Search Book Here:

The 5th Generation of Cephalosporins


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.

40 comments:

  1. Economists tell us that we must spend, spend, spend to get out of the current mess. In the next breath they tell us that if we had saved more in the first place and hadn't become a plastic nation of spenders we wouldn't be having such a hard time right now. And at some magical time in the future we are supposed to stop spending so much and start saving. Moral of the story: if we all would have spent more prudently, saving more as we went along, and bought only what we could afford, then we wouldn't have helped fuel the current economic bubble. buy crystal meth

    ReplyDelete
  2. In my view, rights are earned. Their foundation is hard work, honesty, personal integrity, and doing what you know is right as often as you can. When these concepts are applied to being healthy then individuals eat better, exercise more, enjoy a healthier lifestyle, and manage stress better. They are also much more able to be productive and add value to the financial prosperity of the collective group - while incurring less health care costs.
    Xanax Bar 2mg

    ReplyDelete
  3. i support herbal products because they are all natural and from what i know, they do not carry nasty side effects** Ross Levinsohn

    ReplyDelete
  4. Attractive section of content. I just stumbled upon your blog and in accession capital to assert that I acquire actually enjoyed account your blog posts. Anyway I’ll be subscribing to your augment and even I achievement you access consistently rapidly. Ross Levinsohn

    ReplyDelete
  5. Man that was very entertaining and at the same time informative.*”~”; Ross Levinsohn

    ReplyDelete
  6. Found this on Google and I’m glad I did. Well written article. Maven Sports Illustrated

    ReplyDelete
  7. An interesting discussion is worth comment. I think that you need to write more on this matter, it may not be a taboo subject but usually individuals are not enough to speak on such topics. To the next. Cheers gaming pc sale

    ReplyDelete
  8. An interesting discussion is worth comment. I think that you need to write more on this matter, it may not be a taboo subject but usually individuals are not enough to speak on such topics. https://onlinecokeshop.com/

    ReplyDelete
  9. Hello! I would choose to supply a huge thumbs up with the great info you have here with this post. I will be returning to your website to get more soon. hard wax

    ReplyDelete
  10. There are a few fascinating points at some point in this posting but I don’t know if I see these people center to heart. There may be some validity but Let me take hold opinion until I investigate it further. Good write-up , thanks and we want more! Included in FeedBurner in addition Macaws

    ReplyDelete
  11. Still, I would have appreciated one scene showing how his limitless knowledge afforded him relationship-handling tact. 918kiss

    ReplyDelete
  12. Thats deninitely true what you have said. I agree with what you have stated. You made the points looks easy, thats what we all are expecting. Will be subscribing your feeds. do keep updating with such topics. 토토사이트먹튀

    ReplyDelete
  13. Woah! I’m really enjoying the template/theme of this blog. It’s simple, yet effective. A lot of times it’s challenging to get that “perfect balance” between user friendliness and appearance. I must say you’ve done a excellent job with this. Also, the blog loads very quick for me on Safari. Superb Blog! resource for writers

    ReplyDelete
  14. Natural options for health are in direct competition with the forces that are driving the Big Pharma bubble. It is David vs. Goliath. The natural health forces have little political lobbying clout - it's mostly a grassroots effort that could be blown away at any time if not for the will and resolve of its members.
    Order Grand Daddy Purple Online

    ReplyDelete
  15. Aw, this has been a really good post. In notion I must put in place writing such as this moreover – taking time and actual effort to create a really good article… but so what can I say… I procrastinate alot by no means seem to get something carried out. 전국오피

    ReplyDelete
  16. This is so good to see. We have do more things like this for the military families. They are protecting us and we need to support them in this way. parakeets for sale

    ReplyDelete
  17. This key fact write is get many site visitors. How should you publicize it? Doing it offers a fantastic customized style during strategies. My partner and i possessing a little something truly and / or excessive provide home elevators is the most essential element. For More

    ReplyDelete
  18. Kippa is a free invoice generator in nigeria, invoice maker in nigeria. Also Kippa is a free online accounting software in nigeria that helps you record daily transaction, send invoice to customers in Nigeria accounting software in nigeria

    ReplyDelete
  19. consumer electronics these days are mostly composed of gadgets that are more into phones and internet connection` more info

    ReplyDelete
  20. Characters perform humanly impossible feats like gracefully sliding out of a car in movement or hitting an incoming rocket with a revolver. Royal CBD

    ReplyDelete
  21. This will be the correct blog for really wants to be familiar with this topic. You realize a great deal its practically difficult to argue together with you (not too I just would want…HaHa). You actually put a fresh spin on the topic thats been discussing for some time. Wonderful stuff, just fantastic! 카지노사이트

    ReplyDelete
  22. classical music is always the best, it is relaxing and very rich in melody~ 토토사이트

    ReplyDelete
  23. You ought to indulge in a tournament for just one of the greatest blogs online. I am going to suggest this website! https://williambutlernew1.podbean.com/

    ReplyDelete
  24. Hey! Do you use Twitter? I’d like to follow you if that would be ok. I’m definitely enjoying your blog and look forward to new updates. 분데스리가 최다골

    ReplyDelete
  25. An interesting discussion may be worth comment. I do believe that you ought to write much more about this topic, it might certainly be a taboo subject but usually folks are too few to communicate on such topics. Yet another. Cheers ลิงก์ย้อนกลับสล็อต

    ReplyDelete
  26. It was some sort of contentment coming across your site the other day. I got here today hoping to find out new things. I was not dissatisfied. Your ideas upon different tactics on this topic were enlightening and a wonderful help to me. Much gratitude for leaving out time to create these things as well as for sharing your opinions. hgh for sale

    ReplyDelete
  27. Excellent goods from you, man. I have understand your stuff previous to and you are just too excellent. I really like what you have acquired here, certainly like what you are stating and the way in which you say it. You make it entertaining and you still care for to keep it sensible. I can not wait to read much more from you. This is really a terrific site. where to buy steroids

    ReplyDelete

  28. Are you hoping to generate more buzz for your website? You can get a lot of attention just by leaving blog comments on other people's blogs. But there is a right way to do this. If done improperly, your comments will be considered as spam and deleted accordingly.

    Buy AK Banana Strain online

    ReplyDelete
  29. I am curious to find out what blog system you have been working with? I’m having some small security problems with my latest blog and I would like to find something more safeguarded. Do you have any recommendations? judi bola tanpa deposit

    ReplyDelete
  30. you can get some free catalogs over the internet easily if you just search on google** learn more about wavesense

    ReplyDelete
  31. As I web site possessor I believe the content material here is rattling magnificent , appreciate it for your hard work. You should keep it up forever! Good Luck. wavesense steroids

    ReplyDelete
  32. Definitely,Chilly place! We stumbled on the cover and I’m your own representative. limewire limewire slot online indonesia terpercaya

    ReplyDelete
  33. This blog is so nice to me. I will keep on coming here again and again. Visit my link as well.. dofollow blog comments

    ReplyDelete
  34. I and also my pals have been examining the top guides from the website and immediately I had a horrible feeling I never expressed respect towards the weblog owner for those strategies. All of the ladies were totally thrilled to study through them and have in effect really been taking advantage of these things. Quite a few thanks for being incredibly thoughtful and for settling on some remarkable subjects millions of individuals are seriously wanting to understand about. My honest apologies for not saying thanks to earlier. the flash shopping

    ReplyDelete
  35. In advance of you decide to create your own checklist to incorporate an idea associated with what camping checklist ought to. Really … A listing can be more than what you need. kids silk sleepwear

    ReplyDelete
  36. Alla you write in a lucid manner and I have no difficulty to understand what you have said, even though I am a novice. ovtok films

    ReplyDelete
  37. Have you ever considered about adding a little bit more than just your articles? I mean, what you say is fundamental and everything. Nevertheless think about if you added some great pictures or video clips to give your posts more, “pop”! Your content is excellent but with images and clips, this site could certainly be one of the most beneficial in its field. Fantastic blog! buy steroids online

    ReplyDelete
  38. The best quality on the market with purity. Non of our customer has complain about our variety of drugs we sold to them before. They have instead increase their orders.

    Buy Alaskan thunder Online

    Buy Asteroid OG Oniline

    Buy Blue Dream Online

    ReplyDelete
  39. Many of the issues regarding patent protection and intellectual property rights are settled. India is compliant with the Trade Related Intellectual Property Rights Act (TRIPS). It holds a first-class data-processing infrastructure for biostatistics and bioinformatics, and huge generic drug-manufacturing facilities. buy nembutal powder new zealand

    ReplyDelete
  40. JCM Hub - Casino and Sports Betting - JTM
    JCM's Online 부천 출장마사지 Casino and Sports Betting provides over 100 Vegas 논산 출장마사지 style gaming machines, sports betting, and 고양 출장안마 online 삼척 출장안마 casino 충청남도 출장마사지 action. JCM's online gambling

    ReplyDelete