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Pharma URO Cephalosporins
Pharma URO Cephalosporins
Cephalosporins
Broad-spectrum antibiotics, GPB and GNB
Bactericidal, similar to penicillins, inhibiting bacterial cell wall synthesis
More stable than penicillins to many bacterial β-lactamases, although strains of E. coli and
Klebsiella sp. can express extended spectrum lactamases (ESBLs) that can hydrolyze most
cephalosporins
Cephalosporins are the most widely used antibiotics in urology because of their:
good safety profile -low toxicity and do not easily cause allergic reactions
excellent antimicrobial activity against urological pathogens and most of the bacteria
causing postoperative infections
Pharmacokinetics
Given orally and parenterally (IM, IV)
Widely distributed in body fluids, joint fluid, CNS and cross the placenta
Adequate therapeutic levels in CSF achieved only with third generation cephalosporins;
cefotaxime, ceftriaxone
useful for treatment of neonatal and childhood meningitis caused by Haemophililus
influenzae
Elimination:
eliminated unchanged in urine through tubular secretion and glomerular
filtration.
Doses must be adjusted in cases of renal failure
Ceftriaxone is excreted through bile into feces – used in patients with renal
insufficiency
Plasma half-life: 1- 4 hr. mostly
3
General Indications
Alternatives to penicillin, particularly in allergic patientss
Urinary tract infections caused by GNB, especially Klebsiella, Proteus, Enterobacter,
Serratia
Complicated infections - UTIs and intra-abdominal infections
Surgical prophylaxis and wound infections
Septicaemia, Bacteraemia and Nosocomical infections
Serious respiratory tract infection
Meningitis: ceftazidime + gentamicin; most effective therapy for Pseudomonas
meningitis
Skin and soft tissue infections
Bone and joint infections
Ocular and ENT infections
Typhoid
Mixed aerobic and anaerobic infections in cancer patients
Venereal diseases (sexually transmitted diseases; STD)
Cephalosporins in pregnancy
Generally considered safe throughout pregnancy
Amoxicillin/amoxicillin + clavulanic acid
first-choice for UTIs during pregnancy
usually taken 2 to 3 times per day for 5 to 7 days
Cephalexin (keflex)
may also be a first-choice antibiotic for UTIs during pregnancy. It’s generally
considered safe throughout pregnancy.
Used 4 times/day for 5 to 7 days
Cefaclor, cefuroxime and cefpodoxime can be used to treat a UTI during pregnancy
Adverse effects
Cephalosporins have low toxicity and are generally safe
GIT upset – nausea, vomiting, diarrhea, abdominal pain (more common with oral
cephradine and parenteral cefoperazone)
Local irritation after IM injection and thrombophlibitis after repeated IV
Pseudomembranous Colitis - especially 3ed gen
Increase nephrotoxicity of aminoglycosides - cephaloridine, cephalothin
st nd
Hypersensitivity reactions: infrequent, more common in 1 and 2 generations
4
Drug interactions
1. With aminoglycosides
Synergistic with aminoglycosides – septicemias
Ceftazidime + gentamicin – the most effective therapy for Psuedomonas meningitis
Aminoglycosides + cephalosporin - prophylaxis and treatment of neutropenic patients
May increase the risk of kidney damage
2. Probenecid:
reduces the tubular secretion resulting in prolongation of half-life of cephalosporins
3. Diuretics
Cephalosporins, with a nephrotoxic potential (e.g., cephalotin), may increase risk of
nephrotoxicity when with loop diuretics - furosemide
4. Anticoagulants
May ↑ risk of bleeding as they may be associated with reversible platelet dysfunction
Can potentiate risk of bleeding of anticoagulant drugs, such as warfarin
Interaction with warfarin is more commonly reported compared to newer oral
anticoagulants (NOACs) like rivaroxaban or apixaban
Contraindication
Hypersensitivity to cephalosporin, previous anaphylactic reaction to penicillin or other
beta-lactam antimicrobials
History of clostridium difficile-associated Disease (CDAD)/ pseudomembranous colitis
Renal failure
Neonates with hypaerbilirubinemia
Can displace bilirubin from its binding sites and may lead to an increased risk of
bilirubin-induced neurotoxicity in neonates with hyperbilirubinemia
Classification of cephalosporins
Cephalosporins can be divided into five generations based on their spectrum of
coverage against GPB and GNB, time to market as well as potency
The second and third generation has more GNB activity with decreased activity GPB
bacteria
The fourth and fifth generations has a broad spectrum of activity
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Spectrum of activity
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Parenteral
*Cephalothin
*Cephapirin
*Cefazolin
Active against most GPB, while having minimal coverage against GNB
Most gram positive cocci such as staphylococci spp., streptococci spp., except
enterococci
Limited GNB Covarage: Proteus mirabilis, E. coli, and Klebsiella pneumoniae
(PEK)
Inactive against Pseudomonas, indole +ive proteus species, Enterobacter sp
(produce AmpC BL), MRSA
Do not cross BBB
CEPHALEXIN (Keflex)
Oral and IV administration, but not IM (painful)
Given orally, usually every 6 to 12 hours with or without food
Indications:
UTIs - (Cephalexin and cefadroxil) - Strep. pyogenes and Staph. aureus
Pyelonephritis
Cystitis
Skin/soft tissue infections due to MSSA or strepcoccal spp (Cephalexin and cefadroxil)
Bacterial infections like pneumonia, middle ear and bone infections
Limited use to UTIs and minor infections such as pharyngitis, bronchitis, abscess and
cellulitis
Dose:
0.25-1 g/6-8 hrs orally
Children: 25-100 mg/kg/day
8
CEFAZOLIN (Ancef)
Urological indications
UTIs - uncomplicated UTIs caused by susceptible bacteria
Staphylococci infections
Staphylococcus aureus, including methicillin-sensitive strains.
Wound infections
Preioperative Prophylaxis
st
Preferred paenteral 1 generation drug for surgical prophylaxis - orthopedic,
abdominal, or cardiac surgery
Should be used only to prevent infections that are proven or strongly suspected
to be caused by susceptible bacteria.
Cefazolin can replace penicillin in penicillin-allergic patients - low risk of cross-allergy
nd
(10%), even lower with 2 and 3ed generations
Other uses:
Infection with gram positive cocci
Bone and joint infections - osteomyelitis and septic arthritis
Respiratory tract infections - pneumonia and bronchitis
Endocarditis prophylaxis
Gynecological infections
Bacterial septicemia
st
1 generation indications
Genitourinary tract infections
Surgical prophylaxis - Cefazolin is the cephalosporin of choice for surgical prophylaxis
due to its good tissue penetration
Uncomplicated skin and soft tissue infections such as cellulitis and soft tissue abscesses
commonly due to a Staphylococci spp. or Streptococci spp.
Bone infections, respiratory and biliary tract infections, bloodstream infection, otitis
media and streptococcal pharyngitis (cephalexin)
st
Other 1 generations
Cephalothin - oral
Resistant to staphylococcal beta-lactamase – effective for staphylococcal
infections such as endocarditis
Absorbed after oral absorption, usually given IV (IM route is very painful)
Cefadroxil – 0.5-1g/oral/BD
Cephradine: 0.25-1 g/6-12 hr/IM/IV/oral
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P.O
*Cefuroxime Axetill
*Cefprozil
*Cefaclor
Parenteral
*Cefuroxime
*Cefmetazole
*Cefoxitin
Cephamycin:
cefmetazole, cefotetan, cefoxitin
CEFUROXIME (Ceftin)
Cefuroxime axetil
A prodrug that is an ester of cefuroxime, effective orally - cefuroxime is released by
hydrolysis in the body
Absorption is greater when taken after food, its half-life is about 80 minutes
70-90% is excreted unchanged in the urine
Dose reduction is necessary for renal insufficiency
Dose: Urinary tract infections
0.25–1 g 3 times orally - cefuroxime axetil
750 mg 3 times IV
Cefaclor
has good bioavailability orally
Dosage: 0.25-1 g/TDS/oral
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oral
Cefixime (Suprax(
Cefidinir
Cefpodoxime
Parenteral
Cefotaxime (claforan)
Ceftriaxone (Rocephin)
Cefazidime (Fortaz)
Cefoperazone
Some of them have enhanced ability to cross the BBB (ceftriaxone, cefotazime) -
suitable for treating CNS infections
All are highly resistant to beta-lactamases of GNB and GPB
nd
like the 2 and 3rd-generation drugs are all hydrolyzed by constitutively produced
AmpC β-lactamase, so they are not effective against Enterobacter (E. aerogenes, E.
cloacae)
13
Indications
Urologic indications
Ceftriaxone - commonly used regardless of type of urological surgery done.
Most of patients (86%) were given antibiotics for five days regardless whether it was for
prophylactic or treatment intention
Severe postoperative infections like peritonitis: in combination with gentamicin to
include enterococci.
Severe urinary tract infections: in combination with gentamicin to include enterococci.
Treatment of gonorrhea: ceftriaxone is DOC for beta-lactamase producing Neisseria
gonorrhea - with a single IM injection
H. ducreyi: causes sexually transmitted infection (STI) known as chancroid (genital
ulcerative disease in males)– Ceftriaxone
Ceftazidime - has Pseudomonas aeruginosa coverage
Intra-abdominal infections
Other uses
Effective treatment in pneumonia produced by b-lactamases producing bacteria
Meningitis due to meningococci and Haemophillus influenza - cefatrixone
Respiratory tract infection
Skin and soft tissue infections
Salmonella, typhoid, parathyroid – Ceftriaxone
14
Ceftriaxone (Rocephin)
Administration - IM, IV
95% protein bound → long half-life (8 hrs), good CSF penetration
Excreted in bile, may be used in pts with renal insufficiency
Effective for chemoprophylaxis in urological surgery and therapy of urinary tract
infections:
Has longest half-life of any cephalosporin - permits once a day dosing
Single daily dose represents a considerable advantage both regarding patients'
compliance and clinical convenience
can be given in renal impairment - excreted in bile
Indications
1. UTIs:
Complicated UTIs - pyelonephritis urethritis and pelvic infections
2. Gonorrhea:
uncomplicated and disseminated gonorrhea, including infections affecting the urogenital tract.
Effective against genital, anal and penicillin-resistant Nisseria gonorrhoeae – a single dose of
250 mg
In combination with azithromycin in dual therapy and prevent development of antibiotic
resistance
3. Prostatitis:
Chronic bacterial prostatitis - ceftriaxone in combination with other antibiotics
4. Pelvic Inflammatory Disease (PID)
Ceftriaxone is sometimes included in the treatment regimen for pelvic inflammatory
disease
5. Intra-abdominal Infections:
Involving the urogenital organs or structures, ceftriaxone may be part of the antibiotic
therapy to address the infection
6. Other uses:
Bacterial meningitis and multi-resistant typhoid fever - high level of the drug can be
achieved in blood and CSF
Osteomylitis – good penetration into bones
Community acquired pneumonia caused by pneumococci, H. influenza and staph.
Aureus
Abdominal sepsis and septicaemias
Multi-drug resistance typhoid fever
Dosage
1 g IM once daily → quick resolution of signs and symptoms of infection
1-2 g once daily 4-14 days IM
15
Cefixime - oral
suitable for treating UTIs in children
it has an elimination half-life is 2.5 hrs with 20% renal elimination and high biliary
excretion
Dosage:
200 mg twice daily or 400 mg once daily for adults
4 mg/kg twice daily or 8 mg/kg once daily for children
Cefta idime
Good activity against pseudomonas - best anti-pseudomonal cephalosporin
Indicated for pseudomonal infection with aminoglycosides
Specifically used in febrile neutropenic patients with haematological malignancies
Burn
Limitation – reduced activity against gram positives (GPs) and oral anaerobes
Cefoperazone – is eliminated (70%) in bile, very useful in patients with renal failure
Cefpodoxime - oral
suitable for the oral treatment of UTIs
Dosage:
Adults 200 mg twice daily
Children 4 mg/kg body weight twice daily
Ceftibuten -
oral cephalosporin with high activity against Enterobacteriaceae
It is suitable for treating severe or complicated UTIs in children
It has an elimination half-life is 2.5 h with 70% renal elimination
Dosage:
400 mg once daily for adults and
9 mg/kg once daily for children
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rd
Examples
Ceftazidime + avibactam, IV
ceftazidime has the maximal antipseudomonal effect especially when combined
with aminoglycosides.
This combination may be an option for carbapenemase producing bacteria
Ceftolozane + tazobactam, IV
As an alternative to ceftazidime/avibactam, as treatment option for MDR P.
aeruginosa infections
Therapeutic uses
Complicated urinary tract infections (cUTIs) of adult and pediatric patients including
pyelonephritis
Complicated intra-abdominal Infections (cIAI), used in combination with metronidazole
Hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia
(HABP/VABP
Dosage
Ceftazidime/avibactam –
cUTIs in adults - 1.25 g (1 g ceftazidime and 0.25 g avibactam) administered
intravenously over a 2-hour period every 8 hours
dosage adjustments in patients with varying degrees of kidney impairment
Ceftolozane/tazobactam -
adult patients 18 years and older with creatinine clearance (CrCl) > 50 ml/min –
cIAI and cUTI - 1.5 g (ceftolozane 1 g and tazobactam 0.5 g)
3 g (ceftolozane 2 g and tazobactam 1 g) for HABP/VABP
every 8 hours by IV infusion over 1 hour for 4-14 days
17
Fourth Generation
All parenteral
Cefepime (Maxipime)
Cefpirome
Cefozopran
Cefluprenam
Cefquinome
Fourth Generation
broad-spectrum, penetrate CSF, have enhanced ability to cross outer membrane of GNB
and has good affinity for transpeptidase enzyme
Similar coverage as 3ed generation and are more resistant to chromosomal -
lactamases - e.g. AmpC lactamases produced by Enterobacter
Streptococcus pneumoniae and methicillin-sensitive Staphylococcus
aureus (MSSA), Pseudomonas aeruginosa
Cefepime – HENPECKS +PSA + A + Streptococcus + MSSA
Indications
Although effective against both GPB and GNB, cefepime is reserved for serious systemic
infection in patients who are likely to have multi-resistance organisms
Useful for empiric treatment of serious and resistant hospital acquired infections
Crosses BBB and are highly effective in treating meningitis
Dosage
Severe UTI: 0.5-1g/IV/12 hr/7-10 days
Severe pneumonia: 1-2 g IV/12 hrs/10days
Skin and skin structure infection: 2 g/12 hr/10 days
Cefpirome: 1-2 g/iv/BD
Fifth Generation
All parenteral
Ceftobiprole
Ceftaroline
Ceftolozane
Cephalosporins active against MRSA
Ceftaroline
Broad-spectrum - GPB and GNB.
th
As with 4 generation, they active against HENPECKS + MRSA but not PSA and A
Active against gram-positive cocci - MRSA, penicillin resistant S. pneumonae and
enterococci
Has increased binding to PBP2a which mediates methicillin resistance in Staphylococci,
resulting in bactericidal activity against MRSA
Uses:
Complicated skin and soft tissue infections
Community acquired pneumonia
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General notes
The effect of first-generation cephalosporins on GPBs was stronger than that of second-
and third-generation cephalosporins.
The second-generation cephalosporins – have expanded antibacterial spectrum, and
their effectiveness against GNB was greater than that of the first-generation
cephalosporins.
st
Third-generation cephalosporins exert significantly stronger effects against GNB than 1
nd
- and 2 -generation and have strong tissue penetration and high enzyme resistance.
Fourth-generation cephalosporins - mainly used for severe infections caused by GNB
resistance to third-generation cephalosporins.
The effect of fifth-generation cephalosporins on GPB, particularly drug-resistant
bacteria, is stronger than that of first four generations.
New cephalosporins
th
Ceftaroline fosamil acetate (5 )
exerts a stronger effect on MRSA than vancomycin and linezolid (MIC = 2 μg/ml) and is
less toxic to the kidneys
Treatment of 2-month-old children and elderly patients with cSSTIs as well as
community-acquired pneumonia (CAP)-induced by MRSA.
In 2019, the EMA authorized the use of the drug to newborns and infants.
Cefiderocol
a novel parenteral siderophore cephalosporin that exerts a mechanism of action similar
to other β-lactam antibiotics
it is a siderophore able to undergo active transport into the bacterial cell through iron
channels
Once bound to ferric iron, it is able to undergo active transport into bacterial cells
through iron channels in outer cell membrane
Once inside cell, it binds to and inhibits PBP3 with high affinity and preventing linking of
peptodoglycan layers
effective in vitro against multidrug resistant strains including ESBL producers and
carbapenemase producing bacteria
Indicated for cUTIs in patients with limited or no alternative treatments available
Dosage:
for cUTIs and a creatinine clearance of at least 60 ml/min, doses of 2 g/8 hrs
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Dissimilarity
Resistant to beta lactamase
Antibiotic spectrum