic testing to identify ESβL groups in 9% of isolates, with clinical cure rates being similar between the groups.

Ceftazidime/avibactam also was evaluated in a multinational noninferiority study in combination with metronidazole compared with meropenem alone.7 The study enrolled 1058 patients to evaluate clinical cure, which had the same definition as previously noted for clinical response, but was evaluated at 28 to 35 days after enrollment. Ceftazidime/avibactam plus metronidazole also was shown to be noninferior to meropenem alone (81.6% vs 85.1%; observed difference, −3.5% [95% CI, −8.6% to 1.6%]). A subanalysis of genotypic testing for ESβLs also was conducted, with cure rates continuing to be similar between the 2 groups.

Ceftolozane/tazobactam was approved by the FDA for the treatment of cUTIs based on a multinational study of 1068 patients that compared cephalosporin with levofloxacin for 7 days.8 The primary endpoint was complete resolution or marked improvement of clinical symptoms and microbiological eradication at 7 days after the last dose of the medication. Ceftolozane/tazobactam was shown to have better efficacy compared with levofloxacin (76.9% vs 68.4%; observed difference, 8.5% [95% CI, 2.3%-14.6%]), but 26.5% of patients had isolates that were resistant to levofloxacin. Among the patients with levofloxacin-sensitive organisms, efficacy was similar between the 2 antibiotics (82.6% vs 79.7%; no 95% CI provided).

The approval of ceftazidime/avibactam for cUTIs was granted predominantly based on the results of previous studies on the efficacy and safety of ceftazidime alone forcUTIs7; the contribution of avibactam to the efficacy of the medication was supported by in vitro and animal studies.7 Ceftazidime/avibactam was compared with imipenem-cilastatin in a phase 2 randomized multicenter study of hospitalized patients with cUTIs caused by Gram-negative organisms. 9 The cure’s effectiveness was evaluated in 62 patients who were microbiologically evaluable 5 to 9 days after therapy, with a favorable microbiologic response similar between the groups (70.4% vs 71.4%; observed difference, −1.1% [95% CI, −27.2% to 25%]).

Ceftazidime/avibactam also was compared with doripenem in a postapproval phase 3 noninferiority study for 10 days (up to 14 days, if bacteremia was detected) in 1033 patients with cUTIs.10 Ceftazidime/avibactam was shown to be noninferior to doripenem in patient-reported symptomatic resolution at day 5 (70.2% vs 66.2%; observed difference, 4% [95% CI, −2.39% to 10.42%]) and combined symptomatic resolution and microbiological eradication at test of cure (71.2% vs 64.5%; observed difference, 6.7% [95% CI, 0.3%-13.12%]).

ADVERSE EFFECTS
Adverse effects (AEs) with NGCs typically are mild, but there are several common and serious AEs worth noting. Both agents cause nausea and diarrhea in ≥5% of patients.6-10 Ceftazidime/avibactam also may cause constipation, diarrhea, abdominal pain, dizziness, or anxiety.7 Ceftazidime alone has been associated with more serious central nervous system (CNS) AEs, including seizures, encephalopathy, and coma.7 AEs with ceftolozane/tazobactam include headache and pyrexia.6

DRUG–DRUG INTERACTIONS
Minimal drug–drug interactions have been observed with the NGCs. Both tazobactam and avibactam are substrates of organic anion transporter 1 (OAT1) and OAT3 kidney transporters.6,7 Probenecid, an inhibitor of these transporters, can prolong the half-life of the beta-lactamase inhibitors, and coadministration is not recommended. Cytochrome activity is not affected at clinically relevant blood concentrations, but at supratherapeutic blood concentrations, tazobactam may inhibit cytochrome P450 1A2 (CYP1A2), CYP2D6, and CYP3A4, and avibactam may induce CYP2E1.

SAFETY ISSUES
Ceftolozane/tazobactam and ceftazidime/avibactam are less effective in patients with a baseline creatinine clearance of 30 to ≤50 mL/min.6,7 Creatinine clearance should be monitored daily in patients receiving these antibiotics, and alternative agents, if available, against the target organism should be considered in patients whose kidney function fallsconsistently within these parameters. Studies of both NGCs reported more AEs in geriatric patients.6,7 Clostridium difficile- associated diarrhea has been reported with both agents, with severity ranging from mild to fatal.6,7 Caution should be exercised when determining whether to use either antibiotic in a patient with a penicillin or other beta-lactamase allergy because of the risk of cross-reactivity.

Serious CNS reactions are known to occur with ceftazidime, especially in patients with decreased kidney function.7 Reactions include seizures, encephalopathy, coma, asterixis, myoclonia, and neuromuscular excitability. Ceftazidime/ avibactam should be avoided in patients with other risk factors for these CNS effects whenever possible. However, if the combination must be used in patients with a creatinine clearance ≤50 mL/min, then the dosage should be adjusted to lessen the risk of CNS reactions.7

Both NGCs should be protected from exposure to light.6,7 Ceftazidime/avibactam can be stored at a controlled roomtemperature (77°F, with excursions 59°-86°F permitted).7 Once mixed in fluid, it is stable for 12 hours at temperatures ranging from 68° to 77°F and for 24 hours if refrigerated. Ceftolozane/tazobactam should be refrigerated until it is reconstituted. After dilution, ceftolozane/tazobactam can be stored at room temperature for a maximum of 24 hours or in the refrigerator for up to 7 days.6 
 
Marilyn Novell Bulloch, PharmD BCPS, is an associate clinical professor of pharmacy practice at the Auburn University School of Pharmacy and an adjunct assistant professor at the University of Alabama School of Medicine College of Community Health Sciences Department of Internal Medicine. She serves on multiple committees and in leadership positions for many local, state, and national pharmacy and interdisciplinary medical organizations.

References
  1. Bush K, Bradford PA. β-lactams and β-lactamase Inhibitors: an overview. Cold Spring Harb Perspect Med. 2016;6(8). doi: 10.1101/cshperspect.a025247.
  2. Frey P. FDA Safety and Innovation Act. Paper presented at: FDA Small Business Regulatory Education for Industry conference; June 19, 2016;
  3. FDA approves new antibacterial drug Zerbaxa. Arlington, VA: Infectious Diseases Society of America; December 19, 2014. idsociety.org/FDA_20141222/. Accessed June 7, 2017.
  4. FDA approves new antibacterial drug Avycaz. Silver Spring, MD: FDA; February 26, 2015. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm435629.htm. Accessed August 26, 2016.
  5. Wang DY, Abboud MI, Markoulides MS, Brem J, Schofield CJ. The road to avibactam: the first clinically useful non-β-lactam working somewhat like a β-lactam. Future Med Chem. 2016;8(10):1063-1084. doi: 10.4155/fmc-2016-0078.
  6. Zerbaxa [prescribing information]. Whitehouse Station, NJ: Merck & Co; 2015.
  7. Avycaz [prescribing information]. Cincinnati, OH: Forest Pharmaceuticals; 2.016
  8. Wagenlehner FM, Umeh O, Steenbergen J, Yuan G, Darouiche RO. Ceftolozane-tazobactam compared with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, double-blind phase 3 trial (ASPECT-cUTI). Lancet. 2015;385(9981):1949-1956. doi: 10.1016/S0140-6736(14)62220-0.
  9. Vasquez JA, González Patzán L, Stricklin D, et al. Efficacy and safety of ceftazidime-avibactam versus imipenem-cilastatin in the treatment of complicated urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective investigator-blinded, randomized study. Curr Med Res Opin. 2012;28(12):1921-1931. doi: 10.1185/03007995.2012.748653.
  10. Wagenlehener FM, Sobel JD, Newell P, et al. Ceftazidime-avibactam versus doripenem for the treatment of complicated urinary tract infections, including acute pyelonephritis: RECAPTURE, a phase 3 randomized trial program. Clin Infect Dis. 2016;63(6):754-762. doi: 10.1093/cid/ciw378.

 


 

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