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2

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Monobactams

All of the drugs in this group contain

a β-lactam ring in their structure

Penicillins

NO

S

Carbapenems

NO

NO

NO

S

Cephalosporins

share similar• features of chemistry,• mechanism of action, • pharmacologic and clinical effects.

Same Mechanism of Action : Inhibit cell wall synthesis

Bactericidal (except against Enterococcussp.); time-dependent killers

Short elimination half-life Primarily renally eliminated Cross-allergenicity - except aztreonam

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All penicillin derivatives produce their bacteriocidal effects by inhibition of bacterial cell wall synthesis. Specifically, the cross linking of peptides on the mucopolysaccharide chains is prevented. If cell walls are improperly made cell walls allow water to flow into the cell causing it to burst.

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It is the last step in peptidoglycan synthesis that is inhibited by the beta-lactam antibiotics.

Penicillin binds at the active site of the transpeptidase enzyme that cross-links the peptidoglycan strands.

It does this by mimicking the D-alanyl-D-alanine residues that would normally bind to this site.

Penicillin irreversibly inhibits the enzyme transpeptidase by reacting with a serine residue in the transpeptidase.

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Binding to PBPs results in:› Inhibition of transpeptidase:

transpeptidase catalyzes the cross-linking of the pentaglycine bridge with the fourth residue (D-Ala) of the pentapeptide. The fifth reside (also D-Ala) is released during this reaction. Spheroblasts are formed.

› Structural irregularities: binding to PBPs may result in abnormal elongation, abnormal shape, cell wall defects.

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Figure 45-2. The transpeptidase reaction in Staphylococcus aureus that is inhibited by penicillins and cephalosporins.

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Production of β-lactamase enzymes

Trapping mechanism Modification of target PBPs Impaired penetration of drug to

target PBPs The shortage of antolytic

enzyme The presence of an efflux pump.

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Penicillins› Natural penicillins

PenG, PenVK, Benzathine Pen, Procaine Pen› Aminopenicillins

Ampicillin, Amoxicillin› Anti-Staph penicillins

Oxacillin, Dicloxacillin› Anti-Pseudomonal

[Carboxy] Ticarcillin [Ureido] Piperacillin

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Natural Penicillins Penicillin G Penicillin VK Semisynthetic penicillins:

Acid-stable penicillins

(Penicillin V); Penicillinase-Resistant Penicillins

(Nafcillin, Oxacillin, Methicillin)

Extended-spectrum penicillins

(Ampicillin and Amoxycillin); Antipseudomonal

(Carbenicillin, Ticarcillin)

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Natural Penicillins: extracted from the cultural solution of penicillia. › Prototype is penicillin G› Is pH sensitive. Therefore not given orally.› Effective against Gram-positive cells› Susceptible to penicillinase

Semisynthetic Penicillins: Have broader spectrum. Are effective against

Gram-negative cells, too. Are not resistant to penicillinases

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Gram-positive Gram-negativepen-susc S. aureus Neisseria sp.pen-susc S. pneumoniaeGroup streptococci Anaerobesviridans streptococci Above the

diaphragmEnterococcus Clostridium sp.

Other :Treponema pallidum (syphilis)

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Pharmacokinetics It is relatively unstable in acid, thus the

bioavailability is low. There is poor penetration into the

cerebrospinal (CSF), unless inflammation is present.

Active renal tubular secretion results in a short half-life.

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Oral Administration of Penicillin G. About one-third of an orally administered dose of penicillin G is absorbed from the intestinal tract under favorable conditions.

Gastric juice at pH 2 rapidly destroys the antibiotic. The decrease in gastric acid production with aging accounts for better absorption of penicillin G from the gastrointestinal tract of older individuals

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After intramuscular injection, peak concentrations in plasma are reached within 15 to 30 minutes. This value declines rapidly, since the half-life of penicillin G is 30 minutes.

Repository preparations of penicillin G are employed. The two such compounds currently favored are penicillin G procaine penicillin G benzathine. Such agents release penicillin G slowly from the area in which they are injected and produce relatively low but persistent concentrations of antibiotic in the blood.

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Long acting (every 12 h ) . Acid unstable Penicillinase sensitive Used to prevent subacute bacterial

endocarditis due to dental extraction or tonsillectomy in patients with congenital or acquired valve disease .

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Long acting (every 3-4 weeks ) Acid unstable Penicillinase sensitive Treatment of β-hemolytic streptococcal

pharyngitis. Used as prophylaxis against reinfection

with β- hemolytic streptococci so prevent rheumatic fever .

Once a week for 1-3 weeks for treatment of syphilis (2.4 million units I.M.)

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Therapeutic uses It is the drug of first choice for treating

the infections of the above mentioned pathogens.

The simultaneous administration of the relevant antitoxin is often necessary for the treatment of diphtheria and tetanus.

The combination of an aminoglycoside is also necessary for bactericidal effects in enterococcal endocarditis.

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Penicillin G, Penicillin V

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Pneumococcal Infections› Pneumococcal Meningitis› Pneumococcal Pneumonia

Streptococcal Infections› Streptococcal Pharyngitis (including Scarlet Fever)› Streptococcal Pneumonia, Arthritis, Meningitis, and Endocarditis

Staphylococcal Infections Meningococcal Infections Gonococcal Infections Syphilis Actinomycosis Diphtheria Anthrax Clostridial Infections Fusospirochetal Infections Rat-Bite Fever Listeria Infections Lyme Disease Erysipeloid Surgical Procedures in Patients with Valvular Heart Disease

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Available PO, IM, IV (dosed in units) Drug of Choice (DoC) [2-4 MU IV q4h]

› T. pallidum, N. meningitidis, Group A Strep, and Actinomycosis

Long-acting forms› Procaine PenG (12 hrs)› Benzathine Pen (5 days) [2.4 MU IM for syphilis]

Adverse Reactions – other than skin rash› Penicillin “serum sickness”/drug fever› Jarisch-Herxheimer reaction (1° and 2° syphilis)› Hemolytic anemia, pancytopenia, neutropenia

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The oral form of Penicillins,

Indicated only in minor infections because of their relatively poor bioavailability, weaker antimicrobial activity, the need for dosing many times

Narrow antimicrobial spectrum.

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Hypersensitivity – 5 to 20 % skin rashes, fever, eosinophilia,

angioedema, serum sickness, and anaphylactic shock.

Cross-reactivity exists among all penicillins and even other -lactams

The most serious hypersensitivity reaction is anaphylactic shock. (very rare, the ratio is about 0.5 to 1 of 10000 patients )

As soon as anaphylactic shock occurs, instantly inject adrenaline to deliver trachea edema and spasm.

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Ask allergic history carefully . Must make skin test . The injection of these drugs is made up

before it is injected. As a number of these drugs are

replaced, the skin test must be done again.

After every injection, all of patients must be observed, and the drugs for an emergency treatment are prepared at any time

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How to prevent the occurrence of anaphylactic shock?

Other adverse effects: Gastrointestinal upset, ( orally

administered preparations) Nephrotoxicity, is very rare. Superinfections.

results from alterations in intestinal flora. A higher incidence occurs with broad-spectrum penicillins.

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Penicillins : Adverse effects

Developed to overcome the penicillinase enzyme of S. aureus which inactivated natural penicillins

Gram-positive methicillin-susceptible S. aureus

Group streptococciviridans streptococci

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Methicillin

Nafcillin

Oxacillin

Dicloxacillin

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① Methicillin and isoxazolyl penicillins (e.g. oxacillin, cloxacillin and dicloxacillin)

② They are the drugs of first choice for treating infections of the penicillase-productive aurococcus. But penicillin-susceptible strains of streptococci and pneumococci are also susceptible

③ Enterococci and methicillin-resistant strains of staphylococci are resistant to these penicillins

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IV DoC – MSSA, MSSE [2g IV q4h]

› Actually less active against Pen susceptible isolates than Pen

› More active than Vanc vs. MSSA Significant hepatic metabolism

› No need to dose adjust for renal impairment ADRs

› Hepatotoxicity (cholestatic hepatitis)› Neutropenia› Kernicterus in neonates

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Oral NOT equivalent to IV Ox

(therapeutically)› Poor oral absorption› ~50% (better on empty stomach)

Dose: 250-500mg po QID

Developed to increase activity against gram-negative aerobes

Gram-positive Gram-negative pen-susc S. aureus Proteus mirabilisGroup streptococci Salmonella, Shigellaviridans streptococci some E. coliEnterococcus sp. L- H. influenzae Listeria monocytogenes

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Ampicillin and amoxicillin

① They are similar to penicillin G in the activity against gram-positive organisms but are weaker than the latter.

② They are more satisfactory for the treatment of enterococci and streptococcus viridians.

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③ They are similar to chloramphenicol in the activity against gram-negative organisms.

④ They are acid-resistant but are not penicillase-resistant.

⑤ Pseudomonas aeruginosa are fail to respond to these drugs.

⑥ Amox better tolerated PO and better absorbed (Amp must be taken on empty stomach)

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Developed to further increase activity against resistant gram-negative aerobesGram-positive Gram-negative marginal Proteus mirabilis

Salmonella, Shigellasome E. coliL- H. influenzaeEnterobacter sp.Pseudomonas

aeruginosa

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carbenicillin, ticarcillin① Extend the ampicillin spectrum of

activity to P.aeruginosa and enterobacter species. But their activity to G+ cocci is less than that of ampicillin.

② They are not acid-resistant and penicillase-resistant.

③ Ticarcillin is more active than carbenicillin against P.aeruginosa and enterobacter species.

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④ Chiefly used to treat serious infections caused by G- microorganisms, particular P.aeruginosa, indole-positive proteus and enterobacter.

⑤ Generally used in combination with an aminoglycoside for pseudomonal infections.

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Developed to further increase activity against resistant gram-negative aerobesGram-positive Gram-negative viridans strep Proteus mirabilisGroup strep Salmonella, Shigellasome Enterococcus E. coli

L- H. influenzae Anaerobes Enterobacter sp.Fairly good activity Pseudomonas aeruginosa

Serratia marcescenssome Klebsiella sp.

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IV DoC: Pseudomonas Spectrum: most Enterobacteriaceae (E.

coli, Proteus, Klebsiella, Enterbacter, Serratia, Citrobacter, Salmonella and Shigella)

Most active penicillin vs. Pseudomonas Often used in combination with

Aminoglycoside or Cipro/Levofloxacin ADRs

› Bleeding (platelet dysfunction)› Neutropenia/Thrombocytopenia

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clavulanic acid, sulbactam, tazobactam

① Inactivate bacterial beta-lactamases and are used to enhance the antibacterial actions of beta-lactam antibiotics.

② Only have weak antibacterial action.

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③ Inhibitors of many but not all bacterial beta-lactamases and can protect hydrolyzable penicillins from inactivation by the enzymes.

④ Available only in fixed combinations with specific penicillins.

The companion penicillin, not the beta-lactamase inhibitor, determines the antibacterial spectrum of the combination.

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Augmentin (Amox/Clav) PO Spectrum: MSSA and upper respiratory

infections (S. pneumo, H.Inf, M. catarrhalis) and most anaerobes

Clav is responsible for most of the GI side-effects seen with Amox/Clav

Variable ratios of Amox/Clav in liquids/tabs/chew tabs

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