Цефтаролина фосамил инструкция по применению цена

Teflaro® (ceftaroline fosamil)

Teflaro (ceftaroline fosamil) (Fig. 2), a fifth-generation cephalosporin prodrug, was approved by the US FDA for use in 2010 (Lexicomp, 2021). It is a broad-spectrum antibiotic with activities against aerobic and anaerobic Gram-positive and Gram-negative pathogens, as well as drug-resistant pathogens (Kaushik et al., 2011). Ceftaroline fosamil is indicated for use in adult and pediatric patients with ABSSSIs or CABP (Laudano, 2011), caused by MSSA and MRSA, S. agalactiae, S. pyogenes, E. coli, K. oxytoca, K. pneumoniae, H. influenzae, or S. pneumonia (Media-Allergan, 2020).

The zwitterionic structure of the active form ceftaroline results in poor water solubility, thus preventing its administration via the parenteral route. The prodrug, ceftaroline fosamil, contains a solubilizing phosphonoamino group on the 1,2,4-thiadiazole ring and this structural addition increases the aqueous solubility (Kaushik et al., 2011). This phosphonate group is rapidly hydrolyzed in vivo to produce the active compound, ceftaroline (Duplessis and Crum-Cianflone, 2011). Ceftaroline inhibits PBPs and exerts its bactericidal effects by disrupting bacterial cell wall synthesis (Stein and Johnson, 2011). Ceftaroline inhibits PBP1-4 and has high affinities for PBP2x in S. pneumonia, as well as PBP2a in MRSA, which differentiates it from other cephalosporin antibiotics (Stein and Johnson, 2011; Saravolatz et al., 2011). Ceftaroline contains a characteristic bicyclic cephem ring system with a 3-substituted methylpyridinium-thiazolylsulfanyl motif, as well as a 7-acylated side chain containing the Z-ethoxyimino moiety. These structural features contribute to the compound’s activity against MRSA, with the oxime group improving β-lactamase resistance. The 1,2,4-thiadiazole ring at position 7 aids in increasing the affinity for transpeptidases and disrupting cell wall synthesis in Gram-negative pathogens (Kaushik et al., 2011).

Ceftaroline fosamil is available as 400 and 600 mg powder in single-use vials, which requires reconstitution and dilution before the IV use (Media-Allergan, 2020). In adult patients (CrCl > 50 mL/min), ceftaroline fosamil 600 mg should be given every 12 h via IV over 1 h. For those with impaired renal function (CrCl ≤ 50 mL/min), a dosage adjustment is required (Laudano, 2011; Media-Allergan, 2020). The dosing of pediatric patients with ABSSSI or CABP is based on ranges of weight and age. The adverse effects occurring in more than 2% of patients on ceftaroline fosamil are rash, diarrhea, and nausea (Media-Allergan, 2020). Ceftaroline fosamil has a broader antibacterial spectrum than older cephalosporin agents and serves as a useful alternative for treating patients with ABSSSIs and CABP (Saravolatz et al., 2011).

Drug Class:

Fifth-generation cephalosporin; antibiotic

Use of Vancomycin or Other Gram-Positive Agents

Vancomycin or other agents with potent activity against drug-resistant gram-positive pathogens are not recommended for routine inclusion in the initial empiric regimen. Although a predominance of gram-positive pathogens is isolated in blood cultures from febrile neutropenic patients, these organisms rarely cause life-threatening infections.⁵⁹ In 1992 a large prospective, randomized trial from the European Organisation for Research and Treatment of Cancer failed to show a clinical advantage in adults with fever and neutropenia of use of a regimen containing vancomycin compared with one that did not.⁶⁰ Since then, vancomycin or similar gram-positive active drugs have not been included in the empiric regimen, except in limited circumstances, as shown in Table 34.3. Other agents with activity against gram-positive pathogens include daptomycin, ceftaroline fosamil, and linezolid. Both linezolid and daptomycin are often effective against infections with VRE.⁶¹ Daptomycin has excellent activity in cases of S. aureus bloodstream infections, with some evidence suggesting superior outcomes compared with vancomycin.⁶² Ceftaroline fosamil also appears to show comparable activity in this setting.⁶³ Caution is advised when prescribing these agents because each has significant adverse effects. Myelotoxicity has been associated with prolonged linezolid use (longer than 14 days), primarily in the form of thrombocytopenia and occasionally neutropenia. In the setting of HSCT or induction for acute myeloid leukemia, studies of hematologic parameters have revealed no delay in the times to neutrophil or platelet engraftment between control patients and those receiving linezolid.^64,65

Documented serious infections that are typically caused by gram-positive pathogens, such as cellulitis or obvious catheter-related infections, should be treated with vancomycin or another gram-positive active agent. Many catheter-related bloodstream infections are caused by coagulase-negative staphylococcal isolates with high-level β-lactam antibiotic resistance, and thus vancomycin is indicated. If vancomycin is started empirically because of concerns about drug-resistant gram-positive infections but cultures and examination do not identify infections with such organisms within 2 or 3 days, then empiric vancomycin therapy should be discontinued. Furthermore, in stable patients who remain persistently febrile and neutropenic after several days of empiric broad-spectrum antibiotics, the addition of vancomycin provides no benefit, and in fact yields greater renal toxicity.⁶⁶

In patients colonized with MRSA, a prospective study of 1770 pretransplant patients screened for MRSA colonization demonstrated that the risk of subsequent invasive disease in colonized patients (n = 20) was vanishingly low when they become febrile and neutropenic.⁶⁷ Therefore the addition of empiric coverage for MRSA in colonized patients is unlikely to be beneficial.

VGS bacteremia is uniquely associated with a syndrome of septic shock and acute respiratory distress syndrome (ARDS) in a small proportion of neutropenic patients.⁶⁸ High-dose cytarabine or other intensive therapy that damages oropharyngeal mucosal barriers and allows translocation of VGS from its normal oral habitat is associated with an increased risk of overwhelming VGS sepsis. Prophylaxis with notoriously poor antistreptococcal agents, including ciprofloxacin or trimethoprim-sulfamethoxazole (TMP-SMX), may also predispose to VGS bacteremia and sepsis.^69–72 Viridans streptococcal breakthrough infections may rarely occur during levofloxacin prophylaxis.^69,72

Approximately 18% to 29% of VGS bloodstream isolates from cancer patients are β-lactam resistant.^68,73,74 Accordingly, vancomycin should be included in the initial empiric antibiotic regimen for hypotensive febrile neutropenic patients, or if VGS is identified from blood cultures, pending susceptibility testing.

S. aureus: MRSA, VISA, VRSA

S. aureus causes a wide range of infections, most commonly those involving simple skin and soft tissue, known as SSTIs (e.g., cellulitus, impetigo and furuncles). It can also cause a range of invasive infections, including osteomyelitis, septic arthritis, peritonitis, pneumonia and endocarditis.²⁴ In the pre-antibiotic era, the majority of S. aureusbacteraemia cases resulted in death,⁴ and mortality remains in the range of 20 to 30% in modern times.^24,25

S. aureus is inherently susceptible to many antimicrobials, such as β-lactams (e.g., penicillins, cephalosporins and carbapenems), glycopeptides (e.g., vancomycin), macrolides (e.g., erythromycin), clindamycin, tetracycline and aminoglycosides (e.g., gentamicin). However, the mainstay of therapy has been β-lactams and, for patients with β-lactam allergy, macrolides. When penicillin was first introduced, it was effective against S. aureus infections, but resistance rapidly emerged. Most clinical isolates are now penicillin-resistant. This is secondary to the production of a β-lactamase, which hydrolyses the β-lactam ring and renders the drug inactive.²

Many of the β-lactams that have been developed since pencillin are stable to the S. aureus β-lactamase. They include the cephalosporins, the carbapenems, β-lactam/ β-lactamase inhibitor combinations and the penicillinase-resistant isoxazoylpenicillins such as flucloxacillin.²⁶ Because of their potency, relatively narrow spectrum of activity and favourable side effect profile,²⁷ the latter drugs are the drugs of choice for treating mild to severe invasive infections caused by S. aureus.

Unfortunately, shortly after the introduction of meticillin in 1960, resistant strains of S. aureus were isolated in vitro²⁸ and subsequently from clinical infections.²⁹ Since meticillin was the first of the isoxazoyl penicillins to enter clinical practice, resistance to it and to related agents has been termed meticillin-resistant S. aureus (MRSA), although β-lactam-resistant S. aureus would be a more informative name. In MRSA an altered penicillin-binding protein, PBP2a, for which most β-lactam antibiotics have poor affinity, is the mechanism of resistance.

PBP2a is encoded by the mecA gene, thought to have been horizontally acquired from another bacterial species, on a genetic element called the staphylococcal cassette chromosome mec (SCCmec).^4,30 Until the recent development of cephalosporins with some MRSA activity, this meant that no available β-lactams were considered effective. In August 2012, the European Medicines Agency approved ceftaroline fosamil; it is the first β-lactam agent with activity against MRSA approved in Europe.³¹

Prevalence rates for healthcare-acquired MRSA (HA-MRSA) vary, from greater than 50% in the United States and parts of South America to less than 1% in some Northern European countries.⁴ The United Kingdom, the same as much of the rest of Europe, has seen a relatively high prevalence, which has fallen in recent years. Results for invasive S. aureus infections submitted to the European Antimicrobial Resistance Surveillance System (EARSS) show that the percentage of meticillin-resistant isolates fell from a high of 47.3% in 2001 to 13.6% in 2011.³²

The success of MRSA in spreading widely around the world is due to the epidemiology of S. aureus colonisation, imprudent use of antimicrobials in hospitals and lapses in basic infection control procedures. About 25 to 35% of normal healthy individuals are colonised with S. aureus, providing a reservoir of infection for the colonised individual and his or her contacts.³³ Sites of colonisation are the nose, the skin (especially if broken or damaged), the throat and the groin.³³

S. aureus is a prominent cause of both community-acquired and healthcare-acquired infections, with MRSA being one of the most frequently identified resistant pathogens in hospitals in many parts of the world.⁴ The organism can survive for significant periods of time in the environment and on the skin and hands of patients, visitors and healthcare workers, so it can readily spread in the hospital environment.³⁴

Conventional cleaning regimens do not always eradicate the organism from the environment.^34,35 The success of some MRSA strains in causing hospital infections is a likely result of selection pressure from the large number of hospitalised patients on antibiotics, which reduces the growth of or kills the competing bacterial flora to a greater extent than the more resistant strains.^36,37

S. aureus can form biofilms on prosthetic devices such as cannulas, long lines, prosthetic joints and prosthetic heart valves. In the biofilm, the organism is protected from both the immune system and antimicrobials,³⁸ making treatment a challenge if it is not straightforward to remove the device.

In the 1990s cases of community-acquired or community-associated MRSA (CA-MRSA) began to emerge in the United States. CA-MRSA cases are not linked to hospitalisation and are more likely to affect younger, previously well patients, especially those from certain groups such as participants in team sports or intravenous drug users.³⁹ The strains responsible are more sensitive to antimicrobials than HA-MRSA, and typing methods show them to be distinct from HA-MRSA strains.^39,40

CA-MRSA has since become endemic in the United States and has been reported in many countries, including the United Kingdom,³⁹ where the prevalence of the CA-MRSA strains has been estimated at less than 1% of all MRSA isolates. However, for various reasons this prevalence is likely to have been significantly underestimated.⁴⁰ The boundaries between HA- and CA-MRSA have become blurred as strains previously associated with community infections have displaced the traditional HA-MRSA strains and as antibiotic resistance to other agents has increased in CA-MRSA strains.^4,39–41

Effective and safe treatments for MRSA infections are quite limited, although the proportion of isolates sensitive to alternative antibiotics varies considerably according to strain (i.e., HA-MRSA or CA-MRSA) geographic area and time. Ideally empiric therapy decisions take into account up-to-date local resistance trends.²⁷ Earlier in Figure 15.1 the 2001–2011 resistance rates for MRSA bacteraemia isolates in the United Kingdom are shown, as published by the British Society of Antimicrobial Chemotherapy.⁴²

For severe infections with MRSA, vancomycin has been the treatment of choice,²⁵ although its efficacy has been questioned. For MSSA bacteraemia, most studies suggest that β-lactams are more effective.^43–45 Several studies have also shown that outcomes with vancomycin are worse, with relatively modest MIC increases against it. This is despite the fact that the MICs are below resistance breakpoints and that vancomycin dosing achieves optimal trough blood levels.^25,43,46 Some studies, mainly from the United States, suggest that there has been a steady ‘creep’ upward in MICs to vancomycin.^47–49 In response, treatment guidelines have advised aiming for higher vancomycin levels to maintain the drug’s effectiveness.⁵⁰

A discussion of vancomycin resistance in S. aureus is complicated by the changing definitions and breakpoints applied. The term vancomycin-intermediate S. aureus (VISA) has been commonly used to refer to an organism with MICs that are just above the breakpoint. A phenotype with lower MICs but with sub-populations able to grow at much higher vancomycin concentrations has been termed heteroresistant-VISA (hVISA).⁴⁸ The mechanism of resistance for these phenotypes is not fully understood, but there is cell wall thickening which is thought to limit penetration of the large vancomycin molecule to the site of action.^48,51 Both hVISA and VISA were first isolated in Japan in 1996 and 1997, respectively,^52,53 and have since been encountered in many countries but remain uncommon.^48,51

In 2002 the first case of high-level vancomycin-resistant S. aureus (VRSA) was identified in the United States, in this instance resulting from the vanA gene cluster previously responsible for vancomycin resistance in some Enterococci.⁵⁴ The effect of vanA is that the affinity of vancomycin for its target is reduced and so it is less effective at blocking the cross-linking which gives the bacterial cell wall its strength.^48,55

Most reports of vanA-mediated resistance have been from the United States, but reports from India and Iran have also been published and an isolate from Portugal has been reported.^{48,51,54,56,57} Many of the cases in these studies have been of questionable clinical significance, and colonisation has often been successfully eradicated with other antimicrobials.⁵⁴

Of the more recently available drugs used to treat severe MRSA infections, both linezolid and daptomycin have been shown to be non-inferior to vancomycin for the management of some infections.^25,58 Clinical trials suggest that linezolid is a good alternative to vancomycin in regimens for SSTIs and pneumonia, but the evidence that outcomes are superior is at present unconvincing.⁵⁸ Daptomycin is licensed for both complicated skin and soft tissue infections; it is also licenced for bloodstream infections, including right-sided endocarditis.

In a controlled comparative study between daptomycin and standard therapy for staphylococcal bacteraemia and endocarditis, daptomycin met non-inferiority criteria but outcomes for left-sided endocarditis were disappointing.^27,25 Resistance has been encountered occasionally for both linezolid and daptomycin. In both cases this occurs through mutational changes, which have been observed to arise during therapy.^58,59 The hVISA/VISA-resistance phenotypes also seem to be correlated with increased resistance to daptomycin.⁶⁰ Other recently developed agents active against MRSA are discussed in the section on newer antimicrobials.

10 Ceftaroline fosamil acetate (Teflaro®)

Ceftaroline fosamil acetate (Teflaro®) is a novel cephalosporin with broad-spectrum activity against gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Streptococcus pneumoniae (MDRSP), and common gram-negative pathogens. Ceftaroline fosamil acetate is a N-phosphono type aqueous prodrug of ceftaroline possessing increased solubility compared to the parent drug. Ceftaroline fosamil acetate was discovered by Takeda Pharmaceutical by making a structural modification of the fourth-generation cephalosporin cefozopran. Developed and launched by Cerexa, Inc. and Forest Laboratories, the FDA approved it for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infection (ABSSSI), including MRSA.^79–82 Structure–activity relationship studies indicated that the 5-membered thiazole ring at 3-position of the cephalosporin nucleus and the ethoxyiminoacetamido group in the C-7 acyl moiety were responsible for the enhanced anti-MRSA activity of ceftaroline.⁷⁹

Acyl halide fragment 114 was prepared from commercially available (Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-ethoxyiminoacetic acid (113) in 60% yield by dichlorophosphorylation of the amino group and concomitant acid chloride formation. Acid chloride 114 was then reacted with dihydrochloride salt 112 in the presence of sodium acetate to give N-phosphono cephem 115 in 77% yield. The crystallization of 115 in an aqueous acetic acid solution gave rise to the stable acetic acid solvate ceftaroline fosamil acetate (IX).

4.1.1 Ceftaroline/avibactam

Ceftaroline fosamil, the prodrug of ceftaroline, is an agent approved by the FDA to treat acute bacterial skin and skin-structure infections and community-acquired bacterial pneumonia caused by susceptible bacteria, including meticillin-susceptible Staphylococcus aureus (MSSA) and meticillin-resistant S. aureus (MRSA) [99]. Because of potent binding to PBP2a in MRSA and other critical PBPs in MSSA and streptococci [100], ceftaroline has retained an MIC₉₀ against MRSA of ≤2 mg/L over the past decade [101,102]. However, it is susceptible to hydrolysis by many β-lactamases in Gram-negative pathogens [103,104]. Thus, a combination of ceftaroline with avibactam might provide an anti-MRSA cephalosporin that could be used to treat mixed infections caused by various β-lactamase-producing Gram-negative organisms. In vitro susceptibility testing of ceftaroline with avibactam has shown significant enhancement of ceftaroline microbiological activity against enteric bacteria, with ceftaroline MICs lowered as much as 4096-fold, with MIC_50/90 values typically 0.06/0.12 mg/L and 0.12/1 mg/L for ESBL-positive and KPC-producing Enterobacteriaceae, respectively [78,88,105]. However, the addition of avibactam did not synergise ceftaroline activity in P. aeruginosa or Acinetobacter spp. where ceftaroline MIC₉₀ values exceed 32 g/L [106]. Ceftaroline fosamil in combination with avibactam has been studied in phase 1 trials for evaluation of the pharmacokinetics and safety of the two components [107,108], determination of mass balance [109], assessment of the impact of supratherapeutic doses on the QT/QTc interval of healthy individuals [110] and evaluation of the effect of the two components on normal human intestinal flora [111]. No unexpected adverse events were observed when avibactam was added to ceftaroline fosamil compared with the cephalosporin alone. A phase 2 trial comparing co-administered ceftaroline fosamil and avibactam to intravenous doripenem in adult subjects with cUTIs was completed in 2014 [73].

Ceftaroline

Ceftaroline fosamil (Teflaro^® in the USA and Zinforo^® in Europe) achieved European Medicines Agency (EMA) approval in 2012. An inactive prodrug, ceftaroline fosamil, is rapidly converted in vivo to the active metabolite ceftaroline.

Ceftaroline has a broad range of activity (Table 1). However, both low-level [3] and high-level [4] resistance to ceftaroline have been observed in MRSA strains; particularly concerning are recent reports of resistance discovered in clinical MRSA isolates from patients in geographic regions never exposed to the drug [5,6]. Little is known of ceftaroline’s ecological impact, though it is expected to be minor, as the drug is not excreted in the faeces [7].

Two multicentre international phase III non-inferiority randomized controlled trials (RCT) for community-acquired pneumonia (CAP) were conducted [8,9] in which ceftaroline achieved non-inferiority to ceftriaxone (see Supplementary material, Table S2). Both studies excluded patients admitted to the intensive care unit (ICU) and those with co-morbidities; there were no more than ten multidrug S. pneumoniae isolates and one MRSA isolate in any of these trials. Three phase III non-inferiority RCT for complicated skin and soft-tissue infections (cSSTI) showed ceftaroline to be non-inferior to vancomycin plus aztreonam (see Supplementary material, Table S2) [10–12]. One of the studies had broader inclusion criteria and tested a higher dose of the drug [12]. In these trials, MRSA represented between 30% and 40% of positive cultures. Although retrospective data from the industry-sponsored CAPTURE registry suggest that ceftaroline may have a role in hospital-acquired pneumonia (HAP) [13] and diabetic foot infections [14], patients with these infections were excluded from the trials.

Ceftaroline appeared, in those trials, to be well tolerated (see Supplementary material, Table S3), but several post-market reports of severe myelotoxicity associated with prolonged exposure (>7 days) to ceftaroline have emerged [15,16].

Abstract

Ceftaroline fosamil is a fifth-generation cephalosporin with anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. It has been approved by the EMA and FDA for the treatment of adults and children with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI). However, ceftaroline fosamil has a broad spectrum of activity, and a good safety and tolerability profile, so is frequently used off-label.

The aim of this systematic review was to summarize the safety and efficacy of off-label use of ceftaroline.

The review was conducted according to PRISMA guidelines. MEDLINE, EMBASE and CENTRAL databases (2010-2018) were searched using as the main term ceftaroline fosamil and its synonyms in combination with names of infectious diseases of interest.

A total of 21 studies with 1901 patients were included: the most common off-label indications for ceftaroline use were bacteremia (n=595), endocarditis (n=171), osteoarticular infections (n=368), hospital-acquired pneumonia (n=115) and meningitis (n=23). The most common reasons for off-label use were persistent or recurrent infection after standard treatment or non-susceptibility to vancomycin and daptomycin.

Clinical success was evaluated in 933 patients, and 724 (77%) of these reached this positive outcome. Incidence of adverse events (AEs) was reported in 11 studies. In 83 (9%) cases there were AEs related to the use of ceftaroline; the most common reported AEs were nausea, vomiting, diarrhea, rash and neutropenia.

The review results show that ceftaroline may be used in clinical settings other than those currently approved; however, the use of ceftaroline in these contexts deserves further investigation.

Dosage and Administration

Ceftaroline fosamil is available in powder formulation as a 400-mg single-dose vial and a 600-mg single-dose vial. The recommended dosage for patients 18 years of age and older is 600 mg administered intravenously over 60 minutes every 12 hours. For treatment of cSSSI, the recommended duration of therapy is 5−14 days, and for treatment of CAP, the recommended duration is 5−7 days.²³ Dosage adjustment is necessary in patients with renal impairment (CrCl ≤50 mL/min).^23,49,50 In patients with a CrCl between >30 mL/min and 50 mL/min, the recommended dosage regimen is 400 mg IV over 60 minutes every 12 hours.²³ For patients with a CrCl between 15 mL/min and 30 mL/min, the recommended dosage regimen is 300 mg IV over 60 minutes every 12 hours.²³ For patients with end-stage renal disease, including those receiving hemodialysis, the recommended dose of ceftaroline fosamil is 200 mg IV over 60 minutes every 12 hours, and if applicable, administered after hemodialysis on hemodialysis days.²³ The pharmacokinetic properties of ceftaroline in patients with hepatic impairment has not been studied; however, an in vitro study has shown ceftaroline to be stable in the presence of liver microsomes and unlikely to be significantly affected in this population.^23,48 Although clinical studies in the pediatric population are underway, ceftaroline is currently not indicated for use in pediatric patients.^23,52 The pharmacokinetic properties of ceftaroline in pregnant females has not been studied in humans and is currently labeled pregnancy category B and, therefore, it should only be used in this population if the benefits outweigh the potential risk.²³ Ceftaroline should also be cautioned in nursing women as it is not known whether the drug is excreted in breast milk.²³ No dose adjustment is warranted on the basis of age, sex, or race; however, dosage adjustments should be made for elderly patients with a decline in renal function (CrCl ≤50 mL/min).^23,47,52,53

8.3 Metabolism and excretion

Ceftaroline fosamil is the prodrug that is rapidly converted during intravenous (i.v.) infusion by in vivo phosphatases to its bioactive metabolite, which further undergoes hydrolysis to form the inactive open ring metabolite, ceftaroline-M-1. The primary route of excretion of ceftaroline is renal, with some faecal excretion. The renal clearance rate was 95.6 mL/min (single dose) and 86.7 mL/min (multiple dose), whilst urinary excretion of the prodrug was not reported. The half-lives of bioactive metabolite (ceftaroline) and the inactive form (ceftaroline-M-1) are 2.6 h (range 2.3–2.9 h) and 4.51 h, respectively, in healthy volunteers [7,45].

Haemodialysis in patients with end-stage renal disease (ESRD) can alter the pharmacokinetics of ceftaroline, due to which the C_max, AUC and half-life of ceftaroline-M-1 increases significantly, whilst renal clearance decreases drastically in patients with moderate renal impairment [46]. Therefore, dosage adjustment of ceftaroline is thus necessary in patients with moderate but not in mild renal impairment.