Efficacy of Fifth Generation Cephalosporins against Methicillin-Resistant Staphylococcus aureus- A Review

 

Subashree Rathi Selvan1, Dr. Dhanraj Ganapathy2

1CRRI , Saveetha Dental College and Hospitals, Chennai

2HOD, Dept. of Prosthodontics, Saveetha Dental College, Chennai

Corresponding Author E-mail .: subashree.rathi@gmail.com

 

ABSTRACT:

In recent decades, microbial resistance has reached to an incredibly alarming levels, leading to the development of more potent antimicrobial agents. MRSA (Methicillin-Resistant Staphylococcus aureus) in particular, has become the leading cause of skin and soft tissue infections. Severe or potentially life-threatening MRSA infections occur most frequently among patients in contact with health care settings, according to the Centers for Disease Control and Prevention. Novel fifth generation cephalosporins, including ceftaroline fosamate and ceftobiprole medocaril has shown their efficacy in the treatment of acute bacterial skin and soft tissue infections and  community acquired bacterial pneumonia. Till date, ceftaroline has provided a safe use with minimal side effects and exhibits a low potential to induce resistance, though further clinical data in the long run is required.

 

KEYWORDS :  ceftaroline, cephalosporin, antibiotic, ceftobiprole, MRSA.

 

 

 


INTRODUCTION

Microbial pathogens have the ability to adapt themselves to changes in their environment. In last two decades, there is an exponential increase in the capacity to develop resistance to antimicrobial agents, threatening to outpace the ability to counter with more potent antimicrobial agents.1 Antibiotic use and misuse have largely contributed to the emergence of multidrug-resistant (MDR) pathogens in the health care setting.2 Among the various MDR gram-positive pathogens, methicillin-resistant Staphylococcus aureus (MRSA) strains represent a serious clinical concern.3 Today, MRSA is the leading cause of community-acquired skin and soft tissue infections (SSTI) and a cause of necrotizing pneumonia.4,5 There arose a clinical need for new antibiotics that are effective against multidrug-resistant gram-positive and gram-negative pathogens.6,7  Alternatives to Vancomycin, like Linezolid, Daptomycin, Tigecyclin and Quinupristin-Daflopristin was developed for multi drug resistant Gram-positive organisms. 8,9

 

Despite these novel agents, resistance continues to evolve, and strains resistant to Linezolid, Quinupristin/Dalfopristin and Daptomycin have been described.8,9,10 However, there are disadvantages associated with these antibiotic classes.  Long term use of Linezolid is associated with the development of peripheral neuropathy, lactic acidosis, and thrombocytopenia.11 Daptomycin lacks pulmonary activity, and may cause a pulmonary hypersensitivity reaction and myopathy.12,13 Tigecycline exhibits low serum concentrations, accumulates in bone (contraindicated in children and pregnancy), and is often associated with significant nausea.14

 

Ceftaroline:

Ceftaroline fosamil is a new member of the cephalosporin class of antibiotics with expanded activity against Gram-positive pathogens such as MRSA, vancomycin-intermediate S. aureus, vancomycin-resistant S. aureus and multidrug-resistant Streptococcus pneumoniae, while retaining good activity against common Gram-negative organisms.15 Ceftaroline fosamil (formerly PPI-0903, TAK-599) is a novel, parenteral, cephalosporin prodrug that is converted in vivo to the microbiologically active form, ceftaroline.

 

Ceftaroline fosamil was approved in 2010 by the U.S. Food and Drug Administration (FDA) for the treatment of ABSSSI due to susceptible isolates of S. aureus (including methicillin-susceptible [MSSA] and -resistant [MRSA] isolates), Streptococcus pyogenes, Streptococcus agalactiae, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca.15  Ceftaroline MIC values for MRSA were generally 2- to 4-fold higher than those for MSSA.16 The results of the 2010 U.S. AWARE program indicated that over 99% of S. aureus strains in the United States were susceptible to ceftaroline and that all staphylococcal isolates were inhibited at ceftaroline MIC values of 2 g/ml. Furthermore, ceftaroline was 8- and 64-fold more active than ceftriaxone and amoxicillin-clavulanate, respectively, against penicillin-resistant (MIC, 2 g/ml) strains. 17

 

Less than 20% of the drug is protein bound in serum, and it has a volume of distribution similar to the extracellular fluid volume at around 16–17 L.18 Ceftaroline is primarily eliminated by renal excretion, and multiple-dose pharmacokinetic studies have shown the half-life is around 2.5–3 hours. Early-phase clinical trials established a dosing regimen for ceftaroline of 600 mg intravenously (IV) every 12 hours (as a 1-hour infusion) as the preferred regimen for future study.18

 

Ceftobiprole:

Ceftobiprole medocaril is another fifth generation cephalosporin with broad spectrum activity similar to that of ceftaroline. Ceftobiprole is active against cephalosporin-resistant S. pneumoniae and ampicillin-susceptible E. faecalis, but not E. faecium. Furthermore ceftobiprole has broader gram-negative activity than ceftaroline. It appears to have a gram-negative spectrum of activity intermediate between that of ceftriaxone and cefepime.19 Like ceftaroline, ceftobiprole was designed  to yield potent anti-MRSA activity, with an MIC90 of 2 μg/mL.20

 

The drug is 16% bound to plasma proteins, is primarily eliminated in the urine, and has a half-life of around 3–4 hours. Because of its extensive renal clearance, dose adjustments have been proposed for patients with mild-to-moderate renal impairment.19 Results of early phase clinical trials and Monte Carlo simulations suggested two dosing regimens for ceftobiprole: 500 mg IV as a 1-hour infusion every 12 hours for treatment of gram-positive infections, and 500 mg IV as a 2-hour infusion every 8 hours for empirical treatment of mixed gram-positive and gram-negative infections.21,22

 

Animal Studies:

Regarding the treatment of endocarditis, ceftaroline demonstrated bactericidal activity in a rabbit model by showing a decrease in MRSA and Vancomycin-Intermediate Staphylococcus Aureus(VISA) isolates after four days of treatment.  Ceftaroline was superior to linezolid and comparable to vancomycin in an aortic endocarditis rabbit model with MRSA. Ceftaroline was the only bactericidal agent against VISA isolates .23 Regarding sterilization rates (no bacterial growth after 48 hours of incubation), ceftaroline achieved sterilization in 90% (9/10) of MRSA and 60% (6/10) of VISA compared to vancomycin, which achieved 67% (4/6) and 0% (0/5), respectively, and linezolid achieving 0% (0/7 and 0/8) against both isolates.23

 

In a murine MRSA pneumonia model, ceftaroline decreased the MRSA bacteria counts than that of vancomycin and linezolid when the drugs were begun within two hours of infection. However, ceftaroline started one day after infection demonstrated more than 99.9% reduction in bacterial counts by day 3 in a murine MRSA neutropenic pneumonia model, whereby linezolid and vancomycin had no effect.24

 

In a murine pyomyositis model, ceftaroline demonstrated superior efficacy to vancomycin and linezolid in a rabbit model of joint infection due to MRSA and VISA isolates.24

 

Clinical Trials:

CANVAS (CeftAroliNe Versus VAncomycin in Skin and skin structure infections) I and II  were randomized, double-blind, multinational phase III trials which  investigated complicated SSTI (most commonly extensive cellulitis, major abscess, and infected wounds) among 1,378 subjects comparing ceftaroline to vancomycin +/− aztreonam.25 The clinical cure rates were 92% and 93% (non-significant difference), and microbiological eradication rates were 92% and 94% for ceftaroline vs. the comparator.26 Regarding the treatment of SSTI, ceftaroline (600 mg intravenously every 12 hours) was noninferior to vancomycin (1 gram intravenously every 12 hours) plus aztreonam (1 gram intravenously every 8 hours) administered for 5–14 days.

 

FOCUS (ceFtarOline Community-acquired pneumonia trial Vs ceftriaxone in hospitalized patients) 1 and 2 were randomized Double-Blinded, Multicenter Phase 3 Trials of the Efficacy and Safety of Ceftaroline fosamil versus Ceftriaxone in Patients with Community-acquired Pneumonia.27,28 In these two phase III randomized double-blind multicenter trials, 1,228 hospitalized (but not admitted to the ICU) adults with moderate to severe 

 

CAP were randomized to ceftaroline (600 mg intravenously every 12 hours) or ceftriaxone (1 gram intravenously daily) for 5–7 days. The overall clinical cure rates were similar (84% in the ceftaroline group and 78% in the ceftriaxone group), as well as the overall microbiological response rate (87% for ceftaroline and 81% for ceftriaxone). Thus,  individual and pooled analyses of the FOCUS trials demonstrate ceftaroline to be efficacious, well tolerated, and comparable in efficacy and adverse effects to ceftriaxone in the treatment of CAP.1

 

Adverse Effects:

Based on clinical trial data to date, ceftaroline appears to be safe and well-tolerated. The severity of the adverse effects produced by ceftaroline was found to be mild. The most commonly reported side effects in patients treated with ceftaroline fosamate  included diarrhea, nausea and rash. It should not be used in patients with sensitivities to cephalosporin antibiotics.

 

Clinical Use:

The U.S Food and Drug Administration approved the usage of teflaro(ceftaroline fosamate) in October 2010 for  to treat adults with community acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), including methicillin-resistant Staphylococcus aureus (MRSA).

 

CONCLUSION:

There is an exponential increase in the microbial resistance to antimicrobial agents, threatening to outpace the ability to counter with more potent antimicrobial agents. This necessitated novel antibiotics for its clinical management. There emerged ceftaroline fosamate which showed its usefulness in the treatment of acute bacterial skin and skin structure infections and community acquired pneumonia. Till date, ceftaroline has provided a safe use with minimal side effects and exhibits a low potential to induce resistance. Clinical use of ceftaroline was approved by the U.S FDA in October 2010, the dosage of which is 600mg IV over 5 to 60 minutes every twelve hours for patients with normal renal function. However, the complete efficacy and safety of this novel drug is still to be studied in the long term. To conclude, ceftaroline and ceftobiprole provides an additional option in the management of complex multidrug resistant infections.

 

REFERENCES:

1.     Duplesis C, Crum-Cianflone NF. Ceftaroline: a new cephalosporin with activity against methicillin resistant Staphylococcus aureus. Clinical Medicine Reviews in Therapeutics. 3;2011:a2466.

2.     Rybak, M. J. Resistance to antimicrobial agents: an update.  Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 24;2004:203S-215S.

3.     Jones RN. Key considerations in the treatment of complicated staphylococcal infections. Clinical Microbiology and Infection. 14(s2);2008:3-9.

4.      Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, McDougal LK, Carey RB, Talan DA. Methicillin-resistant S. aureus infections among patients in the emergency department. New England Journal of Medicine. 355(7);2006:666-74.

5.      Gonzalez BE, Hulten KG, Dishop MK, Lamberth LB, Hammerman WA, Mason EO, Kaplan SL. Pulmonary manifestations in children with invasive community-acquired Staphylococcus aureus infection. Clinical infectious diseases. 41(5);2005:583-90.

6.     Talbot GH, Bradley J, Edwards JE, Gilbert D, Scheld M, Bartlett JG. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability Task Force of the Infectious Diseases Society of America. Clinical Infectious Diseases. 42(5);2006:657-68.

7.     Tsiodras S, Gold HS, Sakoulas G, Eliopoulos GM, Wennersten C, Venkataraman L, Moellering RC, Ferraro MJ. Linezolid resistance in a clinical isolate of Staphylococcus aureus. The Lancet. 358(9277);2001:207-8.

8.     Pan A, Lorenzotti S, Zoncada A. Registered and investigational drugs for the treatment of methicillin-resistant Staphylococcus aureus infection. Recent patents on anti-infective drug discovery. 3(1);2008:10-33.

9.     Manfredi R, Sabbatani S. Novel pharmaceutical molecules against emerging resistant gram-positive cocci. Brazilian Journal of Infectious Diseases. 14(1);2010:96-108.

10.   Stefani S, Goglio A. Methicillin-resistant Staphylococcus aureus: related infections and antibiotic resistance. International Journal of Infectious Diseases. 14;2010:S19-22.

11.  Manfredi R. Update on the appropriate use of linezolid in clinical practice. Therapeutics and clinical risk management. 2(4);2006:455.

12.   Nannini E, Murray BE, Arias CA. Resistance or decreased susceptibility to glycopeptides, daptomycin, and linezolid in methicillin-resistant Staphylococcus aureus. Current opinion in pharmacology. 10(5);2010:516-21.

13.  Koplowicz YB, Schwartz BS, Guglielmo BJ. Development of daptomycin-susceptible, methicillin-resistant Staphylococcus aureus pneumonia during high-dose daptomycin therapy. Clinical infectious diseases. 49(8);2009:1286-7.

14.  Reygaert WC. Antibiotic optimization in the difficult-to-treat patient with complicated intra-abdominal or complicated skin and skin structure infections: focus on tigecycline. Therapeutics and clinical risk management.6;2010:419.

15.  Kanafani Z, Corey R. Ceftaroline: A Cephalosporin with Expanded Gram- positive Activity. Future Microbiology. 4(1);2009:25–33.

16.  Flamm RK, Sader HS, Farrell DJ, Jones RN. Summary of ceftaroline activity against pathogens in the United States, 2010: report from the Assessing Worldwide Antimicrobial Resistance Evaluation (AWARE) surveillance program. Antimicrobial agents and chemotherapy. 56(6);2012:2933-40.

17.  Corey GR, Wilcox MH, Talbot GH, Thye D, Friedland D, Baculik T, Mehra P, Alpert M, Baird I, Klein S, Litow J. CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. Journal of antimicrobial chemotherapy. 65(4);2010:iv41-51.

18.  Jacqueline C, Caillon J, Miegeville A, Launay E, Batard E, Ge Y, Potel G. Penetration of ceftaroline (PPI-0903), a new cephalosporin, into lung tissues: measurement of plasma and lung tissue concentrations after a short IV infusion in the rabbit. In46th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy. San Francisco, CA, USA 2006 (pp. 27-30).

19.  Kollef MH. New Antimicrobial agents for Methicillin-resistant'Staphylococcus Aureus'. Critical Care and Resuscitation. 11(4);2009:282.

20.  Fritsche TR, Sader HS, Jones RN. Antimicrobial activity of ceftobiprole, a novel anti–methicillin-resistant Staphylococcus aureus cephalosporin, tested against contemporary pathogens: Results from the SENTRY Antimicrobial Surveillance Program (2005–2006). Diagnostic microbiology and infectious disease.61(1);2008:86-95.

21.  Noel GJ, Strauss RS, Amsler K, Heep M, Pypstra R, Solomkin JS. Results of a double-blind, randomized trial of ceftobiprole treatment of complicated skin and skin structure infections caused by gram-positive bacteria. Antimicrobial agents and chemotherapy. 52(1);2008:37-44.

22.  Noel GJ, Bush K, Bagchi P, Ianus J, Strauss RS. A randomized, double-blind trial comparing ceftobiprole medocaril with vancomycin plus ceftazidime for the treatment of patients with complicated skin and skin-structure infections. Clinical infectious diseases. 46(5);2008:647-55.

23.  Jacqueline C, Caillon J, Le Mabecque V, Miegeville AF, Hamel A, Bugnon D, Ge JY, Potel G. In vivo efficacy of ceftaroline (PPI-0903), a new broad-spectrum cephalosporin, compared with linezolid and vancomycin against methicillin-resistant and vancomycin-intermediate Staphylococcus aureus in a rabbit endocarditis model. Antimicrobial agents and chemotherapy. 51(9);2007:3397-400.

24.  Iizawa Y, Nagai J, Ishikawa T, Hashiguchi S, Nakao M, Miyake A, Okonogi K. In vitro antimicrobial activity of T-91825, a novel anti-MRSA cephalosporin, and in vivo anti-MRSA activity of its prodrug, TAK-599. Journal of infection and chemotherapy. 10(3);2004:146-56.

25.  Corey GR, Wilcox M, Talbot GH, Friedland HD, Baculik T, Witherell GW, Critchley I, Das AF, Thye D. Integrated Analysis of CANVAS 1 and 2: Phase 3, Multicenter, Randomized, Double-blind Studies to Evaluate the Safety and Efficacy of Ceftaroline Versus Vancomycin Plus Aztreonam in Complicated Skin and Skin-structure Infection. Clin Infect Dis. 51(6);2010:641–650. 

26.  Talbot GH, Thye D, Das A, Ge Y. Phase 2 study of ceftaroline versus standard therapy in treatment of complicated skin and skin structure infections. Antimicrobial agents and chemotherapy. 2007 Oct 1;51(10):3612-6.

27.  Eckburg P, Friedland HD, Lee J, Llorens L, Critchley IA, Thye D. FOCUS 1 and 2: randomized, double-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline (CPT) vs ceftriaxone (CRO) in community-acquired pneumonia (CAP). InForty-ninth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Francisco, CA 2009 Sep 12.

28.  File TM, Low DE, Eckburg PB, Talbot GH, Friedland HD, Lee J, Llorens L, Critchley I, Thye D. Integrated analysis of FOCUS 1 and FOCUS 2: randomized, doubled-blinded, multicenter phase 3 trials of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in patients with community-acquired pneumonia. Clinical infectious diseases.51(12);2010:1395-405.

 

 

 

 

Received on 04.07.2016             Modified on 20.07.2016

Accepted on 28.07.2016           © RJPT All right reserved

Research J. Pharm. and Tech 2016; 9(10):1815-1818.

DOI: 10.5958/0974-360X.2016.00369.3