CEPHALOSPORIN’s

andCARBAPENEM’s

Cephalosporin

• semisynthetic antibiotics derived from cephalosporin C. like penicillin.• exhibit their bacterial killing occurs by inhibiting cell wall synthesis• they are selectively toxic with a wide margin of safety.• commonly classified into generations based on their spectrum of

activity. • The higher the generation, the more superior the activity against

gram negative organisms, and more resistant to beta lactamases.

Pharmacokinetics• after oral administration, absorption differs greatly for diff.

cephalosporin's. • eliminated unchanged mainly through the kidneys by GFR and tubular

secretion except ceftriaxone, which is eliminated by both renal and hepatic pathways, and cefoperazone which is eliminated mainly by the hepatobilliary route. • distribute well into body tissues and fluids, but penetration into the

CNS is poor except when meninges are inflamed. • Cefazolin has poor penetration into the CNC and should not be used

for meningitis.

GENERATION Prototype drugs Useful spectrumFirst Cefazolin (IV)

Cephalexin (PO)Cephalotin (IV)Cephadrine(PO, IV)Cefadroxil(PO)

Gram positive strep, s.aureus, some gram negative organism

Second Cefuroxime(IV,PO)Cefaclor (PO)CefamandoleCefonicidCefprozil Cefoxitin (IV,IM)

Community acquired E.coli, klebsiella, proteus, h.influenza, m.catarrhalis, less active against gram postitive bactreia

Added activity against bacteroides fragilis

Third Ceftriaxone (IV, IM)Cefotaxime (IV)Cefixime (PO)Cefdinir (IV)Cefpodoxime (IV)

Ceftazidime (IV, IM)

Enterobacteriaceae, serratia, Neisseria gonorrhea, less active than 1st gen against gram positive cocci

Active against pseudomonas aeruginosa

Fourth Cefipime(IV, IM)Ceftolozane (IV)Cefpirome (IV)

Comparable to 3rd gen but more stable to b-lactamases of gram negative bacteria

Fifth Ceftobiprole(IV, IM) not FDA approvedCeftaroline (IV)

Activity against MRSA, gram negative bacteria including pseudomonas

*all cephalosporin's have no activity against enterococci and listeria

1st Gen Cephalosporin [Gram (+) strength: ++++, Gram (-) strength: - ]• effective against gram (+) cocci, including b-lactamase producing S.aureus

and variability against gram (-) enteric bacilli. • No drug from this gen. will attain appreciable concentrations in the CNS. • They are valuable in children who have non anaphylactic allergy to

penicillin’s. • used to treat staph. & strep. skin structure infections, bone and joint

infections, pharyngitis and uncomplicated community acquired UTI cause by susceptible bacteria.• Cefazolin produces higher concentrations in blood than do the other

parenteral 1st gen drugs.

*According to DOH 2009, the resistances of 1st gen rates are: e coli-48.6%, klebsiella-53.4%, enterobacter-85.3%

2nd Gen Cephalosporin [Gram (+) strength: +++, Gram (-) strength: + ]

• Have similar or somewhat less activity against gram positive cocci such as staph.aureus, streptococci.• Better activity against H.influ, M.catarrhalis, N.meningitides,

N.gonorrhea and some members of the enterobacteriaciae. • The cephamycins (cefoxin) are more active than are the 1st or second

gen ceph against gram negative enteric bacteria and B.Fragilis, but they have poor activity against gram (+) cocci.

*According to DOH, the resistance of 2nd gen rates for cefuroxime were: e.coli-20.3% kleb-28.9%

3rd Gen Cephalosporin [Gram (+) strength: +, Gram (-) strength: +++]

• potent against gram-negative enteric bacteria. • excellent activity against H.influ, M.catarrhalis, N.meningitides,

N.gonorrhea, Grp.A strep and pen-susceptible pneumococci but relatively poor activity against staph.• Ceftazidime and cefoperazone are the only 3rd gen with activity

against P.aureginosa. • Parenteral cephalosporin provide high concentrations of drug

in serum and adequate concentrations in the CSF.

*According to DOH the resistance rates for ceftriaxone were: e.coli-17.6%, klebsiella-29.7%, enterobacter-27.4%, n.gonor-0% for ceftazidime resistance for P.aeruginosa was 15.4%

4th Gen Cephalosporin [Gram (+) strength: -, Gram (-) strength: ++++]

• has activity against P. aeruginosa and retains good activity against methicillin-susceptible staphylococcal infections• Sensitive to oxacillin-susceptible staphylococci, penecillin-resistant

strains of S.pneumonia, viridians streptococci and most strains of enterobacteriaceae, including ESBL-producing strains of E.coli and k.pnuemoniae.• It is indicated for the parenteral treatment of LRT, urinary tract, skin

and skin structure, intraabdomonal infections as well as empiric monotheraphy in pediatric patient with cancer who have fever and neutropenia.

*According to DOH resistance rates for cefipime were: e.coli-21.4%, Klebsiella-14.3%, enterobacter-14.4%, pseudomonas aeriginosa-11.2%.

Adverse EffectsAdverse Reaction Frequency (%)

Hypersensitivity reactions(cross react with penicillin's in 5-20%)

1-3

Hematologic 1-5

Diarrhea 2-5

Abnormal Liver function tests 1-7

Biliary Sludge (ceftriaxone) 20

Interstitial nephritis rare

- Generally well tolerated by children. - The usual reactions experienced are local, including the pain at

injection site or thrombophlebitis wen given parenterally, and mild GI complaints when given orally.

- Drug fever has been associated as well as non-specific antibiotic associated diarrhea.

Adverse Effects• Hypersensitivity reactions such as rash, pruritus and urticaria have

been seen in 1-3% of px’s. • often prescribed for patient’s allergic to penicillin but cross reactivity

may occur in 2-30% of px’s. • Cephalosporins with the methylthiotetrazole side chain

(cefamandole, cefofetan) may produce coagulation problems due to its inhibition of vitamin k dependent carboxylase. This enzyme converts certain factors (II,VII, IX and X) to their active form. • Ceftriaxone is associated with biliary sludging, biliary pseudolithiasis

and symptomatic obstructive biliary disease. • Serum sickness like disease has been described with the intake of

cefaclor.

DOSAGES OF COMMON CEPHALOSPORIN’S1st Generation:

• Cefaclor: children >6mo: 20-40mg/kg/day q8, max 1g/day• Cefalexin: children: 25-50 mg/kg/day div q6-8hrs PO, max 4g/day• Cefazolin (IV): >7days: 20mg/kg/dose q8-12hr, children 50-100mg/kg/day q6-8, max 6g/day

•2nd Generation:• Cefuroxime: neonates: 50-100mg/kg/day q12, children 75-150 mg/kg/day q8 max:6g/day

•3rd Generation: • Cefixime: children: 8-10mg/kg/day q12-24hrs, mas 400mg/day• Ceftriaxone: >7days: 50-75mg/kg/dose q24hr, children 50-100mg/kg/day q24, max 4g/day

•4th Generation: • Cefipime(IV): neonates: <14days: 30mg/kg/dose q12, children: 50mg/kg/dose q12 IV 20-30min

CARBAPENEMS (Imipenem-cilastatin, meropenem

and ertapenem)• Similar to other beta lactams, these drugs also inhibit bacterial cell

wall synthesis. • composed of a fused b-lactam ring and a five membered ring system.• different from other b-lactams in being unsaturated and containing

carbon atom instead of the sulfur atom.• Of all the beta lactam antibiotics, carbapenems have the broadest

spectrum.• have a high affinity to penicillin binding proteins and are not

hydrolyzed by most b-lactamases.

Carbapenem’s• these drugs have activity against gram-positive cocci including most

streptococci, staphylococci, although variable activity against MRSA. • Carbapenems have moderate activity against Enterococus faecalis but

most E.faecium are resistant. • very active against many enterobacteriaceae, pseudomonas

aeruginosa, acinetobacter, anaerobic bacteria including Bacteroides fragilis are susceptible to carbapenems.

CarbapenemsDRUG Bacteria wher in Carbapenem’s have good activity

Gram Positive Gram Negative Anaerobes

MeropenemAnd Imipenem

S. aureus (MSSA only), S. agalactiaeS.pneumoniae (including penicillin resistant strains)S.pyogenes

e.coli, h.influenza, klebsiella, M.catarrhalis, Proteus mirabilis, Pseudomonas aeruginosa, including ESBL producing org

Bacteroides sp. Including fragilisClostridium spp.Peptostreptococcus spp.PorphyromonasPrevotella bivia

Ertapenem S. aureus (MSSA only), S. agalactiaeS.pneumoniae (including penicillin resistant strains)S.pyogenes

E.coli,H.influenza (beta-lactamase negative isolates)K pneumoniae, M.catarrhalis, Proteus mirabilis,

Bacteroides sp. Including fragilisClostridium spp.PeptostreptococcusPorphyromonasPrevotella bivia

Pharmacokinetics

• Imipenem is excreted in the urine and undergoes partial metabolism in the kidneys.• Cilastatin does not affect serum concentrations of imipenem.• Meropenem and ertapenem are more stable, less likely to induce

seizures than imipenem. • Slightly more active against enterobacteriaceae and slightly less

active against gram positive bacteria.• Safety and efficacy of meropenem has been established in pedia px

and well as in px with CNS infection. • Ertapenem has poor activity to pseudomonas and acinetobacter spp.

Adverse Effects

• Carbapenems are indicated for: documented multidrug resistant gram negative infectionn due to org proven or suspected to be susceptible to carbapenems and polymicrobial infections in which other agents have insufficient activity or are contraindicated due to its toxic potential. • Some adverse reactions include: diarrhea, nausea, vomiting and skin

rashes. • Toxic levels of imipenem in patient’s may produce seizures.

• Cross reactions in penicillin allergic patients may occur. • Candidemia may occur with prolonged use of carbapenems.• Carbapenems are poorly absorbed from GI tract and must be

given parenterally. • Ertapenem has a longer serum half-life which allows for dosing

every 24hrs. • it is widely distributed in the body such as int tissue fluids,

bone and pleural fluid.• It reaches low concentrations in the CSF but increases if the

meninges are inflamed.

*DOH resistance rats for imipenem: pseudomonas – 13.5%, klebsiella – 0.7% and enterobacter-2.3%

• Sources:• Philippine Pediatric Antibiotic Manual• Nelsons Textbook of Pediatrics 20th Ed.

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