1

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 b 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

 satisfactory penetration into critical tissues

 a strong record of efficacy in clinical trials.

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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
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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
 6 – 20% of patients sensitive to penicillins will be also sensitive to
cephalosporins
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 Drug-induce Immune Hemolytic Anemia (DIIHA) –

 IgG antibodies formed against the drug bind to RBC → hemolysis (cefotetan and
ceftriaxone)
 Vitamin K deficiency and bleeding tendency
 certain cephalosporins - cefoperazone, cefotetan and cefamandole - can inhibit
vitamin K epoxide reductase, preventing production of reduced (active) vitamin K
→ ↓ coagulation factors synthesis, and hypoprothrombinemia
 Disulfiram-like Reaction - some cephalosporins can inhibit aldehyde dehydrogenase
enzyme resulting in accumulation of acetaldehyde (cefamandole, cefoperazone)
nausea, vomiting with 72 hrs

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

5. Interaction with Live Bacterial Vaccines

 Cephalosporins may interfere with the effectiveness of live bacterial vaccines
 Recommended to administer live bacterial vaccines either before start of cephalosporin
therapy or at least 72 hours after the last dose
6. Interaction with Alcohol
 disulfiram-like reaction flushing, nausea, and vomiting. It's advisable for patients
to avoid alcohol during cephalosporin therapy
Contraindication
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 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

 Previous Seizures or CNS Disorders

 Certain cephalosporins (cefepime), may have a higher risk of causing
neurotoxicity and seizures, especially in patients with a history of seizures or CNS
disorders
 Concurrent use with Calcium-Containing Solutions
 Ceftriaxone should not be administered concurrently with or within 48 hours of
IV calcium-containing solutions, as it may lead to the formation of precipitates
and the risk of ceftriaxone-calcium crystals

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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First gen. Cephalosporins

P.O
*Cephalexin (prototype)
*Cephradine
*Cefadroxil

Parenteral
*Cephalothin
*Cephapirin
*Cefazolin

First Gen. Cephalosporins

 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
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CEFAZOLIN (Ancef)

 Active against most Penicillin G sensitive organisms - has a comparable antibiotic

spectrum to penicillin.
 The half-life of cefazolin is 2 h allowing for 8 or 12 hourly dosing
 Can cross the placenta and is excreted in breast milk but it is considered safe to fetus
and the nursing infant

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

Dosage and administration

 2 g IV 1/2 hour to 1 hour prior to start of surgery adequate antibacterial concentrations
in serum and tissues at the time of initial surgical incision
 Therapeutic dosage:
 0.25 g/8 hrs (mild cases) IM, IV
 1 g/6 hrs (severe cases) IM, IV
 Use in patients whose creatinine clearance is greater than or equal to 35 ml/min, dose
reduction is necessary for chronic kidney disease
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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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Second Generation Cephalosporins

P.O
*Cefuroxime Axetill
*Cefprozil
*Cefaclor

Parenteral
*Cefuroxime
*Cefmetazole
*Cefoxitin

Cephamycin:
cefmetazole, cefotetan, cefoxitin

 Exhibit somewhat increased activity against GNB and anaerobes

 indole-positive Proteus, Enterobacter species, Klebsiella species + Haemophilus
influenzae, Neisseria species (HNPEK)
 The cephamycin subgroup has increased coverage against Bacterides species
st
 Less active against GPB compared to 1 generation drugs
 More resistant to beta-lactamases

 Good activity against streptococci, gonococci, meningococci, staphylococci.

 No efficacy against Pseudomonas, mycoplasma, and chlamydia
 These drugs do not achieve adequate levels in CSF

CEFUROXIME (Ceftin)

 Given orally, IM and IV, resistant to beta-lactamases produced by staphylococcus and

GNB
 Crosses blood-brain barrier
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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

CEFOXITIN, CEFOTETAN – cephamycins

 They are used IV only
 They are effective against anaerobes (B. fragilis)
 Cefoxitin showed improved stability in the presence of ESBLs produced by E. coli and
Klebsiella

Therapeutic uses of second-generation cephalosporins

 UTIs - pyelonephritis, cystitis
 Surgical prophylaxis for colorectal surgery, treatment of post-operative wound infections
 Upper and lower respiratory tract infections.
 Cefoxitin and cefotetan have anaerobic coverage - can be used in anaerobic mixed
infections such as peritonitis and pelvic inflammatory diseases.

 Cefuroxime can be used for treatment of:

 community-acquired pneumonia caused by β-lactamase producing H.
influenzae, K. pneumonia and some penicillin-non-susceptible Pneumococci.
 Meningitis caused by H. influenzea
 Penicillin resistant gonorrhea, bone, respiratory tract, biliary tract and bloodstream
infections, otitis media

Cefaclor
 has good bioavailability orally
 Dosage: 0.25-1 g/TDS/oral
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Third generation cephalosporins

oral
Cefixime (Suprax(
Cefidinir
Cefpodoxime

Parenteral
Cefotaxime (claforan)
Ceftriaxone (Rocephin)
Cefazidime (Fortaz)
Cefoperazone

Third gen. Cephalosporins

 Have an extended GNB coverage, used to treat gram-negative serious infections
st nd
resistant to 1 and 2 generation or other beta-lactams:
 H. influenzae, Proteus, E. coli, Klebsiella spp. , Neisseria spp. (HNPEK) +
Enterobacteriaceae, Citrobacter, Serratia (HENPECKS)
 Ceftazidime – add pseudomonas and acinetobacter and lack activity against
Streptococcu, MSSA and MRSA (HENPECKS + PsA + A)
st
 Have lower efficacy against GPB cocci than 1 generation cephalosporins

 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)
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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
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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
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Other 3ed gen.

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

Ceftazidime
 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
3 -generation agents with ẞ-lactamase inhibitors

 These combinations have potent in vitro activity against GNB, including:

 P. aeruginosa
 AmpC and ESBLs-producing Enterobacteriaceae
 Not active against bacteria producing metallo ẞ-lactamases or anaerobes
(combined with metronidazole)

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
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 every 8 hours by IV infusion over 1 hour for 4-14 days

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 b lactamases produced by Enterobacter
 Streptococcus pneumoniae and methicillin-sensitive Staphylococcus
aureus (MSSA), Pseudomonas aeruginosa
 Cefepime – HENPECKS +PSA + A + Streptococcus + MSSA

 Like 3rd-generation cephalosporins, they are hydrolyzed by ESBLs.

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 Cifepime has good activity against P. aeruginosa (other cephalosporins, except

ceftazidime are not effective)
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
 20

 Dosage:
 for cUTIs and a creatinine clearance of at least 60 ml/min, doses of 2 g/8 hrs
Comparison with penicillin
Similarity
 Both obtained from fungus
 Structural similarity
 Mechanism of action (Cell wall Is)

Dissimilarity
 Resistant to beta lactamase
 Antibiotic spectrum

Why cephalosporine is used?

 Broad spectrum of activity
 Stability to beta-lactamase
 Oral and parenteral preparations
 Widely accepted
 Treats day to day as well as serious infections
 High safety profile
 Side effects specific to individual members of the family as well as the family as a
whole
 Not necessarily cross reaction with penicillin hypersensitivity