Pharmacokinetics parameter of cephalosporin

CEPHALOSPORIN Oral i.v. T1/2 (hrs)

st
1 GENERATION
Cefalotin - Yes 0,5
Cefazolin - Yes 2,0
Cefalexin Yes - 1,0
Cefradin Yes Yes 0,5
Cefadroxil Yes - 1,5
Cefachlor Yes - 1,0
2nd GENERATION
Cefamandol - Yes 0,7
Cefuroxim Yes Yes 1,7
Cefoksitin - Yes 3,5-4,0
Cefotetan - Yes 0,8

3rd GENERATION
Cefotaxim - Yes 1,0
Ceftizoxim - Yes 1,8
Ceftriaxon - Yes 6-8
Moxalactam - Yes 2,0
Cefiksim Yes - 3-4
Ceftazidim - Yes 1,6-2
Cefoperason - Yes 2,0
 Current ‘Mainstream’ drugs
• Cephalosporins
• ß-lactam – ß-
1st., 2nd & 3rd.
lactamase inhibitors
• Aminoglycosides
• Quinolones
• Macrolides
 Cephalosporins

Numerous
1st.
/ 2nd.
/ 3rd. / 4th
compounds in this
generations
class of drugs

Most commonly used

Common ß-lactam ring
antibiotics in many
compound
parts of the world.

Mechanism of action similar to

penicillin: interferes with Overall good safety
synthesis of the peptidoglycan
component of the bacterial cell profile
wall.
 1st. Generation Cephalosporins

Eg. cefazolin, cephalexin

Active against Gm +ve cocci

Moderately active against community acquired

E.coli, M. catarrhalis, Proteus mirabilis (indole –
ve)

Other enterbactericeae: unpredictable

Poor activity against MRSA, PRSP &

eneterococci
 1st. Generation Cephalosporins
• Clinical Uses:

• Skin & soft tissue infections

• Strept pharyngitis (Penicillin still drug of choice)

• Community acq. UTI (SMX-TMP: > effective & cheaper)

• Cefazolin: prophylactic antibiotic for surgical procedures involving

implants & clean + clean comtaminated procedures
 1st Generation Cephalosporin
Skin infect, resp tract infect, urinary tract infect.

Surgical pophylaxis for cardiac surgery or prosthetic implant in

orthopaedic surgery.
Cefalotin is not absorbed orally, painfull via i.m. recommended
i.v. Very short half live, rarely used.

Cefazolin (i.m./ i.v)., widely distributed, does not penetrate CSF

Clearence through glomerular filtration & tubular secretion, is not

metabolized.

Cefalexin, Cefadroxil, and cefradin: oral absorption: good

They are not metabolized, eliminated through glomerular

filtration & tubular secretion.

Dose adjustment is required in renal failure.

2nd. Generation Cephalosporins

Eg. cefuroxime, cefprozil, cefaclor*

Significantly  activity against

H. influenzae, M. catarrhalis, P. mirabilis, N. gonorrhoea

 activity against
Staph. & nonenterococcal strept

 activity against some enterobactericeae eg.

klebsiella spp., salmonella, shigella.

(cefaclor: poor activity generally to enterobactericeae)

2nd Generation Cephalosporin

Drugs

• Cefamandole
• Cefuroxime
• Cefoksitin
• Cefotetan
2nd Generation Cephalosporin
Common characters
More active on gram-negative bacteria

Less active on gram-positive bacteria

More stable to β-Lactamase produced by gram-

negative rods

Some are effective on anaerobes

No effect on P. aeruginosa

Less renal toxicity

2nd. Generation Cephalosporins

Clinical Uses:
Gram-negative bacteria infections: first choice
Anaerobic infections
CAP (Community acquired pneumoniae)
Epiglotitis, Sinusitis
Uncomplicated UTI
Meningitis (3rd. Gen cephalosporins preferred)
3rd. Generation Cephalosporins

Eg. ceftriazone, cefotaxime, cefoperazone,

ceftazidine

Main distinguishing feature:

Good activity against Gm-ve bacilli.

Potent activity against Strept pneumoniae

including those with relative penicillin resistance.

2 groups: non-antipseudomonal &

antipseudomonal (ie. cefoperazone, cefpodoxime
& ceftazidine)
Lacks activity against: enterococci, MRSA, highly
resistant PRSP, Stenotrophomonas, Acinetobacter
(variable sensitivity)
 3rd. Generation Cephalosporins
Clinical uses:

Serious infections caused by Gm –ve bacilli (due to the

superior activity against GNB that are resistant to other ß-
lactam antibiotics.)

If pseudomonas infection is suspected: ceftazidine is the

option from this class. (cefoperazone,, has little role in
such clinical setting)

Ceftazidine + AMG: option for febrile neutropenia

 Overuse of 3rd. generation
cephalosporins
Has been linked to Extended spectrum ß-lactamase producing
organisms eg. Klebsiella, E. coli

Rahal et al. JAMA2008:280;14:1233-7

Also linked to  MRSA

Washio et al. Pub Health 20077;111:187-190
 3rd Generation Cephalosporin

• nosokomial respiratory tract, urinary tract, skin

Ceftizoxim, Ceftriaxon, & infection, osteomyelitis, and meningitis
cefotaxim: (penetrate CSF).

• long half live (6-8 hrs, once/day)

Ceftriaxon: • is not metabolized, 60% are excreted
through gall bladder,
• Dose adjustment might be needed in
hepatic and renal disfunction.
• is eliminated via gall bladder (75%)
Cefoperason and kidney (25%).

• is absorped orally,
Cefixim • half live: 4 hours.
3rd Generation Cephalosporin
Common characters
Much more active on gram-negative bacteria

To gram-positive bacteria: third<second<first

Stable to extended β-Lactamase produced by

gram-negative bacteria

Effective on anaerobes and P.aeruginosa

No renal toxicity

Penetrating body fluids and tissues well

 Fourth- generation cephalosporins

Example: Character: Clinical uses:

• Cefpirome, • Enhanced • infections
cefepime, antimicrobial caused by
cefclidin activity organisms that
• Stable to ESBLs are resistant to
(extended third-
spectrum beta generation
lactamase) cephalosporins
• More activity
on gram-
positive cocci
 Side effect of cephalosporins

• Allergic effect
• Gastrointestinal reactions
• Renal toxicity
• Other : bleeding
Other β-Lactam drugs
 Cephamycins
Cefoxitin
Similar to second-generation
cephalosporins
More activity on anaerobes

β-Lactamase resistant

High concentration in CSF

Treatment of mixed anaerobic and aerobic
infections
 Carbapenems

• The most important antimicrobial agents in

1990’s

• Wide spectrum and high activity

• Resistant to mostβ-Lactamase (including

ESBLs and cephalosporinase)
 Carbapenems
Thienamycin

Imipenem

Carbapenems Imipenem-cilastatin:tienam

Meropenem

Panipenem
β-Lactamase inhibitors

• Clavulanic acid
• Sulbactam
• tazobactam
 β-Lactamase inhibitors

• Weak antimicrobial action

• Protect β-lactams from inactivation by
β-lactamase
• Synergism
• Compound preparation
 Monobactams
Aztreonam, carumonam

No effect on Gram (+) bacteria and anaerobes

High activity on gram-negative bacteria

No cross-allergic reaction with penicillin

Penicillin-allergic patients tolerate well

Low toxIcity
 VANCOMYCIN

Bacterial cell wall synthesis inhibitor.

Is not absorbed in GI tract, i.m, painfull.

Reaching various body fluid: gall bladder,

pleura, pericard, peritoneum, and synovial
fluid; penetrate inflammed meninges.

Dose adjustment is required in patient with

renal disfunction.
TEICOPLANIN & BACITRACIN

Teicoplanin: i.m / per oral,

Very long half live, 50-100 hrs

Reaching various body fluid,

To attain steady state: bigger initial dose.

Bacitracin can not be given parenterally, very toxic,

only available topically.
 Vancomycin & Teicoplanin

• Severe infection esp staphylococcus

• For MRSA

 Vancomycin: pneumonia, endocarditis, emphysema, osteomyelitis,

surgical site infection
 Oral: particularly enterocolitis pseudomembranose due to C. difficile
 Adverse Events
Vancomycin

Erythema, Nephrotoxic if given

Painfull at
Ototoxic hipotension, concurrently with
injection site aminoglycoside
chest pain

Nephrotoxic if reaching systemic

Bacitracin
circulation
ANTIBIOTICS WHICH INHIBIT BACTERIAL PROTEIN SYNTHESIS

Chloramphenicol

Tetracycline

Erythromycin

Streptomycin
 MACROLIDE

• Inhibit bacterial protein synthesis

• Bound to 50S ribosome sub unit, preventing prolongation

of peptide chain

• Bacteriostatic or bactericidal (higher concentration)

• Antibacterial effect increased in neutral pH or alkaline

 Erythromycin
from Streptomyces erythreus

Esp. active against mycoplasma, chlamydia and treponema

DOC for C diphteriae, M. pneumoniae, E. hystolitica & Chlamydia

Available as estolat, stearat, etilsuccinate, base

Eliminated via hepatic metabolism

CSF concent in inflammed meninges: 25% blood concent

Children: estolate is better absorbed

Adult: estolate is not recommended (causing cholestatic hepatitis)

Oral dose: 4 x 250-500 mg per day

Child dose: 30-50 mg/kgBW/day divided into 4 dose

 AZITHROMYCIN
Compared to erythromcin: more stable in acid environment

37% dose are absorbed, affected by food, t-max: 2 hours

Low serum concent, high tissue concent

Reaching therapeutic level in lung, genital, liver

High concent in phagocytes, macrophage and fibroblast cells

Streptococcal pharyngitis/tonsilitis
Indication

Acute exacerbation of Chronic Bronchitis

Pneumonia due to S. pneumoniae/H. influenzae
Uncomplicated skin infection due to S. aureus, S. pyogenes
Urethritis & cervicitis due to C. trachomatis
Antimicrobic inhibition of protein synthesis
Tetracycline
H3C
N CH3
H3C OH
OH

OH C ONH2
OH O OH O
TETRACYCLINE
Inhibits bacterial protein synthesis

Bound to 30S ribosome sub unit,

preventing the formation of peptide
chain
Between 2 meals

+ milk, antacide, metal will form chelating agent

Widely distributed

CSF concent: 10% serum

In bone and teeth could bind calcium

Children < 8 yrs, discolorisation of teeth,

enamel hypoplasia
 TETRACYCLINE

• From streptomyces species.

• Good absorption in GI tract.
• Esp bacteriostatic,
• efektive for Gram (+) aerob coccen, riketsia, chlamydia, and treponema.

Short acting Intermediate acting Long acting

Oxytetracycline Doxyciclin
Tetracycline Demeclosilin Minosiklin
 TETRACYCLINE

Short acting Intermediate acting Long acting

A b s o r p s i on

Oxytetracycline 58% Demeclocylin 66% Doxicyclin 93%

Tetracycline 77% Minocyclin 95%

Half lives

Oxytetracycline 9 hrs Demeclocilin 12 hrs Doxicyclin 18 hrs

Tetracycline 8 hrs Minocyclin 16 hrs
 Tetracycline

• Infection esp due to M. pneumoniae

• Acute exacerbation of chronic bronkitis
• Acute diarrhoea due to shigella, Vibrio cholerae
• Acne (low dose 250-500mg), inhibits proliferation of Corynebacterium acnes

Adverse events
 Nausea, vomites
 Stomatitis
 Depressed bone growth
 Teeth discoloritation esp during formation of permanent teeth
 1st Trimester pregnancy should be discouraged
 Chloramphenicol
• blocks 50S ribosome, preventing peptide bond
formation.
 CHLORAMPHENICOL

Streptomyces species

Broad spectrum

Induce bone marrow aplasia

Difusion to bacterial cell, bound to 50S ribosome sub unit,

preventing formation of peptide chain

Bacteriostatic • S. aureus & enterobacteriaceae

Bactericidal • H. influenzae, S. pneumoniae, N. meningitidis

 CHLORAMPHENICOL

• Good absorption
• iv 25-50mg/kgBW, serum concent < oral
• Distribution: CSF, CNS
• Metabolism: conjugated by glucoronic acid

• DOC typhoid (S. typhi)

• Dose: 2-3g atau 30-50mg/kgBW/day (divided in 4 doses), 2-3 weeks to prevent
relapse
• Meningitis: H influenzae (second line)
• Eye infection
 CHLORAMPHENICOL

Contraindication:
• leukopenia, trombositopenia, severe
anemia
• Pregnancy
• Prematurity/ < 2 weeks
Adverse event:
Bone marrow suppression
Grey baby syndrome
 AMINOGLYCOSIDE

MECHANISM OF ACTION

• Bound to 30S subunit ribosome: preventing formation of

peptide chain

PHARMACOKINETICS

• Poor absorption in GI tract.

• Only available parenterally (except neomisin)
• Low concent in tissue and CSF
• Narrow therapeutic margin
• Highest concent: renal cortex, endolymphe and
perilymphe of middle ear
 AMINOGLYCOSIDE

ADVERSE EVENTS

• Ototoxic (t1/2: 5-6times higher than plasma:

vestibular damaged
• Gentamycin, streptomycin: vestibular
• Amikacin, kanamicin, neomicin: auditory function
• Nephrotoxic (8-26% renal function impairment,
reversible.
• Neomisin: topical only
AMINOGLYCOSIDE
Nephrotoxicity of
aminoglycoside
Ototoxicity of aminoglycoside
Gentamycin

Ps. Aeruginosa, E.coli, Proteus, Staphylococcus

+ penicillin for septicaemia due to Gram (-)

Good concent in cornea and humor aqueous:

topical

Increase nephrotoxicity if given concurrently with

cephalosporin or diuretics

Inactivated if given concurrently with carbenicilin,

penicillin, cefalexin
METRONIDAZOL

• Bactericidal for T. vaginalis, G. lamblia, E.

hystolitica
• Active against anaerobic bacteria: Bacteroides sp,
Clostridium

PHARMACOKINETICS

• Well absorbed in GI tract

• Distributed to all body fluid, pleura, vagina, CSF,
breast milk
• Is metabolised in liver, excreted via kidney
 CLINICAL USE OF METRONIDAZOLE

Trichomoniasis Amoebiasis Giardiasis

2 gr. Single dose OR 3x250 mg, 5 days 3x250 mg, 5 days

3x250 mg, 7 days Child: 3x5mg/kgBB
+ partner

ADVERSE EFFECT

• Alcohol intolerance: nausea, vomit,

• Gastrointestinal symptom: nausea, vomits
• Peripheral Neuropathy with high dose administration
SULFA AND
TRIMETOPHRIM
 TRIMETOPRIM

• Antibacterial spectrum = sulfametoksazol

• 20-50 more poten than sulfonamid
• High concentration: prostate and vaginal fluid
• For the treatment of UTI & prostatitis
Adverse event

• megaloblastic anemia, leukopenia,

granulocytopenia
 COTRIMOKSAZOL
(trimetoprim + sulfametoksazol

Greater antibacterial effect

Expand antibacterial spectrum
1 trimetoprim + 20 sulfametoksazol
Indication: UTI

Adverse event:

• Erythema, nausea, vomit

• megaloblastic anemia, leukopenia, trombositopenia
• Haemolytic anemia in patient with G-6PD deficiency
 Fluoroquinolones
Novel group of synthetic antibiotics developed in
response to growing resistance

Agents available today are all structural derivatives of

nalidixic acid

The fluorinated quinolones (FQs) represent a major

therapeutic advance:
• Broad spectrum of activity
• Improved PK properties – excellent bioavailability, tissue
penetration, prolonged half-lives
• Overall safety

Disadvantages: resistance, expense

 Fluoroquinolones
Mechanism of Action

Unique mechanism of action

Inhibit bacterial topoisomerases which are necessary for

DNA synthesis
• DNA gyrase – removes excess positive supercoiling in the DNA helix
• Primary target in gram-negative bacteria
• Topoisomerase IV – essential for separation of interlinked daughter DNA
molecules
• Primary target for many gram-positive bacteria

FQs display concentration-dependent bactericidal activity

 Fluoroquinolones

• Mechanisms of Resistance
 Alteredtarget sites – chromosomal
mutations in genes that code for DNA
gyrase or topoisomerase IV
 most important and most common
 Altered cell wall permeability –
decreased porin expression
 Expression of active efflux – transfers FQs
out of cell
 Cross-resistance occurs between FQs
 The Available FQs

1. Norfloxacin (Noroxin®) - PO
Older FQs 2. Ciprofloxacin (Cipro®) – PO, IV

1. Levofloxacin (Levaquin®) – PO, IV

2. Gatifloxacin (Tequin®) – PO, IV
Newer FQs 3. Moxifloxacin (Avelox®) – PO, IV
 FQs Spectrum of Activity

Gram-positive – older agents with poor

activity; newer FQs with enhanced
potency
• Methicillin-susceptible Staphylococcus aureus
• Streptococcus pneumoniae (including PRSP)
• Group and viridans streptococci – limited activity
• Enterococcus sp. – limited activity
 FQs Spectrum of Activity

Gram-Negative – all FQs have excellent

activity (cipro=levo>gati>moxi)
• Enterobacteriaceae – including E. coli,
Klebsiella sp, Enterobacter sp, Proteus sp,
Salmonella, Shigella, Serratia marcescens,
etc.
• H. influenzae, M. catarrhalis, Neisseria sp.
• Pseudomonas aeruginosa – significant
resistance has emerged; ciprofloxacin and
levofloxacin with best activity
 FQs Spectrum of Activity
Anaerobes
• only trovafloxacin has adequate activity against Bacteroides sp.

Atypical Bacteria

• all FQs have excellent activity against atypical bacteria including:

• Legionella pneumophila - DOC
• Chlamydia sp.
• Mycoplasma sp.
• Ureaplasma urealyticum

Other Bacteria –
• Mycobacterium tuberculosis, Bacillus anthracis
 Fluoroquinolones
Pharmacology
Remark
• Concentration-dependent bacterial killing – AUC/MIC (AUIC) correlates
with efficacy
Absorption
• Most FQs have good bioavailability after oral administration
• Cmax within 1 to 2 hours; coadministration with food delays the peak
concentration

Distribution
• Extensive tissue distribution – prostate; liver; lung; skin/soft tissue and
bone; urinary tract
• Minimal CSF penetration

Elimination – renal and hepatic;

• not removed by HD
 Fluoroquinolones
Adverse Effects
Gastrointestinal – 5
Nausea, vomiting, diarrhea, dyspepsia
%
Headache, agitation, insomnia, dizziness,
Central Nervous System
rarely, hallucinations and seizures (elderly)
LFT elevation (led to withdrawal of
Hepatotoxicity
trovafloxacin)
Phototoxicity
More common with older FQs (halogen at
(uncommon with
current FQs) position 8)

Variable prolongation in QTc interval

Cardiac
Led to withdrawal of grepafloxacin,
sparfloxacin
 Fluoroquinolones
Adverse Effects

Articular Damage

• Arthopathy including articular cartilage damage, arthralgias,

and joint swelling
• Observed in toxicology studies in immature dogs
• Led to contraindication in pediatric patients and pregnant
or breastfeeding women
• Risk versus benefit
Other adverse reactions: tendon rupture, dysglycemias,
hypersensitivity
 Fluoroquinolones
Drug Interactions

• Divalent and trivalent cations – ALL FQs

 Zinc,Iron, Calcium, Aluminum, Magnesium
 Antacids, Sucralfate, ddI, enteral feedings
 Impair oral absorption of orally-administered
FQs – may lead to CLINICAL FAILURE
 Administer doses 2 to 4 hours apart; FQ first
• Theophylline and Cyclosporine - cipro
 inhibition of metabolism,  levels,  toxicity
• Warfarin – idiosyncratic, all FQs