Академический Документы
Профессиональный Документы
Культура Документы
CONTENTS
1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Introduction ............................................................................... Description ................................................................................ Clinical pharmacology ............................................................. Microbiology .............................................................................. Antimicrobial spectrum ............................................................ Pharmacokinetics ..................................................................... Tissue Penetration .................................................................... Indications ................................................................................. Dosage and administration ...................................................... Side Effects, Drug Interactions, Warnings, Precautions, Overdose, Contraindications .............................
1 2 2 4 5 5 6 6 7
9 12 15
Preamble :
The antibiotics known as cephalosporins were first discovered and isolated in 1948 from Cephalosporium acremonium, in sewage remnants off of the Sardinian coast . They are members of the class of antibiotics known as -lactams. Cephalosporins are a type of antibiotic in the same class as penicillins (-lactams), but have a broader spectrum than penicillins, meaning they can be used to treat more types of bacteria.
Evolution of Cephalosporins
Cephalosporin C, was the first cephalosporin to be isolated. The drug showed very low antibacterial activity due to low potency. However, it was resistant to -lactamases and consequently, appeared to be effective against penicillin-resistant cultures [2]. As scientists continued to investigate these drugs, they realized that enzymatic and chemical techniques could be used to take Cephalosporin C and create the 7-amino-cephalosporanic acid (7ACA) core that is possessed by all cephalosporins. Consequently, this led to the creation of multiple classes of cephalosporins that differed in spectrum, potency, -lactamase stability, and pharmacokinetic properties [2]. Of these classes, the third generation cephalosporins have played a significant role in treating bacterial infections that are not responsive to penicillins or the first and second generations of cephalosporins. These agents have exceptional activity against Gram-negative bacteria and Pseudomonas infections and also can be useful in the treatment of multiresistant hospital infections. A few agents, like ceftriaxone, are able to pass through the blood brain barrier into the cerebrospinal fluid. Consequently, they are of use with some cases of bacterial meningitis. None of the first and second generation cephalosporins are able to pass through the blood brain barrier in levels that will produce a therapeutic effect. The third generation agents are almost completely resistant to -lactamases, with the exception of a few Gram-negative species of the enzymes. The two main downfalls of this group of cephalosporins are their low antistaphylococci activity and high expense. However, overall they are excellent agents that have made a considerable impact on the treatment of bacterial infections and have demonstrated the importance of continuing research that will allow for the production of newer and even more effective agents [1,7].
Classification
Cephalosporins are classified by 4 different generations, based partly on chronology of discovery, but more so on their broadness of use. The first generation drugs are mostly active against gram positive bacteria (Staphylococcus, Streptococcus, etc.). A common example of a first generation cephalosporin is cephalexin. The second generation drugs are more useful against gram negative bacteria (Enterobacter, E.Coli, etc.). A common example of a second generation cephalosporin is cefuroxime axetil. The third generation drugs are less active against the gram positive bacteria, but are more active against gram negative than either the first or second generation.
Introduction
DESCRIPTION Cefprozil
Cefprozil is a semi-synthetic broad-spectrum cephalosporin antibiotic. Cefprozil is a cis and trans isomeric mixture (> 90% cis). The chemical name for the monohydrate is (6R,7R)-7-((R)-2-amino-2-(p-hydroxy-phenyl)acetamido) -8-oxo-3-propenyl-5-thia-1-azabicyclo (4.2.0)oct-2-ene-2-carboxylic acid monohydrate, and the structural formula is:
CLINICAL PHARMACOLOGY
Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours,
while the steady state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 ml/min/kg and 2.3 ml/min/kg, respectively.
Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 mcg/ml, respectively, and were obtained within 1.5 hours after dosing. Urinary
recovery accounted for approximately 60% of the administered dose. Dosage (mg) Mean Plasma Cefprozil Concentrations (mcg/ml) Peak appx. 1.5 hr 250 mg 500 mg 1000 mg 6.1 10.5 18.3 4 hr 1.7 3.2 8.4 8 hr 0.2 0.4 1.0
During the first 4-hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 mg/ml, 1000 mcg/ml, and 2900 mcg/ml, respectively.
Administration of cefprozil tablet or suspension formulation with food did not affect the extent of absorption (AUC) or the peak plasma concentration (Cmax) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (Tmax). The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.
Bactericidal Activity
MIC = MBC Against the majority of organism examined, cefprozil was bactericidal at a concentration similar to the MIC. The minimum bactericidal concentration (MBC) for cefprozil was identical to the MIC in 89% of isolates which included S. pneumoniae. S. pyogenes, S. aureus, H. influenzae and in none of the isolates was the MBC/MIC ratio greater than 2. [17]
Microbiology
Cefprozil has in vitro activity against a broad range of gram-positive and gramnegative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis.
Cefprozil has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections.
Aerobic Gram-positive Microorganisms Staphylococcus aureus (including -lactamase-producing strains) Streptococcus pneumoniae Streptococcus pyogenes Aerobic Gram-negative Microorganisms Haemophilus influenzae (including -lactamase-producing strains) Moraxella (Brannamella) catarnalis (including -lactamase-producing strains) Aerobic Gram-positive Microorganisms Enterococcus durans Enterococcus faecalis Listeria monocytogenes Staphylococcus epidermidis Staphylococcus saprophyticus Staphylococcus warneri Streptococcus agaiactiae Streptococci (Groups C.D.F. and G) Viridans group Streptococci Aerobic Gram-negative Microorganisms Citrobacter diversus Escherichia coli Kiebsiella pneumoniae Neisseria gonorrhoeae (including -lactamase-producing strains) Proteus mirabilis
Anaerobic Microorganisms Prevotella (Bacteroides) melaninogenicus Clostridium difficile Clostridium perfringens Fusobacterium spp. Peptostreptococcus spp. Propionibacterium acnes
Antimicrobial spectrum
Cefprozil inhibit cell wall synthesis and is bactericidal in nature. It has demonstrated significant in-vitro activity against most common pathogens in upper and lower respiratory tract infection, Skin and skin structure infection, and uncomplicated Urinary tract infection. According to reports, the MIC break point was <8 mcg/ml for susceptibility, 16 mcg /ml for moderate susceptibility and > 32 mcg /ml for resistance. In studies evaluating the activity of Cefprozil, Cefuroxime axetil, Locarbef and Ceftixime against S.pneumoniae isolates that were susceptible , intermediately resistant, and resistant to pencilline.Only Cefprozil and Cefuroxime axetil had MIC50 value in the susceptible range against intermediate penicillin resistant strains. Cefprozil is relatively stable to other E.coli derived beta lactamase as well,with all MICs remaining in the susceptible range.[8] Antibacterial activity of cefprozil were compared with those of beta oral cephems and three Macrolides (including Cefprozil,Cefixime,Cefuroxime axetil,Cefodoxime proxetil,Cefetamet, Loracarbef, Cefaclor, Cefdinir, Cefadroxil, Cephradine, Cephalexin) of the oral Cephems. Only Cefprozil and Cefdinir had MICs (<1 mcg /ml) at which 90% of the isolates of Methicillin susceptible S.aureus were inhibited[9].
Pharmacokinetics
Following oral administration Cefprozil is well absorbed (Bioavailability 90%)[10,11] and it is not affected by food.[12].Comparable pharmacokinetic parameter of cefprozil have been observed between pediatric patient and adult[13]
Tissue penetration
Skin and Blister Fluid The skin blister fluid half life estimate for Cefprozil were significantly longer than they were for comparator drugs. The level of cefprozil in skin blisters declined more slowly than plasma level[14]. Cefprozil appears to be as efficacious as amoxicillin/clavulanate or Cefaclor in case of skin and soft tissue infection[15,16] Middle ear fluid Cefprozil achieves up to 8.67mcg/ml concentration in middle ear fluid [18]
INDICATIONS
Cefprozil is indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the conditions listed below:
* In the treatment of infections due to Streptococcus pyogenes, cefprozil should be administered for at least 10 days. Not to exceed recommended adult doses.
Renal Impairment
Cefprozil may be administered to patients with impaired renal function. The following dosage schedule should be used. TABLE 5 Creatinine Clearance (ml/min) 30-120 0-29* Dosage (mg) standard 50% of standard Dosing Interval standard standard
Hepatic Impairment
No dosage adjustment is necessary for patients with impaired hepatic function.
TABLE 4 Population/Infection Infants & Children (6 months-12 years) Upper Respiratory Tract Otitis Media 15 mg/kg q 12h Acute Sinusitis For moderate to severe infections, (the higher dose should be used) 7.5 mg/kg q 12h or 15 mg/kg q 12h 10 10 Dosage (mg) Duration (days)
* In the treatment of infections due to Streptococcus pyogenes, cefprozil should be administered for at least 10 days. Not to exceed recommended adult doses.
* Cefprozil is partly removed by hemodialysis: therefore, cefprozil should be administered after the completion of hemodialysis.
SIDE EFFECTS
The adverse reactions to cefprozil are similar to those observed with other orally administered cephalosporins. Cefprozil was usually well tolerated in controlled clinical trials. Approximately 2% of patients discontinued cefprozil therapy due to adverse events. The most common adverse effects observed in patients treated with cefprozil are:
Gastrointestinal: Diarrhea (2.9%), nausea (3.5%), vomiting (1%) and abdominal pain (1%). Hepatobiliary: Elevations of AST (SGOT) (2%), ALT (SGPT) (2%), alkaline phosphatase (0.2%), and bilirubin values (<0.1%). As with some penicillins and some other cephalosporin antibiotics, cholestatic jaundice has been reported rarely. Hypersensitivity: Rash (0.9%), urticaria (0.1%). Such reactions have been reported more frequently in children than in adults. Signs and symptoms usually occur a few days after initiation of therapy and subside within a few days after cessation of therapy. CNS: Dizziness (1%). Hyperactivity, headache, nervousness, insomnia, confusion, and somnolence have been reported rarely (<1%). All were reversible. Hematopoietic: Decreased leukocyte count (0.2%), eosinophilia (2.3%). Renal: Elevated BUN (0.1%), serum creatinine (0.1%). Other: Diaper rash and superinfection (1.5%), genital pruritus and vaginitis (1.6%). The following adverse events, regardless of established causal relationship to cefprozil have been rarely reported during post-marketing surveillance: anaphylaxis, angioedema, colitis (including pseudomembranous colitis), erythema multiforme, fever, serum-sickness like reactions. Stevens-Johnson Syndrome and thrombocytopenia.
DRUG INTERACTIONS
Nephrotoxicity has been reported following concomitant administration of aminoglycoside antibiotics and cephalosporin antibiotics. Concomitant administration of probenecid doubled the AUC for cefprozil. The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.
WARNINGS
Pseudomembranous colitis has been reported with nearly all antibacterial agents, including cefprozil, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is one primary cause of "antibiotic-associated colitis". After the diagnosis of pseudomembranous colitis has been established, appropriate therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to drug discontinuation alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.
PRECAUTIONS General
Prescribing CEFPROZIL in the absence of proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. In patients with known or suspected renal impairment, careful clinical observation and appropriate laboratory studies should be done prior to and during therapy. The total daily dose of cefprozil should be reduced in these patients because high and/or prolonged plasma antibiotic concentrations can occur in such individuals from usual doses. Cephalosporins, including cephprozil, should be given with caution to patients receiving concurrent treatment with potent diuretics since these agents are suspected of adversely affecting renal function. Prolonged use of cephprozil may result in the overgrowth of nonsusceptible organisms. Careful observation of the patient is essential. If superinfection occurs during therapy, appropriate measures should be taken. Cefprozil should be prescribed with caution in individuals with a history of gastrointestinal disease particularly colitis. Positive direct Coombs' tests have been reported during treatment with cephalosporin antibiotics.
10
Nursing Mothers
Small amounts of cefprozil (<0.3% of dose) have been detected in human milk following administration of a single 1 gram dose to lactating women. The average levels over 24 hours ranged from 0.25 to 3.3 mcg/ml. Caution should be exercised when cefprozil is administered to a nursing woman, since the effect of cefprozil on nursing infants is unknown.
Pediatric Use
The safety and effectiveness of cefprozil in the treatment of otitis media have been established in the age groups 6 months to 12 years. Use of cefprozil for the
treatment of otitis media is supported by evidence from adequate and well-controlled studies of cefprozil in pediatric patients The safety and effectiveness of cefprozil in the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin structure infections have been established in the age groups 2 to 12 years. Use of cefprozil for the treatment of these infections is supported by evidence from adequate and wellcontrolled studies in pediatric patients. The safety and effectiveness of cefprozil in the treatment of acute sinusitis have been established in the age groups 6 months to 12 years. Use of cefprozil in these age groups is supported by evidence from adequate and well controlled studies of cefprozil in adults.
11
Safety and effectiveness in pediatric patients below the age of 6 months have not been established for the treatment of otitis media or acute sinusitis, or below the age of 2 years for the treatment of pharyngitis/tonsillitis or uncomplicated skin and skin structure infections. However, accumulation of other cephalosporin antibiotics in newborn infants (resulting from prolonged drug half-life in this age group) has been reported.
Geriatric Use
Of the more than 4500 adults treated with CEFPROZIL in clinical studies, 14% were 65 years and older, while 5% were 75 years and older. When geriatric patients received the usual recommended adult doses, their clinical efficacy and safety were comparable to clinical efficacy and safety in nongeriatric adult patients. Other reported clinical experience has not identified differences in responses between elderly and younger patients, but greater sensitivity of some older individuals to the effects of CEFPROZIL cannot be excluded. CEFPROZIL is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.
OVERDOSE
Single 5000 mg/kg oral doses of cefprozil caused no mortality or signs of toxicity in adult, weaning or neonatal rats, or adult mice. A single oral dose of 3000 mg/kg caused diarrhea and loss of appetite in cynomolgus monkeys, but no mortality. Cefprozil is eliminated primarily by the kidneys. In case of severe overdosage, especially in patients with compromised renal function hemodialysis will aid in the removal of cefprozil from the body.
CONTRAINDICATIONS
Cefprozil is contraindicated in patients with known allergy to the cephalosporin class of antibiotics.
12
Safety
The incidence of adverse events, primarily diarrhea and rash*, were clinically and statistically significantly higher in the control arm versus the cefprozil arm. TABLE 7 Age Group 6 months - 2 years 3 - 12 years Cefprozil 21% 10% Control 41% 19%
Study Two
In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific beta-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of beta-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10-16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (i.e., clinical success) were obtained.
TABLE 6 U.S. Acute Otitis Media Study Cefprozil vs beta-lactamase inhibitor-containing control drug Efficacy: Pathogen % of Cases with Pathogen (n = 155) 48.4% than control Cefprozil success rate 17% less Outcome Cefprozil success rate 5% better
S. pneumoniae
H. influenzae
M. catarrhalis S. pyogenes
Overall
13.5% than control 2.6% 100.0% than control Cefprozil equivalent to control Cefprozil success rate 5% less
13
Safety
The incidence of adverse events in the cefprozil arm was comparable to the incidence of adverse events in the control arm (agent that contained a specific beta-lactamase inhibitor).
Study 3
Three recently completed clinical studies have demonstrated therapeutic advantages of cefprozil over cefaclor and erythromycin in the treatment of skin and skin-structure infections. Specifically, cefprozil offers clinical efficacy equivalent to those of cefaclor and erythromycin both at lower total doses and on a less frequent dosing schedule (once or twice daily vs. three to four times daily). The advantage of once-daily or twice-daily dosing with cefprozil may contribute to patient convenience and compliance.[1]
Study 4
In a multicenter study, 598 patients with skin or skin-structure infections were randomly assigned to receive 500 mg of cefprozil once daily (or 20 mg/kg once daily) or 250 mg of cefaclor three times daily (or 20 mg/kg daily in three equal doses) for 5 to 10 days. Treatment was evaluated in 212 cefproziltreated patients and in 210 cefaclor-treated patients. The patients were aged 2 to 99 years (mean, 28 years) and their primary diagnoses were impetigo (in 99 patients), pyoderma (in 98), superficial abscess (in 70), and cellulitis (in 64). A satisfactory clinical response was found in 93%
of the cefprozil-treated patients and in 92% of the cefaclor-treated patients, the pathogens were eradicated in 91% and 89%, and overall treatment was rated effective in
87% of both groups. Adverse clinical events were reported by 5% of the patients in both groups; one cefprozil-treated patient and three cefaclor-treated patients withdrew from treatment because of adverse events. It is concluded that cefprozil administered once daily is as effective
and safe as cefaclor administered three times daily in the treatment of mild to moderate skin and skin-structure infections[2].
14
TABLE 8 European Acute Otitis Media Study Cefprozil vs beta-lactamase inhibitor-containing control drug Efficacy: Pathogen % of Cases with Pathogen (n=47) 51.0% 29.8% 6.4% 12.8% 100.0% Outcome Cefprozil equivalent to control Cefprozil equivalent to control Cefprozil equivalent to control Cefprozil equivalent to control Cefprozil equivalent to control
Summary
Oral cephalosporin have been available for over 25 years and continue to undergo chemical manipulation and development to yield agent with: 1.Greater beta lactamase stability against pathogens resistant to current antimicrobials 2.Better tolerability to promote patient compliance 3. An expanded spectrum of activity against community and nosocomial pathogens. Cefprozil, a third generation Cephalosporin, with a twice daily dosing schedule, have all these properties
1.) 2.) 3.) 4.) Basic and Clinical Pharmacology, 8th ed., Ed. B.G. Katzung, 2001, pp. 762, 764-66. Foye's Principles of Medicinal Chemistry, 5th ed., Ed. D.A. Williams and T.L. Lemke, 2002, pp. 842, 849. The Medical Letter: On Drugs and Therapeutics, vol. 44 (issue 1122), 21 Jan. 2002, pp. 5-6 National Foundation for Infectious Diseases: Clinical Updates in Pediatric Infectious Diseases, vol. 4 (issue 1), Nov. 2001, pp. 4-5,
The Pharmacological Basis of Theraputics, 10th ed., Eds. J.G. Hardman, L.E. Limbird, and A.G. Gilman, 2001, pp. 1206, 1209. Targocid (teicoplanin) Leaflet, Aventis Pharma Limited, pp. 1-2, Cephalosporins Lectures, Medicinal Chemistry 412, University of Michigan, January 2003. Thornsberry C,Brown SD,yee C et al.Increasing penicilline resistance in streptococcus pneumonia in the US effect on susceptibility to oral Cephalosporins. Infect med 1993;10 Suppl D :15- 24. Fung-Tom JC, Huczko E, Stickle t et al.Antibacterial activities of Cefprozil compared of those 13 oral Cephems and 3 Macrolides. Antimicrob agents chemother 1995;39;533-538. Barbhaiya RH, Gleason CR, Shyu WC et al. Phase I study of single-dose BMY-28100, a new oral cephalosporin. Antimicrob Agents Chemother 1990c; 34:202-205. Barbhaiya RH, Shukla UA, Gleason CR et al: Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob Agents Chemother 1990a; 34:1204-1209. Barbhaiya RH, Shukla UA, Gleason CR et al: Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor. Anticrob Agents Chemother 1990b; 34:1210-1213. Nagano K, Maeda H, Yangai T et al.Pharmacokinetic and clinical studies of cefprozil fine granule in children. Jpn J Antibiot1992; 45:1736-1744 Barbhaiya RH, Shukla UA, Gleason CR et al: Comparison of cefprozil and cefaclor pharmacokinetics and tissue penetration. Antimicrob Agents Chemother 1990a; 34:1204-1209. Soloman E, McCarty JM, Morman MR et al.Comparision of Cefprozil and amoxicillin/clavulanate potassium in the treatment of skin and skin stucture in infection in adults.Adv Ther;1992;9: 156-165. Parish LC, Doyle CA, Durham SJ, Wilber RB. Cefprozil versus Cefaclor in treatment of mild to moderate skin and skin structure infection. Drugs 45 (2): 295-317, 1993 Antimicrob Agents Chemother 1994; 38:2210-2212.
5.)
6.) 7.) 8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
15
l l l l l l l l l l l l l l l l
16
Cefuroxime
Cefprozil
Cefixime
Cefaclor
Cefdinir
Drug
S.aureus
0.25-1
0.25
32
16
Cefuroxime
Cefprozil
Cefixime
Cefdinir
Drug
Strep. pneumoniae
MIC Comparison
0.016
0.25
0.13
0.13
0.5
17
Tmax(Hrs)
1.5
H.influenzae
0.06
1 1 2
M.catarrhalis