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
Peptidoglycan
 HOW??? layer

 Function: Prevent the

synthesis of the
bacteria cell wall

3
Classification
Natural Penicillin

Aminopenicillin

Penicillinase resistant penicillin

Betalactam beta lactamase inhibitor combination

Anti pseudomonal
penicillin

4
 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 Alexander Fleming
 Source: ?????? receiving Nobel Prize, 1945

 Penicillin G, Penicillin VK, Benzathine

Penicillin, Procaine Penicillin

5
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 6
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)
7
Natural Penicillin

 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
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
Natural penicillin
Penicillinase-resistant penicillin
Aminopenicillin
Beta-lactam–beta-lactamase
inhibitor combination
Antipseudomonal penicillin
Drug
Penicillin V
Cloxacillin (Tegopen)
Dicloxacillin (Dynapen)
Nafcillin (Unipen)*
Oxacillin (Prostaphlin)*
Amoxicillin
Ampicillin
Bacampicillin (Spectrobid)
Amoxicillin-clavulanate (Augmentin) Same coverage as aminopenicillins,
Carbenicillin (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
plus betalactamase–producing
strains of methicillin-sensitive S.
aureus, Haemophilus influenzae and
Moraxella (formerly Branhamella)
catarrhalis
Limited activity against
Pseudomonas and Klebsiella species
16
Problems of Penicillins

 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
Cephalosporin
Based on spectrum of antimicrobial activity

18
Cephalosporin: 1st generation
 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 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
▪ Can’t 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
21
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 3rd gen. but more
active against most penicillin-resistant strains
of streptococci
24
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
25
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
26
 Comparison
Class
First-generation cephalosporin
Second-generation cephalosporin
Carbacephem
Third-generation cephalosporin
Fourth generation cephalosporin
Drug
Cefadroxil (Duricef)
Cephalexin (Keflex)
Cephradine (Velosef)
Cefaclor (Ceclor, Ceclor CD)
Cefprozil (Cefzil)
Cefuroxime axetil (Ceftin)
Loracarbef (Lorabid)
Cefdinir (Omnicef)
Cefixime (Suprax)
Cefpodoxime (Vantin)
Ceftibuten (Cedax)
Cefepime
Cefpirone
Antimicrobial spectrum
Improved coverage of methicillin-sensitive
S. aureus, E. coli, P. mirabilis and Klebsiella
species
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
Same coverage as second-generation
cephalosporins
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
More resistance to Enterobacter spp,
Pseudomonas
More active against penicillin-resistant
streptococci
27
 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, Macrolide antibiotics, quinolone antibiotics, second-

amoxicillin-clavulanate generation cephalosporins, some third-generation
cephalosporins

Skin and soft tissue infections (cellulitis) First-generation cephalosporins, cloxacillin (Tegopen), Macrolide antibiotics, amoxicillin-clavulanate,
dicloxacillin (Dynapen) cefpodoxime (Vantin), cefdinir (Omnicef)

Urinary tract infection Quinolone antibiotics, trimethoprim-sulfamethoxazole Amoxicillin, amoxicillin-clavulanate, cefuroxime axetil or
other cephalosporins, doxycycline, nitrofurantoin
(Furadantin)
28
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)
29
 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
30
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)

33
References

 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

34
What do you need?

35