betalactam

7/27/2019 Betalactam

http://slidepdf.com/reader/full/betalactam 1/45

Dr. Hj. Rika Yuliwulandari, PhD

Department of Pharmacology, Faculty of Medicine, YARSI University1



Penicillin

Cephalosporin

Monobactam

Carbapenem2



HOW??? Function: Prevent the

synthesis of thebacteria 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 Flemingreceiving 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 pain6



Widely distributed in body fluids ([within cell] <[intracellular fluids]) and tissues

Poor penetration into eye, prostate, central nervoussystem (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, Bacteroiddesspp), 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



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-lactam–

beta-lactamaseinhibitor combination

Amoxicillin-clavulanate (Augmentin) Same coverage as aminopenicillins,plus betalactamase–producing

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-lactamaseproducers Broad spectrum penicillin also eradicate

normal flora ---- superinfection withopportunistic 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, Serratiamarcescens, 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 function19



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 penicillinhypersensitivity

▪ Can’t cross Blood Brain Barrier (BBB) ----- not effective for meningitis

20



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 (~ 1st 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 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



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



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-resistantstrains 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

2nd and 3rd gen are ineffective against methicillin-resistantstaphylococci and enterococci --------- possible superinfection duringtreatment

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

streptococci27



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 topenicillin

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 renaldehydropeptidase)

▪ 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 ofpneumococcus

Adverse reaction:▪ Minor reaction: phlebitis, chills, fever

▪ Administration with aminoglycoside: ototoxicity and nephrotoxicity

▪ Red man or red neck syndrome32



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 pharyngitiscaused 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 Proceedings2001; 14:106-107

Goodman & Gilman’s. The PharmacologicalBasis of Therapeutics

44

betalactam

Documents