doc. 3rd generation cephalosporins, antibiotics

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3rd Generation Cephalosporins
Pharmacist Ala’a Fadhel Hassan
Al-mahmoudia general hospital

2. MECHANISM OF ACTION
Prevents cell wall synthesis by binding to enzymes called
penicillin binding proteins (PBPs) which are essential for the
synthesis of the bacterial cell wall
They have concentration-independent bactericidal activity,
with maximal killing at 4-5 times the MIC of the organism
Clinically significant post-antibiotic effect is not observed
MECHANISMS OF BACTERIAL RESISTANCE
Destruction of beta-lactam ring by beta-lactamases; (an intact
beta-lactam ring is essential for antibacterial activity
Altered affinity of cephalosporins for their target site, the
penicillin binding proteins
Decreased penetration of antibiotic to the target site, the PBPs
(This is only applicable to gram-negative bacteria)
SPECTRUM OF ACTIVITY
Gram-positive aerobic cocci: Cefotaxime, ceftriaxone, and
ceftizoxime are active against methicillin-susceptible
Staphylococcus aureus (though less than 1st and some 2nd
generation agents), very active against Groups A and B streptococci,
and viridians streptococci.
Cefotaxime and ceftriaxone are more active than ceftizoxime
against Streptococcus pneumoniae, particularly intermediately-
penicillin resistant species
None are active against methicillin-resistant Staphylococci,
Enterococci, and Listeria monocytogenes

3. Gram-negative aerobes: Very active against Haemophilus
influenzae, Moraxella catarrhalis, Neisseria meningitides, and
Enterobacteriaceae (ex: Escherichia coli, Klebsiella species, Proteus
mirabilis, Providencia) found in hospital and community-acquired
infections
Some Enterobacter species have a tendency to become resistant
during cephalosporin therapy, and thus cephalosporins are not the
drugs of choice for Enterobacter infections.
Only ceftazidime and cefoperazone are active against Pseudomonas
aeruginosa & the 1st is preferred because it is more potent than
cefoperazone against gram-negative bacteria
Anaerobes: Cefotaxime, ceftriaxone, and ceftizoxime are adequate
for oral anaerobes
Clinical Uses
Gram negative septicemia & other serious Gm –ve inf.
Pseudomonas aeruginosa infections (Ceftazidime - 90%
effective)
Gram negative meningitis - Cefotaxime, Ceftriaxone, for
empiric therapy add vancomycin ± rifampin to cover
resistant Streptococcus pneumoniae
Gonorrhea - Single shot of Ceftriaxone is drug of choice
also oral cefixime and ceftibuten are ok
Complicated urinary tract infections, pyelonephritis
Osteomyelitis & Lyme disease - Ceftriaxone in home
health care situations

4. Inappropriate Uses (yet widely prescribed)
Surgical prophylaxis (use 1st or 2nd generation agents)
Otitis media, URIs – (Cefixime & ceftibuten) have poor Gm
+ve activity
Uncomplicated UTIs
Doses
Cefotaxime
Adults: 1-2 g q 8 h for moderate to severe infections.
For life-threatening infections: 2 g q 4 h
Gonorrhea: 1 g IM as single dose.
Children (1 month - 12 yrs): 50-180 mg/kg/day in 4-6 divided doses
Children (1-4 weeks): 50 mg/kg q 8 hrs.
Children (<1 week): 50 mg/kg q 12 h
Ceftriaxone
Adults: 1-2 g once a day.
Gonorrhea (uncomplicated): 250 mg single IM dose plus doxycycline
or erythromycin (if pregnant)
Children( <45kg) : 125 mg IM once.
Surgical prophylaxis: Single 1 g dose 0.5-2 hours before surgery.
Children: 50-75 mg/kg/day (not to exceed 2 g) in divided doses q 12
h for serious infections.
Meningitis: 100 mg/kg/day (not to exceed 4 g) every 12 hour, with
or without a loading dose of 75 mg/kg
Ceftizoxime sodium
Adults: 1-2 g q 8-12 h IM or IV
For life-threatening infections 3-4 g q 8 h
Uncomplicated UTIs: 500 mg q 12 h
Children (⩾6 months): 50 mg/kg q 6-8 h
Cefoperazone sodium
Adults: 2-4 g/day in equally divided doses q 12 h
For severe infections: 6-12 g/day

5. Ceftazidime
Adults: 1g q 8-12 h
For life-threatening infections 2 g IV q 8 h
Uncomplicated UTIs: 250 mg q 12 h
Complicated UTIs: 500 mg q 8-12 h
Pseudomonal lung infections in cystic fibrosis patients: 30-50 mg/kg
IV to a maximum of 6 g/day
Infants and children (1month-12 yrs): 30-50 mg/kg IV q 8 h to a
maximum of 6 g/day.
Neonates ⩾4 weeks: 30 mg/kg IV q 12 h
Cefixime.
Adults: 400 mg/day (for gonococcal inf.) or 200 mg b.i.d
Children: 8 mg/kg/day as single dose or 4 mg/kg q 12 h
Ceftibuten
Adults: 400 mg/day
Children: 9 mg/kg/ day for pharyngitis, tonsillitis or otitis media
due to Streptococcus pyogenes and for otitis media due to
Haemophilus influenzae and Moraxella catarrhalis
Cefdinir
Adults: 600 mg once daily or 300 mg BID – use BID dosing for
pneumonia and skin infections
Children: 14 mg/kg once daily or 7 mg/kg BID for otitis media,
sinusitis, or pharyngitis due to Streptococcus pyogenes
ADVERSE EFFECTS & CAUTIONS
Coagulation defect & bleeding

6. Caused by moxalactam &cefoperazone doses higher than 4g/day
,also occur with Ceftriaxone (due to presence of N-methyl
thiotriazone) but still here controversial
Antibiotic produced hypobrothrombinemia
This observed with moxalactam doses higher than 4g/day for
1week, No demonstrable effected noticed with ceftriaxone or
ceftazidime even at doses as 6g/day
Hypersensitivity reactions
Immune mediated hematologic reactions
Described with Ceftriaxone (falsely +ve coombs test), while
Leucopenia was reported with high dose cephalosporins for 2-
3 weeks duration specially with Ceftriaxone & cefotaxime
Gastrointestinal side effects
Symptoms includes nausea, vomiting, anorexia,
abdominal cramps and diarrhea
Attributed to:
+direct irritation of intestinal mucosa
+increased bile salt secretion in intestine
+changes in fecal flora (lead to both vit. K synthesis impair as
well as super infection),that’s mostly marked change with
Ceftriaxone & cefoperazone while least with cefotaxime
Hepatic & biliary system
Mild reversible abnormalities in liver function test was
observed in patients treated with cephalosporins

7. Ceftriaxone has unique property of causing sludge
(pseudolithiasis) to form in the gallbladder particularly in
children(when given as bolus dose over 3-5 minutes)
Associated symptoms: nausea, epigastric distress, colic,
tenderness to palpitation or fist percussion in the right
upper quadrant which resembles cholecystitis in clinical
picture
The sludge has uncertain composition, mobile & best
detected using ultrasonography however this syndrome
subsides & sludge dissolve when treatment discontinued
Also Ceftriaxone in circulation binds to serum proteins
causing highly displacement of bilirubin from its protein
binding site leading to hyperbilirubinemia (frequent
increasing noticed specially with already hyperbilirubinemic
neonates (so it should be avoided)
Superinfections
Due to their broad spectrum of microbial activity a profound
changes in normal flora occurs at various site of the body like
vagina, GIT, skin & upper respiratory tract causes increased
rate of mucocutaneous & systemic infections
Also 3rd generation treated patients may have facilitated
acquisition of pathogens from exogenous nosocomial sources
Reported bacterial agents
Pseudomonas aeruginosa, Enterobacter cloacae

8. Citrobacter, Serratia, Proteus spp.
Providancia & Acinctobacter
As well as fungal infections (candidiasis) reported
Nephrotoxicity
Agents causes renal injury either by
hypersensitivity induced interstitial nephritis (direct toxicity
to renal tubules)
synergistic action with other nephrotoxic agents
(Still nephrotoxic potential is non-significant & low)
Neurotoxicity
Associated headache, paresthesias & other mild CNS side
effects reported with these agents, seizures reported in cases
treated with ceftazidime (but neither Ceftriaxone, ceftizoxime
nor cefotaxime)
Disulfiram like reaction
Occurred with patients consuming ethanol and receiving
3rd generation agents that contains methylthiotrazol side
chain at position 3 at the nucleus
Here agents binds to the hepatic enzyme aldehyde
dehydrogenase that metabolizes acetaldehyde(the break
down product of ethanol) to water and carbon dioxide
causing aldehyde accumulation in the liver
Aggravating factors :elixir and cough preparations which
contains alcohol

9. Mostly obvious with moxalactam & cefoperazone