Dr. Hj.

Rika Yuliwulandari, PhD

Department of Pharmacology, Faculty of Medicine, YARSI University
1
Penicillin
Cephalosporin
Monobactam
Carbapenem
2
HOW???
Function: Prevent the
synthesis of the
bacteria cell wall

Peptidoglycan
layer
3

4
Natural Penicillin
Aminopenicillin
Betalactam beta lactamase inhibitor combination
Penicillinase resistant penicillin
Anti pseudomonal
penicillin
First noticed by Ernest Duchene, 1896
Rediscovered by Alexander Fleming
(founder of the name), 1929
Further intensive research and
production
Dr. Howard Florey, 1939
Andrew J. Moyer with mass production
patent, 1948
Natural Penicillin
Source: ??????
Penicillin G, Penicillin VK, Benzathine
Penicillin, Procaine Penicillin
Alexander Fleming
receiving Nobel Prize, 1945
5
General mechanisms of resistant
Inactivation of antibiotic by beta-lactamase (most common)
Staphylococcus aureus, Haemophillus species, E. coli
Pseudomonas aeruginosa, Enterobacter species
Modification of target PBP
Impaired penetration of drug to target PBPs
The presence of an efflux pump
Pharmacokinetics (PK)
Po:
vary among Penicilin depend on acid stability and protein binding
Methicillin: acid labile ---- not for Po
Dicloxacillin, Ampicillin, Amoxicillin: acid-stable, well absorbed,
impaired by food (except Amoxicillin)
Pe:
Absorption is complete and rapid
Preferable by iv than im, due to local pain
6
Widely distributed in body fluids ([within cell] <
[intracellular fluids]) and tissues
Poor penetration into eye, prostate, central nervous
system (CNS)
Excretion:
Mostly: in urine, also sputum, milk
Nafcillin: biliary tr
Oxacillin, Dicloxacillin, Cloxacillin: kidney and biliary
Clinical uses
Most widely effective and extensively used antibiotic
Avoid meal time when taking drugs (except
Amoxicillin)


7
Penicillin V
Potassium salt phenoxymethyl penicillin
Oral: well absorbed
T max: 60 mnt
Indication:
Mild gr + infection in throat, resp tr, soft tissue
Doc. for Gr A Streptococcal pharyngitis
Useful in oral cavity inf. due to anaerobic bacteria
Penicillin G
Not well absorbed po
8
Penicillin G
Major limitation:
Instable in acidic pH
Susceptible to beta-lactamase (Penicillinase)
Inactive against gram - bacilli
Pe: im, iv
DoC: Gram +, -, spirochaeta (ex: T. pallidum, N.
meningitidis, Group A streptococcus and Actinomycosis)
Long acting forms:
Procaine PenG (12 hrs)
Benzathine Pen (5 days)
Clinical use:
Pneumonia, Meningitis, Endocarditis, Syphilis, Pharyngitis


9
Pharmacokinetic (PK):
Sensitive to gastric acid (pH<2)
T1/2: 0.5 hr
Distribution: wide, except CSF (Cerebro Spinal Fluid)
Excression: renal
Inhibited by Probenecid, Fenilbutazon, Sulfinpirazon, Acetozal,
Indometacine to increase blood level
Pharmacodynamics (PD):
Time dependent
10
Increase resistance of staphylococci to natural penicillins
Active againts Streptococcous and Staphylococcus
producing penicillinase
Not active:
Methicillin-resistant S. aureus
Gram negative
Best oral absorption (1 or 2 hrs before meals)
Cloxacillin
Dicloxacillin
Poor absorption
Nafcillin
Oxacillin
Indication: Skin and soft tissue infection
11
First penicillin active against gram negative rods (E. coli and H.
influenzae)
Ampicillin: PO, IV, Amoxicillin: PO
Spectrum almost similar
Amox than Ampi
Absorption is better than ampicillin
Serum 2x serum ampicillin level
Smaller amount remain in intestinal tract
Less diarrhea
Less effective for shigella enteritis
Indication:
Mild infections (Otitis media, sinusitis, bronchitis, uti, bacterial diarrhea)
Less effective in H. influenzae and E. coli
Dental prophylaxis: amox 1 gr po
ADR:
Stomachache: for ampicillin
Allergic reaction to penicillin

12
Adverse Reaction
In general: non toxic
Cross-sensitizing (duration and total dose)
Hypersensitivity: mild to severe allergic reaction:
Serum sickness: Skin rash, urticaria, fever, joint swelling,
angioneurotic edeme, intense pruritus
Oral lessions, interstitial nephritis, eosinophilia,
hemolytic anemia
GI upset (nausea, vomiting, diarrhea)
Anaphylactic shock

13
Oral combination: only amoxicillin-clavulanate
Coverage:
Beta lactamase producing strain (S. aureus, H. influenza, N.
gonorrhoeae, E. coli, M. catarrhalis, Proteus, Klebsiella, Bacteroiddes
spp), anaerobic bact.
Less activity: Psudomonas, methicillin resistant S. aureus
Doc
Otitis media, sinusitis, bronchitis, uti, skin and soft tissue infections
Animal and human bites (anaerobic inf)
SE
GI distress
Diarrhea
Rashes
Candida superinfection
14
Po: Carbenicllin
Absorption: excellent
Metabolism: too rapid, serum level low
Limited clinical usage



15
Class Drug Antimicrobial spectrum
Natural penicillin Penicillin V Streptococcus species and oral cavity
anaerobes
Penicillinase-resistant penicillin Cloxacillin (Tegopen) Methicillin-sensitive Staphylococcus
aureus and Streptococcus species
Dicloxacillin (Dynapen)
Nafcillin (Unipen)*
Oxacillin (Prostaphlin)*
Aminopenicillin Amoxicillin Same coverage as penicillin V, plus
Listeria monocytogenes,
Enterococcus species, Proteus
mirabilis and some strains of
Escherichia coli
Ampicillin
Bacampicillin (Spectrobid)
Beta-lactambeta-lactamase
inhibitor combination
Amoxicillin-clavulanate (Augmentin) Same coverage as aminopenicillins,
plus betalactamaseproducing
strains of methicillin-sensitive S.
aureus, Haemophilus influenzae and
Moraxella (formerly Branhamella)
catarrhalis
Antipseudomonal penicillin Carbenicillin (Geocillin) Limited activity against
Pseudomonas and Klebsiella species
16
Misused and overused antibiotic
Penicillin-resistant organism---90% of
staphylococcal strains are beta-lactamase
producers
Broad spectrum penicillin also eradicate
normal flora ---- superinfection with
opportunistic and drug resistant species
(proteus, pseudomonas, enterobacter,
serratia, staphylococci, yeast, etc)
17

18
Based on spectrum of antimicrobial activity
Similar to Penicillins
gr +, gr -
Broader coverage: Methicillin sensitive S. aures. E. coli, P.
mirabilis, Klebsiella spp
Poor: P. aeruginosa, indole+ proteus, enterococcus spp, Serratia
marcescens, H. influenzae, gr- producing beta lactamase
PK:
Oral: Cephalexin, cephradine, cefadroxil
Absorption in GI tr: good (not influenced by food)
Excretion: Urine (high concentration--- !!! In severe renal failure)
Impaired renal function: reduce dose
Probenecid (tubular blocking agent): increase serum level of drugs
Pe:
The only 1
st
gen. given Pe: cefazolin
Excretion: kidney
Be careful in impaired renal function
19
Clinical use
Skin and soft tissue infection due streptococcus spp and methicillin
sensitive S. aureus
Preferable to penicillinase-resistance penicilline due to lower GI se, better taste
UTI
2
nd
line drug after quinolone and TMP/SMX for UTI by gr organisms
Not active to Pseudomonas, Enterococcus spp
Relative safe for pregnant woman
Pharyngitis with delayed type penicillin allergy
Generally: not effective againts H. influenza, M. catarrhalis, gr beta
lactamase producing bacteria
Cefazolin:
DOC for surgical prophylaxis
For staphylococcal or streptococcal infections with history of mild penicillin
hypersensitivity
Cant cross Blood Brain Barrier (BBB) ----- not effective for meningitis
20
Heterogenous group of drugs
Different in activity, pharmacokinetics, toxicity
Spectrum:
Better spectrum than 1
st
generation
Againts beta-lactamase producing respiratory pathogens: H. influeanza, M. catarrhalis
Plus gr
Clinical usage:
Otitis media, bronchitis, sinusitis --- consider TMP/SMX (cheaper)
Second line of UTI
In general:
Less active againts gr + than 1
st
gen.
Not active againts enterocci or P. aeruginosa (~ 1
st
gen)
Cefamandole, cefuroxime, cefonicid, ceforanide, cefaclor:
Active to: H. influenzae
Not active: Serratia, B. fragilis
Cefoxitin, cefmetazole, cefotetan
Active: B. fragilis
Less active: H. influenzae

21
PK:
Po: Cefaclor, cefuroxime axetil, cefprozil, loracarbef
Pe: Cefotetan, cefonicid, ceforanide, cefprozil
Dosage adjustments in renal failure
Clinical use:
Oral 2
nd
gen:
Active: beta-lactamse-producing H. influeanzae or B. catarrhalis
Sinusitis, otitis, lower respiratory tract infection (LRI)
Cefoxitin, cefotetan, cefmetazole
Peritonitis or diverticulitis (anaerobic infection capacity advantage)
Cefuroxime:
Community-acquired pneumonia (CAP)
Cross BBB but not effective for meningitis

22
Spectrum
Extended gr coverage (except cefoperazone)
Cross BBB
Ceftazidime, cefoperazone: P. aeruginosa
Loss efficacy to Strept. Pneumoniae, Staphylococcus spp
Not active against enterobacter species
Convenient dosing schedule, more expensive
Clinical use
To treat a wide variety of serious infections that are resistant to most
other drugs
Ex: Ceftriaxone and cefixime for gonorrhea resistant to penicillin
Meningitis, sepsis
2
nd
line to otitis media, resp tr inf
Not effective for skin and soft tissue infections


23
Better activity than 3
rd
gen.
More resistant to hydrolysis by chromosomal
beta-lactamase (ex. Produced by enterobacter)
Active: P. aeruginosa, enterobacteriaceae, S.
aureus, S. pneumonia, haemophillus,
neisseria
Excression: kidneys
Clinical role almost similar to 3
rd
gen. but
more active against most penicillin-resistant
strains of streptococci
24
Allergy
Variety of hypersitivity:
Anaphylaxis, fever, skin rashes, nephritis, granulocytopenia, hemolytic anemia
Cross allergenicity between cephalosporin-penicillin is around 5-10%
Be careful with history of anaphylaxis to penicillin
Toxicity
Local irritation with possible severe pain after i.m. injection
Thrombophlebitis after i.v. injection
Renal toxicity (interstitial nephritis, tubular necrosis) ---- withdrawal of
cephalosporin
Cefamandole, moxalactam, cefmetazole, cefotetan, cefoperazone:
hypoprothrombinemia and bleeding disorders
Superinfection
2
nd
and 3
rd
gen are ineffective against methicillin-resistant
staphylococci and enterococci --------- possible superinfection during
treatment

25
What is the likely organism?
What is the major mode of resistance
Where is the infection
What is the local (ex. Hospital) environment?
What does the microbiology lab say?
How much does it cost?
Comorbid condition in the patient
Risk of side effect?
Availability of drug
Insurance support
26
Class Drug Antimicrobial spectrum
First-generation cephalosporin Cefadroxil (Duricef) Improved coverage of methicillin-sensitive
S. aureus, E. coli, P. mirabilis and Klebsiella
species
Cephalexin (Keflex)
Cephradine (Velosef)
Second-generation cephalosporin Cefaclor (Ceclor, Ceclor CD) Compared with first-generation agents,
better coverage of beta-lactamase
producing organisms such as methicillin-
sensitive S. aureus, H. influenzae, M.
catarrhalis, E. coli, P. mirabilis and Klebsiella
species
Cefprozil (Cefzil)
Cefuroxime axetil (Ceftin)
Carbacephem Loracarbef (Lorabid) Same coverage as second-generation
cephalosporins
Third-generation cephalosporin Cefdinir (Omnicef) Variable loss of Staphylococcus and
Pneumococcus coverage; compared with
second-generation cephalosporins,
somewhat expanded coverage of gram-
negative organisms; enhanced coverage of
Proteus vulgaris and Providencia species
Cefixime (Suprax)
Cefpodoxime (Vantin)
Ceftibuten (Cedax)
Fourth generation cephalosporin Cefepime
Cefpirone
More resistance to Enterobacter spp,
Pseudomonas
More active against penicillin-resistant
streptococci
27
Infection Preferred drug(s) Alternative drug(s)
Otitis media Amoxicillin Amoxicillin-clavulanate (Augmentin), trimethoprim-
sulfamethoxazole (Bactrim, Septra), second-generation
cephalosporins, some third-generation cephalosporins,
macrolide antibiotics
Streptococcal pharyngitis Penicillin V In patients with penicillin allergy: macrolide antibiotics,
first-generation cephalosporins
Sinusitis Amoxicillin, trimethoprim-sulfamethoxazole Amoxicillin-clavulanate, second-generation
cephalosporins, third-generation cephalosporins
Animal and human bites Amoxicillin-clavulanate Depends on type of bite (e.g., cefuroxime axetil [Ceftin]
or doxycycline [Vibramycin] for cat bites)
Bacterial endocarditis prophylaxis Amoxicillin In patients with penicillin allergy: clindamycin (Cleocin),
cephalexin (Keflex), azithromycin (Zithromax),
clarithromycin (Biaxin)
Pneumonia Macrolide antibiotics, quinolone antibiotics Amoxicillin-clavulanate, second-generation
cephalosporins, third-generation cephalosporins
Bronchitis (controversial) Doxycycline, trimethoprim-sulfamethoxazole,
amoxicillin-clavulanate
Macrolide antibiotics, quinolone antibiotics, second-
generation cephalosporins, some third-generation
cephalosporins
Skin and soft tissue infections (cellulitis) First-generation cephalosporins, cloxacillin (Tegopen),
dicloxacillin (Dynapen)
Macrolide antibiotics, amoxicillin-clavulanate,
cefpodoxime (Vantin), cefdinir (Omnicef)
Urinary tract infection Quinolone antibiotics, trimethoprim-sulfamethoxazole Amoxicillin, amoxicillin-clavulanate, cefuroxime axetil or
other cephalosporins, doxycycline, nitrofurantoin
(Furadantin)
28
Factors Cephalosporins Penicillin V*
Allergic reactions Fewer immediate and delayed
hypersensitivity reactions; must be
avoided in patients with a history of
immediate hypersensitivity to
penicillin
Allergic reactions common
Patient tolerance Better taste, which increases
compliance in children; fewer
gastrointestinal side effects
More gastrointestinal side effects
Cost More expensive Less expensive
Antimicrobial
spectrum
Broader antibacterial spectrum Narrower antibacterial spectrum;
less likely to induce antimicrobial
resistance; some penicillins cover
anaerobes, Listeria, Enterococcus
or Pseudomonas species
29
Monobactams
Aztreonam
Relatively resistant to beta-lactamases
Active: gram-negative rods (pseudomonas, serratia)
Not active: gr + or anaerobes
Good for penicillin-allergic patients
Adv. Rx
Skin rashes
Elevation of serum aminotransferases
Beta-lactamase inhibitors
Calvulanic acid, Sulbactam, Tazobactam
Active: class A beta-lactamases (staphylococci, H. influenzae, N. gonorroeae,
salmonella, shigella, E. coli, K. pneumoniae)
Not good: class C beta-lactamases (enterobacter, citrobacter, serratia,
pseudomonas)
Available in fixed combination with specific penicillins
Ampicillin-Sulbactam: beta-lactamase producing S. aureus, H. influenzae (except,
Serratia)
30
Carbapenems
For infections by organisms resistant to other drugs
Imipenem:
Wide spectrum: gr rods, gr +, anaerobes
Inactivated by dehydropeptidases in renal tubules
Administered together with cilastatin (inhibitor of renal
dehydropeptidase)
Adverse effect:
Nausea, vomiting, diarrhea, skin rashes, reaction at infusion sites, seizures
Meropenem
More active against gr , but less active against gr+
Not degraded by renal dehydropeptidases
Adverse effect: less effect of seizures

31
Vancomycin
Produced by Streptococcus orientalis
Active only against gr + bacteria (esp. staphylococci)
Mechanism:
Inhibit transgycosylase, prevent elongation of peptidoglycan and weakend the cell wall ---
lysis of cell
Active against gr +
PK:
Poorly absorbed from GI tr.
PO: only for enterocolitis by Clostridium difficile, Pe (iv.) for severe infection
Widely distributed in the body, CSS
Excreted mainly by glomerular filtration
Indication:
Pe: sepsis, endocarditis caused by methicillin-resistant staphylococci
Vancomycin+Gentamycin: enterococcal endocarditis with penicillin allergy
Vancomycin+cefotaxim/ceftriaxon/rifampin: meningitis by penicillin resistant strain of
pneumococcus
Adverse reaction:
Minor reaction: phlebitis, chills, fever
Administration with aminoglycoside: ototoxicity and nephrotoxicity
Red man or red neck syndrome


32
Teicoplanin
Very similar to vancomycin in mechanism of action and spectrum
Can be given im. Or iv.
Fosfomycin
Active: gr + and gr
Available oral and pe.
Excretion via kidney
For treatment of uncomplicated lower urinary tract infection in
women
Bacitracin
Active: gr +
No cross-resistance between bacitracin-other antimicrobial drugs
Nephrotoxic
Only for topical use
Bacitracin+plymixin/neomycin: surface lessions of skin, wounds,
mucous membranes
33
Cycloserine
Produced by Streptomyces orchidaceus
Inhibit gr+ and gr-
For tuberculosis by M. tuberculosis resistant to
first line drugs
Adverse reaction:
Dose-related central nervous system toxicity
(headaches, tremors, acute psychosis, convulsions)
34
Active:
Many gram-positive
Gram-negative
Anaerobic organisms
Treatment guidelines:
Antimicrobial susceptibility testing for common
infections
Less evidence-based literature is available to
guide treatment decisions.
35
Amoxicillin as first-line antibiotic therapy for acute otitis media
Alternative drugs for resistant infections :
Amoxicillin-clavulanate
Trimethoprim-sulfamethoxazole
Cefuroxime axetil
Penicillin V remains the drug of choice for the treatment of pharyngitis
caused by group A streptococci.
Amoxicillin or trimethoprim-sulfamethoxazole are first-line therapy for
sinusitis.
Animal and human bites can be treated most effectively with amoxicillin-
clavulanate.
For most outpatient procedures, amoxicillin is the preferred agent for
bacterial endocarditis prophylaxis.
Beta-lactam antibiotics are usually not the first choice for empiric
outpatient treatment of community-acquired pneumonia.
Role of beta-lactam antibiotics in the treatment of bronchitis, skin
infections and urinary tract infections remains unclear.
36

37

38

39

40

41

42

43
Farmakologi dan Terapi (FKUI, 2007)
Basic and Clinical Pharmacology (The
McGraw-Hill, 2001)
James CW, Gurk-Turner. Cross-reactivity of
beta-lactam antibiotics. BUMC Proceedings
2001; 14:106-107
Goodman & Gilmans. The Pharmacological
Basis of Therapeutics

44

45