The Beta-Lactam (BLA)

Antibiotics

Dr. Hj. Rika Yuliwulandari, M.Hlt.Sc., PhD

Department of Pharmacology, Faculty of Medicine, YARSI University
1

Structure

Penicillin

Monobactam

Cephalosporin

Carbapenem
2

How do BLA work

HOW???
Function:

Peptidoglycan
layer

Prevent
the synthesis of
the bacteria cell
wall

Classification
Natural Penicillin

Aminopenicillin
Penicillinase resistant penicillin

Anti
pseudomonal
penicillin

Betalactam beta lactamase inhibitor

combination

History
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

Alexander Fleming
receiving Nobel Prize,
1945

Penicillin, Procaine Penicillin

General features
General

mechanisms of resistancy

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

General features (2)

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)
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Natural Penicillin
Penicillin

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

Not well absorbed po

8

 Penicillin

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

Penicillinase-Resistant
Penicillins
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

Aminopenicillins
Ampicillin/Amoxicillin
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

Beta lactam beta lactamase

inhibitor combination
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

Antipseudomonal
penicillin
Po:

Carbenicllin
Absorption: excellent
Metabolism: too rapid, serum level
low
Limited clinical usage

15

Oral Penicillin
comparison
Class

Drug

Natural penicillin

Penicillin V

Penicillinase-resistant
penicillin

Cloxacillin (Tegopen)
Dicloxacillin (Dynapen)
Nafcillin (Unipen)*
Oxacillin (Prostaphlin)*
Amoxicillin
Ampicillin
Bacampicillin (Spectrobid)

Aminopenicillin

Beta-lactambetalactamase inhibitor
combination

Amoxicillin-clavulanate
(Augmentin)

Antipseudomonal penicillinCarbenicillin (Geocillin)

Antimicrobial
spectrum
Streptococcus species and
oral cavity anaerobes
Methicillin-sensitive
Staphylococcus aureus and
Streptococcus species
Same coverage as penicillin V,
plus Listeria monocytogenes,
Enterococcus species, Proteus
mirabilis and some strains of
Escherichia coli
Same coverage as
aminopenicillins, plus
betalactamaseproducing
strains of methicillin-sensitive
S. aureus, Haemophilus
influenzae and Moraxella
(formerly Branhamella)
catarrhalis
Limited activity against
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Pseudomonas and Klebsiella

Problems of Penicillins
Misused

and overused antibiotic

Penicillin-resistant organism---90% of
staphylococcal strains are betalactamase producers
Broad spectrum penicillin also
eradicate normal flora ---superinfection with opportunistic and
drug resistant species (proteus,
pseudomonas, enterobacter,
serratia, staphylococci, yeast, etc)

17

Cephalosporin
Based on spectrum of antimicrobial
activity

18

Cephalosporin: 1
generation
Similar

st

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 1st gen. given Pe: cefazolin
Excretion: kidney
Be careful in impaired renal function

19

1st generation (2)

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
2nd 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

2nd generation
Heterogenous

group of drugs

Different in activity, pharmacokinetics, toxicity

Spectrum:
Better spectrum than 1st 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 1st 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
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2nd generation (2)

PK:
Po: Cefaclor, cefuroxime axetil, cefprozil, loracarbef
Pe: Cefotetan, cefonicid, ceforanide, cefprozil
Dosage adjustments in renal failure

Clinical

use:

Oral 2nd 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

3rd generation
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
2nd line to otitis media, resp tr inf
Not effective for skin and soft tissue infections
23

4th generation
Better

activity than 3rd 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 penicillinresistant strains of streptococci
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Adverse Effects
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
2nd and 3rd gen are ineffective against methicillin-resistant

staphylococci and enterococci --------- possible superinfection during

treatment
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How to choose?
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
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Comparison
Class

Drug

Antimicrobial spectrum

First-generation cephalosporin Cefadroxil (Duricef)

Cephalexin (Keflex)
Cephradine (Velosef)

Improved coverage of methicillinsensitive S. aureus, E. coli, P.

mirabilis and Klebsiella species

Second-generation
cephalosporin

Cefaclor (Ceclor, Ceclor CD)

Compared with first-generation

agents, better coverage of betalactamaseproducing organisms

Cefprozil (Cefzil)

such as methicillin-sensitive S.
aureus, H. influenzae,

Cefuroxime axetil (Ceftin)

M. catarrhalis, E. coli, P. mirabilis

and Klebsiella species

Loracarbef (Lorabid)

Same coverage as secondgeneration cephalosporins

Carbacephem

Third-generation cephalosporin Cefdinir (Omnicef)

Cefixime (Suprax)
Cefpodoxime (Vantin)
Ceftibuten (Cedax)

Variable loss of Staphylococcus and

Pneumococcus coverage;
compared with second-generation
cephalosporins, somewhat
expanded coverage of gramnegative organisms; enhanced
coverage of Proteus vulgaris and
Providencia species

Fourth generation cephalosporin

More resistance to Enterobacter spp,

Pseudomonas

Cefepime
Cefpirone

More active against penicillin-resistant

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streptococci

Clinical indication for oral

beta lactam antibiotic
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 thirdgeneration 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

Amoxicillin, amoxicillin-clavulanate, cefuroxime

axetil or other cephalosporins, doxycycline,
nitrofurantoin (Furadantin)

Quinolone antibiotics, trimethoprimsulfamethoxazole

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Other beta-lactam drugs

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)
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 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
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Other inhibitors of cell wall

synthesis
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

31

 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
32

 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)
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References
Farmakologi

dan Terapi (FKUI, 2007)

Basic and Clinical Pharmacology (The
McGraw-Hill, 2001)
James CW, Gurk-Turner. Crossreactivity of beta-lactam antibiotics.
BUMC Proceedings 2001; 14:106-107

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