Johnson, Steven W. PharmD*†; May, D. Byron PharmD*
Cephalosporin antibiotics have been a mainstay in the treatment of gram-positive and gram-negative bacterial infections since their introduction in the 1960s.1,2 These agents share similar mechanisms of action and structure with penicillin.3–9 Penicillins and cephalosporins have the same 4-member β-lactam ring, but cephalosporins have an additional atom in the side ring.4 Modified side chains on either ring alter antimicrobial activity, resistance to β-lactamases, and/or pharmacokinetics.3,4,6,9 Cephalosporins are often categorized by 4 class generations (first thru fourth generation). In general, lower-generation cephalosporins have more gram-positive activity and higher-generation cephalosporins have more gram-negative activity.3–9 The fourth-generation cephalosporin, cefepime, is the exception. It possesses gram-positive activity equivalent to first generation and gram-negative activity equivalent to third-generation cephalosporins.4 However, individual cephalosporins in the higher generations have differentiating properties allowing for different indications (ie, activity against Pseudomonas or anaerobes).3–9 In efforts to enhance the spectrum of activity and attempt to confront the emergence of cephalosporin resistance, successive generations of cephalosporins have been developed.10
Ceftaroline is a new broad-spectrum cephalosporin approved in the United States for the treatment of acute bacterial skin and skin structure infection (ABSSSI) and community-acquired bacterial pneumonia (CABP). Ceftaroline has been designated by the Clinical and Laboratory Standards Institute as a member of a new subclass of cephalosporins with activity against methicillin-resistant Staphylococcus aureus (MRSA).5 Regardless, ceftaroline has been more commonly described in many published reviews as an advanced or fifth-generation cephalosporin.5,11–14 This classification would suggest a broader gram-negative coverage; however, ceftaroline’s spectrum of activity is unique with more extensive gram-positive coverage than other available cephalosporins.5
Cephalosporins are considered by many institutions as the “workhorse” antibiotics and are widely used in the therapy of urinary, respiratory, and intra-abdominal infections.15 Consequently, this usage exerts a great selection pressure for resistance. Furthermore, with multiple agents available with varying spectrums of activity, especially among different generations, the need to select the most appropriate cephalosporin is crucial. Therefore, the purposes of this article are the following: (1) to provide a brief overview of the available intravenous cephalosporins, (2) to highlight the recent Food and Drug Administration (FDA) approval of ceftaroline and provide a brief overview of its properties (more extensive reviews of ceftaroline’s properties have been published elsewhere),4–9,13,14,16–19 and most importantly, (3) to provide recommendations for the place in therapy for ceftaroline compared to the available intravenous cephalosporins.
FDA-APPROVED INTRAVENOUS CEPHALOSPORINS
There are currently 9 FDA-approved intravenous cephalosporins available to the US market. Their pharmacokinetics are summarized in Table 1 and spectrum of activity are summarized in Table 2. Cefazolin is the only available intravenous first (oldest)-generation product available. The second-generation agents can be divided into 2 subgroups, those with activity against Haemophilus influenza (cefuroxime), and the cephamycins (cefoxitin and cefotetan), with activity against anaerobic bacteria. Third-generation cephalosporins can be described as those with activity against Pseudomonas aeruginosa (ceftazidime, and cefoperazone [withdrawn from US market]) as those without (cefotaxime and ceftriaxone).30 There are currently one FDA-approved fourth-generation (cefepime) and advanced-generation (ceftaroline) agents. Ceftobiprole, also commonly referred to as a fifth- or advanced-generation cephalosporin,31,32 was not approved by the FDA and was recently withdrawn from Switzerland and Canada markets.
COMPARATIVE PLACE IN THERAPY OF THE INTRAVENOUS CEPHALOSPORINS
The intravenous first-generation cephalosporin (cefazolin) has great activity in vitro against gram-positive organisms and is superior to that of second- or third-generation cephalosporins in this regard. However, like all other cephalosporins, its gram-positive activity lacks clinical use against enterococci (except ceftaroline), methicillin-resistant staphylococci (except ceftaroline), and Listeria. Cefazolin, similar to ceftazidime, also lacks clinical use against penicillin-resistant pneumococci.20,33–36 Furthermore, the activity of cefazolin against gram-negative bacteria is inferior to that of second- and, especially, third-generation cephalosporins.3–9
Cefazolin may be used in the treatment of various infections (eg, bacterial septicemia, respiratory tract infections, urinary tract infections, ABSSSI, infective endocarditis, and bone and joint infections), although not frequently.21,37–39 However, similar to second-generation cephalosporins, with the exception of cefuroxime, cefazolin has poor penetration into the cerebral spinal fluid (CSF) even in those with inflamed meninges.40 Therefore, cefazolin should not be used to treat infections of the central nervous system.
Cefazolin is used primarily for surgical prophylaxis. It is considered the drug of choice in the Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery for most types of procedures.41 However, cefazolin lacks activity against anaerobes and, therefore, should not be used as monotherapy in the prophylaxis of appendectomies for uncomplicated appendicitis, obstructed small intestine procedures, colorectal procedures, and clean-contaminated procedures of the head and neck (except tonsillectomy and functional endoscopic sinus procedures).41
Second-generation cephalosporins, in general, are considered to have a broader spectrum of activity compared with cefazolin. For instance, the cephamycins, cefoxitin and cefotetan, have activity against many strains of Bacteroides. Conversely, these agents have less activity against gram-positive cocci than cefazolin. However, cefuroxime is more effective in vitro than cefazolin against some strains of methicillin-sensitive staphylococci.42
Similar to cefazolin, second-generation cephalosporins are used for surgical prophylaxis. In particular, cefuroxime has been studied extensively for the use in cardiac procedures.41,43–57 A meta-analysis performed on antibiotic prophylaxis for cardiothoracic surgeries indicated that cefuroxime and cefamandole (removed from US market) were more effective than cefazolin.57 Approximately 1½-fold reduction in wound infection rate after cardiothoracic surgery was seen with the use of cefuroxime or cefamandole compared to cefazolin.57 However, other studies find no difference in wound infection rates after surgery when comparing these 2 agents.47,52,58 The Clinical Practice Guidelines for Antimicrobial Prophylaxis in Surgery concluded that superiority of one class over another has not been proven.41 Therefore, several institutions use cefazolin before cardiac surgery, with cefuroxime considered an alternative option.41,54,55
Cephamycins have also been studied for antibiotic prophylaxis in surgery.39,59 These agents have a unique role among the cephalosporins for mixed aerobic-anaerobic infections where Bacteroides may be present. For example, cephamycins have a role in appendectomies for uncomplicated appendicitis, obstructed small intestine procedures, colorectal procedures, and clean-contaminated procedures of the head and neck (except tonsillectomy and functional endoscopic sinus procedures).41 For these indications, cefotetan offers an advantage over cefoxitin by having a relatively longer half-life (2.8–4.6 hours vs. 0.7–1.1 hours, respectively). This provides cefotetan a 6-hour redosing interval compared to 2 hours with cefoxitin, thus making cefotetan a more cost-effective option over cefoxitin.22,23 However, outside of the previously mentioned indications, many studies do not show second-generation cephalosporins to have an obvious advantage over the first-generation cephalosporins. Therefore, these agents should not be routinely used for other indications.60–62
The third-generation cephalosporins have broad-spectrum gram-negative coverage with activity against gram-negative bacilli (including β-lactamases). Furthermore, these agents are very active against Enterobacteriaceae, Neisseria, and Haemophilus influenzae.24–26,30,63 However, the third-generation cephalosporins are generally less active against most gram-positive organisms than the first generation. Cefotaxime and ceftizoxime (withdrawn from US market) have the best gram-positive coverage of the third-generation agents, whereas, ceftazidime and cefoperazone (withdrawn from US market) have antipseudomonal coverage.25,30,63
Third-generation cephalosporins are considered the drugs of choice for the treatment of gram-negative bacillary meningitis in adults and pediatrics given their excellent central nervous system penetration.63,64 These agents are also indicated in serious infections caused by Enterobacteriaceae, thereby avoiding the use of aminoglycosides.65 However, like all cephalosporins, these agents have no use against extended-spectrum β-lactamase–producing Enterobacteriaceae.24–26,65 Third-generation cephalosporins are also not indicated for surgical prophylaxis as they offer no benefit over first-generation cephalosporins.65
Among the third-generation cephalosporins, ceftriaxone has a similar spectrum of activity to that of its counterparts (especially cefotaxime).24–26,65 Ceftriaxone is considered a first-line treatment for complicated and uncomplicated gonococcal infections.66 It has been used as a single dose for the treatment of uncomplicated gonorrhea and in multiple doses for more serious infections such as septicemia and meningitis.24,66 However, studies evaluating the clinical efficacy of the drug have not revealed significant advantages of ceftriaxone over other antimicrobials for any infection.67 Pharmacokinetic properties of ceftriaxone may offer advantages over other cephalosporins within the class. Ceftriaxone has a longer half-life (5.8–8.7 hours) than any other cephalosporin derivative, enabling once-daily dosing in many situations.24 Furthermore, given that ceftriaxone is eliminated equally hepatically and renally, dosage adjustments are only required in those with renal and hepatic impairment.24 Consequently, ceftriaxone is easy to dose in patients receiving continuous renal replacement therapy (CRRT), peritoneal dialysis (PD), and hemodialysis therapy.
Cefotaxime, given its very similar spectrum of activity to that of ceftriaxone,24–26,65 is infrequently used except in neonates. In this patient population, cefotaxime is used as an alternative to ceftriaxone because calcium-containing products can precipitate with ceftriaxone in the lungs and kidneys in infants 28 days old or younger.68 Therefore, ceftriaxone if often avoided in the Neonatal Intensive Care Unit and sometimes the Pediatric Intensive Care Unit, where kids are often on total parenteral nutrition (TPN) and/or other calcium-containing products. Ceftriaxone is also often avoided in neonates owing to the risk of biliary stasis.24 However, in patients 28 days or older, ceftriaxone and calcium-containing products may be used concomitantly if the infusion lines are thoroughly flushed between infusions.68
Ceftazidime has less gram-positive activity compared to other third-generation cephalosporins (specifically Streptococcus pneumoniae, viridans streptococci, and S aureus (methicillin-susceptible S aureus]).69 However, ceftazidime is unique among the third-generation cephalosporins by having extremely potent activity against Pseudomonas and Serratia, and will have a place in the treatment of multiresistant strains of these organisms.69 In the empiric treatment of febrile neutropenic patients, ceftazidime is preferred over other third-generation cephalosporins because of its superior activity against Paeruginosa.70 However, ceftazidime use had been found to be a risk factor for the development of serious viridans streptococci bacteremia during neutropenia,71 which may result in shock and respiratory distress syndrome.72,73 Consequently, institutions have found that ceftazidime is not a reliable agent for empirical monotherapy of neutropenic fever owing to its decreasing potency against gram-negative organisms and its poor activity against many gram-positive pathogens.74–77
Cefepime, the only available fourth-generation cephalosporin, has an overall spectrum of activity similar to that of other third-generation agents. However, it has a degree of antipseudomonal activity similar to ceftazidime and has good β-lactamase stability and improved gram-positive activity over existing cephalosporins.3,27,78 Cefepime is a broad-spectrum cephalosporin that most closely resembles ceftazidime in its spectrum of activity, with possibly increased activity against many Enterobacter species and gram-positive organisms.78 However, cefepime, like other cephalosporins, is not useful against MRSA (except ceftaroline) or enterococcal species (except ceftaroline) and has poor activity against anaerobic organisms.27
Cefepime is used primarily for its role in neutropenic fever3 and is considered a first-line option with an A1 designation for high-risk patients in this population.79 Furthermore, according to the 2010 Clinical Practice Guidelines for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer, cefepime remains an acceptable monotherapy regimen for empirical coverage of febrile neutropenia, despite a recent controversy that stemmed from a meta-analysis by Yahav et al.80 This meta-analysis of randomized control trials involving neutropenic patients found an increased 30-day mortality (risk ratio [RR], 1.41; 95% confidence interval [CI], 1.08–1.84) associated with the use of cefepime, compared with other β-lactams.80 However, this association was not found in previously published neutropenic fever randomized control trials.81 Furthermore, a meta-analysis performed by the FDA found no statistically significant increase in 30-day mortality associated with cefepime use (RR, 1.20; 95% CI, 0.82–1.76).82 The meta-analysis performed by the FDA included and expanded data set of studies that included studies not included in the previous meta-analysis.79 Therefore, the current neutropenic fever guidelines still recommend cefepime as a monotherapy option for high-risk patients.
Cefepime may also have role in treating AmpC β-lactamase producers. AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of Enterobacteriaceae and a few other organisms.83 These bacteria are sometimes collectively referred to as SPACE (ie, Serratia, Pseudomonas, Acinetobacter, Citrobacter, and Enterobacter) organisms. AmpC enzymes are inducible and can be expressedat high levels by mutation. Beta-lactams differ in their ability toinduce this enzyme.83–86 Cefazolin and cefoxitin are strong inducers; whereas cefuroxime, ceftriaxone, cefotaxime, ceftazidime, and ceftaroline are weak inducers.83,87 Beta-lactams, especially cephalosporins, can be hydrolyzed if enough enzyme is made. Overexpression of the enzyme confers resistance to cephalosporins except cefepime. Cefepime is a poor inducer of AmpC β-lactamases and is little hydrolyzed by the enzyme; therefore, many AmpC-producing organisms test cefepime-susceptible.83
Fifth (Advanced)-Generation Cephalosporin
Similar to other cephalosporins, ceftaroline exhibits time-dependent killing.8,9 In vitro and in vivo models show time above the minimum inhibitory concentration (MIC) is the primary pharmacodynamic parameter predicting activity. Ceftaroline exerts its bactericidal effect by binding to penicillin-binding proteins (PBP) preventing the synthesis of peptidoglycan, a major component of the bacterial cell wall.88 Its high affinity for penicillin-binding protein 2a (mecA), which is associated with methicillin resistance, makes ceftaroline unique among the cephalosporins.89
Ceftaroline has potent in vitro activity against gram-positive organisms (including some multidrug-resistant pathogens) and common gram-negative organisms.11,90–92 Ceftaroline has antimicrobial activity against multidrug-resistant S aureus (including MRSA, vancomycin-intermediate S aureus [VISA], heteroresistant VISA (hVISA), and vancomycin-resistant S aureus [VRSA]), S pneumoniae (including penicillin- and macrolide-resistant strains), and “typical” respiratory gram-negative pathogens such as Moraxella catarrhalis and H influenzae (including β-lactamase–positive strains).90,91 Furthermore, ceftaroline compared to ceftriaxone against penicillin-, cephalosporin-, and levofloxacin-resistant S pneumoniae showed a MIC90 value at least 2 double dilutions less than ceftriaxone.28 Ceftaroline has similar in vitro activity against Enterococcus faecalis to that of imipenem.90 However, like all cephalosporins, ceftaroline lacks activity against Enterococcus faecium and extended-spectrum β-lactamase–producing Enterobacteriaceae.90,91 Ceftaroline is also a weak inducer of AmpC β-lactamases.87 Consequently, similar to other cephalosporins (with the exception of cefepime), expression of AmpC β-lactamases greatly limits activity.83,87 Relative to the third- and fourth-generation cephalosporins, ceftazidime, and cefepime (respectively), ceftaroline also lacks in vitro activity against P aeruginosa.90,91
Ceftaroline has several attractive pharmacokinetic/pharmacodynamic properties. It has a longer half-life, which allows for twice-daily dosing, versus other cephalosporins, which must be dosed more frequently (cefazolin, cefoxitin, cefuroxime, cefotaxime, and ceftazidime).93 Like other cephalosporins, no clinically relevant drug interactions have been identified,93 and adverse effects are usually mild with gastrointestinal effects being the most common. However, neurotoxicity thus far has not been reported with the use of ceftaroline unlike other cephalosporins.94–99
Resistance to ceftaroline is expected to be minimal.100 This was demonstrated through a multistep resistance selection study, which showed that MICs remained low and did not yield clones with increased MICs after serial passages observed with H influenzae, M catarrhalis, MRSA, methicillin-susceptible S aureus, Enterobacter faecalis, S pneumoniae, and Streptococcus pyogenes. The only exception was vancomycin-resistant Enterococcus faecalis (VRE), which slowly developed resistance; and Enterococcus faecalis, which demonstrated spontaneous resistance development.100 Furthermore, adverse effects from ceftaroline described in clinical trials are similar to that of comparator drugs and other cephalosporins.101–104
When comparing ceftaroline to cefazolin, ceftaroline would not be considered an alternative to the first-generation cephalosporin. Ceftaroline is not approved for surgical prophylaxis, and there is no clear benefit of using ceftaroline in patients who could be treated with cefazolin. Compared to the second-generation cephalosporins, ceftaroline, similarly offers no therapeutic advantage over infections that could be treated with the second-generation agents. This would also be true when comparing ceftaroline to the third and forth generation cephalosporins. Ceftaroline would not be appropriate for empirically treating neutropenic fever given its poor antipseudomonal activity, and its role in meningitis and gonococcal infections is unknown. Therefore, ceftaroline’s greatest benefit rests in its ability to treat infections that cephalosporins traditionally could not treat, namely, infections due to MRSA.
TREATMENT OF MRSA
Ceftaroline has a role for treating infections associated with MRSA organisms.4–7,9–11,16,19,90,105–116 However, several other parenteral options exist for treating such infections (ie, clindamycin, linezolid, vancomycin, daptomycin, telavancin, quinupristin-dalfopristin, and sulfamethoxazole-trimethoprime); therefore, ceftaroline’s place in therapy among antimicrobials with activity against MRSA is unknown. Ceftaroline does haveattractive activity (in vitro and in vivo) against MRSA andhas favorable pharmacokinetic/pharmacodynamic properties compared to other agents with activity against these organisms.4–7,9–11,16,19,90,105,108,112–115
Vancomycin is typically considered the mainstay of parenteral therapy for infections due to MRSA.117 However, concerns over the use of vancomycin have recently developed with the emergence of resistant strains (eg, hVISA, VISA, and VRSA) that are associated with vancomycin treatment failures and poor outcomes.118,119 Furthermore, among susceptible strains, the “MIC creep” instigates higher vancomycin doses to obtain an AUC/MIC of 400 or greater.117–119 Consequently, higher doses and troughs have been associated with increases inadverse effects, namely, nephrotoxicity.120–122 Furthermore, elevated vancomycin MICs and previous exposure to vancomycin has been associated with increases in daptomycin MICs.123–125 Daptomycin-nonsusceptible strains of S aureus have also emerged during therapy.125–127 Ceftaroline will likely have a role in treating these resistant strains of MRSA (hVISA, VISA, and VRSA), including stains that are daptomycin-nonsusceptible.106,109,113,114
The pharmacokinetic/pharmacodynamic properties of ceftaroline may support its use compared to other agents that treat MRSA. Unlike clindamycin, linezolid, and tigecycline, cefaroline is bactericidal; therefore, it may be an attractive option even in serious MRSA infections.9,93,107,109–111,116 However, studies are warranted to evaluate ceftaroline’s activity in such infections. Ceftaroline’s long half-life without extensive protein binding is advantageous in the hospital or outpatient-parenteral therapy by allowing for twice-daily dosing.93 Furthermore, ceftaroline has a favorable side effect profile compared to the other MRSA treatment options, especially compared to linezolid and quinupristin-dalfopristin.107 As a final point, unlike vancomycin, ceftaroline does not require therapeutic drug monitoring.
Cephalosporins are very common antimicrobials used by many clinicians. Ceftaroline is a new, advanced/fifth-generation, broad-spectrum cephalosporin approved in the United States for the treatment of ABSSSI and CABP. However, the exact role of ceftaroline in clinical practice is currently unknown. Ceftaroline offers clear advantages over other existing cephalosporins, and its place among these agents is apparent through its spectrum of activity. Unfortunately, its current FDA-approved indications (ie, CABP and ABSSSI) offer little benefit for the antimicrobial given that cheaper and more experienced antimicrobials for these indications exist. Furthermore, several oral options are available for these infections. Ceftaroline may be a more attractive antibiotic in the treatment of infections that require a broad-spectrum intravenous antibiotic empirically, such as endocarditis, bacteremia, meningitis, and osteomyelitis, especially if MRSA is a concern. However, future studies are warranted to evaluate the efficacy of ceftaroline for these indications to define a unique role among other antimicrobials that have MRSA activity.
Based on evaluated studies and clinical practice, we recommend that first-generation cephalosporins be reserved for surgical prophylaxis. The second-generation cephalosporin, cefuroxime, should be considered an alternative to cefazolin for cardiac surgical prophylaxis. Cefoxitin or cefotetan should be used for appendectomies for uncomplicated appendicitis, obstructed small intestine procedures, colorectal procedures, and clean-contaminated procedures of the head and neck (except tonsillectomy and functional endoscopic sinus procedures). The third-generation cephalosporin, ceftriaxone, should be considered for gonococcal infections, meningitis, and empiric therapy in complicated cystitis or acute pyelonephritis where Escherichia coli resistance to fluoroquinolones is greater than 10%. Cefotaxime should be considered as an alternative to ceftriaxone in neonates. Ceftazidine can be considered for empiric treatment of neutropenic fever; however, cefepime is considered the drug of choice for this indication. Ceftaroline should be considered as an alternative for CABP and ABSSSI at this time, especially if MRSA is a concern epidemiologically.
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