Penicillins Antibiotics Classification PDF

2 45 Ph 1100-116 Penicillins Orabi – AY 2024-2025 ANTIBIOTICS CLASSIFICATION s.by Antibiotics can be classified according to their activities, mode of action or...

2 45 Ph 1100-116 Penicillins Orabi – AY 2024-2025 ANTIBIOTICS CLASSIFICATION s.by Antibiotics can be classified according to their activities, mode of action or chemistry. Based on their structures, they can be classified into: 1. -Lactam antibiotics: all of them have a common functional group; -lactam group. NH O -lactam group For example: a) Penicillins. Ed na Fb) Cephalosporins. l c) Monobactams: Aztreonam (Azactam®) d) Carbapenems: imipenem, meropenem, ertapenem. 2. Aminoglycoside Antibiotics: these have NH2 groups and glycosidic linkages with one exception. For example, streptomycin and related compounds. 3. The tetracyclines: they have this ring system (4 cycles). For example, tetracycline and related compounds. w̅ 4. The macrolide antibiotics: “lide” = lactone. They contain large (macro) ring system. 8 10 6 12 14 O 4 1 O 2 Cyclic ester group = lactone For example: erythromycin, clarithromycin, azithromycin. classification activity 5. Antifungal Antibiotics: including the polyenes agbond(amphotericin B, nystatin), the azoles (imidazoles and triazoles), and the Echinocandins (caspofungin, micafungin). 6. The Quinolone Antibiotics: contain quinolone ring system. There are 1st, 2nd, 3rd, and 4th generations quinolones. 1|Page  Ph 1100-116 Penicillins Orabi – AY 2024-2025 is 7. Miscellaneous Antibiotics: antimycobacterial, griseofulvin, others. 8. Ancillary Antibiotics: those are of a lesser importance and of a limited usage. They include bacitracin, polymyxins, colistin. used loans m ainly Both Gmt S.at eus Pen G Penf yeild same notation chrysogenium Fungus iiT a ou 2|Page Ph 1100-116 Penicillins Orabi – AY 2024-2025 CHAPTER ONE CELL WALL SYNTHESIS INHIBITORS A. The -Lactam Antibiotics: This is by far the largest group of antibiotics and comprises around 60% of all antibiotics (not including the synthetic ones). They contain a -lactam group; lactam = cyclic amide …… O O O O - H2O C NH2 O NH2 HN HN HN OH fee.in Resonance in a -lactam group So, the nitrogen atom is neutral in reactions because its lone pair of electrons is not free anymore but involved in delocalization. Classification of -lactam antibiotics: 1) Penicillins 2) Cephalosporins 3) Monobactam 4) Carbapenems 1) Penicillins: o Penicillins are classified according to their sources. Penicillin G is a natural penicillin, and the prototype of all penicillins. In fact, it is the prototype for all -lactam antibiotics. Penicillins JYI.TO Natural N Semisynthetic (Penicillin II) or G Penicillinase-Resistant A Broad Spectrum Penicillins: Penicllins: Megaspectrum Penicillin V (Ureidopenicillins): Ampicillin, Amoxicillin, Methicillin, Oxacillin, (biosynthetic) Carbenicillin, Ticarcillin Cloxacillin, Dicloxacillin, Piperacillin Flucloxacilln, Nafcillin 3|Page  Ph 1100-116 Penicillins Orabi – AY 2024-2025 a) Natural Penicillins: Penicillin G: IE He In 1928, Alexander Fleming was growing S. aureus in a Petri dish, but was not careful enough, so contamination occurred by a fungus, where no bacterial growth was observed near it, i.e., this fungus produced substances that killed or prevented bacterial colonies from growth. This fungus was identified as Penicillium notatum. Moreover, a compound was isolated from this fungus and called Penicillin F (after Fleming). This penicillin was also called British Penicillin or Penicillin I. H C C O H H 2C C N H H 6 5 1 S 2 CH3 penam ring system veijiactive FÉ N 3 CH3 H3CH2C H O 7 4 COOH 6- amino penicillanic acid suntetic pharmacophore to -lactam m EÉ thiazolidine manuity s T C6 side chain changer Penicillin F - This is very effective against Gr +ve bacteria, e.g., S. aureus and is very safe. - Disadvantages: expensive (because the yield is low). on - In 1939-1945 was used to treat military people (WW II). - The Americans found another species of the genus Penicillium chrysogenum that gave higher yields. Penicillin Pentining O H H H S H 2C C N CH3 N CH3 liquor O steep acid cornphenylacetic COOH Penicillin G derived from phenylacetic acid - This is called Penicillin G or Penicillin II, or benzylpenicillin or American penicillin. - This penicillin is very cheap. Its activity and safety are the same as penicillin F. - In penicillin G production, the used media is corn steep liquor which is rich in phenylacetic acid. However, in the production of penicillin F, they used defined __ 00 (synthetic) media that contain sucrose, vitamin B1, C6 fatty acid. So, the produced penicillin depends on the composition of the media, i.e., if P. notatum is grown on corn steep liquor, it will give penicillin G. - Penicillin G is the only natural penicillin in use. 4|Page  m nature  Ph 1100-116 Penicillins Orabi – AY 2024-2025 Benzylpenicillin (Pen II or Pen G): COMP PenG waterinsoluble O H H Acedia H H 2C C N S CH3 PenG salt watersoluble N CH3 a tii many O COOH name in siggs t.EE EzT - - Has two neutral nitrogen atoms. In fact, it is acidic. orallyunstate It is water-insoluble, and to solubilize it, it should be used as a salt. Commercially, it is available as, mostly, potassiumo (K) salt (safe to patients with congestive heart failure e o Ls and hypertension), sodium, benzathine and procaine. The potassium and sodium salt are referred to as the aqueous or crystalline forms of the drug and are administered oo intravenously. The benzathine and procaine forms are sparingly soluble salts and used intramuscularly. - Disadvantages: 1) Orally inactive (acid-unstable), i.e., decomposes in acidic solutions. 2) Penicillinase-sensitive: penicillinases are bacterial enzymes excreted as a type of me resistance. 3) Narrow spectrum: covers only Gram +ve bacteria (and 2 Gram -ve bacteria). __ Pharmacophore: H H 1 H 2N S CH3 6 5 2 7 N 3 CH3 O 4 COOH 6-aminopenicillanic acid (derivative of penicillanic acid) o - Any modification on this part leads to loss of activity. - Modifications in the side chain; activity remains, but compound might be more potent of less potent. o Stability of Penicillin G: waterxx i) Action of acids: pen G is acid-unstable, especially in solution, i.e., in the presence of water. This means dry form is more stable than solution form. - pH of maximum stability (optimum) = 6.8 (less or more pH stability will be less). a 5|Page 6.8 A B  Ph 1100-116 Penicillins Orabi – AY 2024-2025 - All penicillins are used in dry form and reconstituted immediately before use. - In the presence of acid (as a catalyst) and water two reactions happen (nucleophilic reactions): both runs inter intraywillhappen a. Intermolecular reaction: 10 decomposition 2diffmolecules O H H O H H O H H H S CH H S CH H S CH H 2C C N 3 H 2C C N 3 H2C C N 3 + N CH3 N CH3 - H O N CH3 O O O H COOH O H COOH O CH2OOH H H H Shibtong H H H catalyst Benzylpenicilloic acid (inactive) so H2O, the nucleophile (Nu) attacks the C=O of the -lactam ring and not of the side chain because -lactam ring is a 4-membered ring fused to a 5-membered ring and, thus, highly strained. So, to relief this strain, -lactam ring readily opens by this reaction to give benzylpenicilloic acid. However, the amide side chain is more stable than the -lactam ring! b. Intramolecular reaction: 90 decomposition H H O H H H S H S CH H 2C C N CH3 H 2C C N 3 O N CH3 Several intermediates N CH3 O O O H COOH CH2OOH moreefficient H H Benzylpenicilloic acid (inactive) - The above two reactions are mechanistically different; however, the products are the same. - So: Pen. G + H2O + acid benzylpenicilloic acid, 90% of the product is from the intramolecular reaction; almost sure the amide C=O attacks the -lactam C=O, and 10% is from the intermolecular reaction; low possibility that H2O attacks the C=O of the - lactam. - So, to design a more acid-stable (orally active) penicillin, the intramolecular reaction should be addressed. The amide side chain should contain an electron withdrawing group c too to decrease the electron density on the C=O of the amide, therefore, it won’t be a good S nucleophile to attack the C=O of the -lactam the intramolecular reaction doesn’t occur a more acid-stable product. A good example of such a product is ampicillin. waste 6|Page Ph 1100-116 Penicillins Orabi – AY 2024-2025 111111rem H H e densityon co H H S C C N CH3 NogoodNutoattack O N CH3 nointramolecularmn NH2 O Ew COOH Ampicillin (acid-stable) So, when there is an electron-withdrawing group in the side chain the product is acid- stable, hence, can be taken orally. ii) Action of bases: again, the base here is just a catalyst. Any nucleophile, like water, can make this reaction. O H H O H H H S CH H S CH H 2C C N 3 H 2C C N 3 N CH3 O N CH3 O O H COOK O H COOK + OH H H Nu Benzylpenicilloic acid (inactive) (H2O) - This reaction is not as significant as the reaction of acids. Stomach acidity affects oral intake, however, basicity, as in glass containers, can produce this reaction. So, all pharmaceutical products should be stored in neutral glass containers. iii) Action of penicillinases ( -lactamases): they are enzymes hat hydrolyze penicillins (or hydrolyze -lactams). -lactamases can be pencillinases or cephalosporinases, …. etc. These enzymes are produced by some bacteria like Neisseria gonorrheae, Staphylococcus aureus and hydrolyze penicillins penicilloic acid (inactive). sensitive o Therefore, penicillin G is only active on bacteria that do not produce penicillinases. Acid-instability affects some pharmacokinetic parameters of penicillin G salts: a) Administration: Pen. G K and Na salts are used IV or IM, not orally. 0 Kinat IV - G moiety to the circulation. o Slightly water-soluble salts of pen G: are used only IM to delay the reach of penicillin For example: IM Procaine Penicillin (Pen G Procaine): it is slightly water-soluble (1 g/250 ml). O H H H Of S O H 2C C N CH3 HN N CH3 H 2N O O COO Penicillin G Procaine acid base Salt 7|Page  Ph 1100-116 Penicillins Orabi – AY 2024-2025 - Procaine is used as a base to form salt, and in the body the ester bond is hydrolyzed (red line in the structure above) to give two non-toxic compounds. - Because it is slightly soluble, it is used as a suspension intended for IM injection, and not IV. This gives sustained release pen G and procaine is readily hydrolyzed by esterase enzymes at the injection site, therefore, the dose of procaine penicillin can stay in the body for one week. 1wk Er Benzathine Penicillin: (1 g/5000 ml) O H H come at 2 H H 2C C N S CH3 qig.at calling NH2 N CH3 H 2N O COO Penicillin G N,N'-dibenzylethylene diamine 1M - I The solubility order is Pen G K or Na > procaine pen G > benzathine pen G. off - Since benzathine pen G is less soluble than procaine pen G, it has a longer duration, - 0 i.e., the dose stays in the body for a month. This base (dibenzylethylene diamine) is hydrolyzed by oxidases oxalic acid (COOH)2, which reacts with Ca++ renal calculi of calcium oxalate. Despite of that, benzathine pen. is preferred over procaine pen. because it is administered once/month. b) Distribution: after administration, it reaches all body fluids and tissues, except cerebrospinal fluid (CSF), under normal conditions. c) Excretion: penicillin is excreted mainly in urine. It is the fastest antibiotic to be excreted. t0.5 = 1 hr o so, blood level concentration (BLC) is low. Therefore, it should be administrated frequently, or as an IV infusion. Exception: sparingly soluble salts. en d) Toxicity: Penicillin G is the safest anti-infective agent. People can tolerate up to 50 mega units / day, provided the patient is not allergic. Antimicrobial Spectrum: It has a narrow spectrum of activity; effective against a small number of microorganisms, mostly Gram +ve bacteria. penicillin G Penicillin V: In producing penicillin G, Penicillinum chrysogenum combines cycteine and valine 6- pÑÑ aminopenicillanic acid, and then combines phenylacetic acid benzylpenicillin (penicillin 8|Page  Ph 1100-116 Penicillins 00Orabi – AY 2024-2025 G). If the media is lacking phenylacetic acid the fungus will form 6-aminopenicillanic acid Pinene only, and when phenoxyacetic acid is added to the media phenoxymethyl penicillin (Penicillin V). Theoretically, we can put any acid, but this does not occur practically, because the incorporated acid should resemble the original substrate, i.e., phenylacetic acid, in order to fool the enzyme in charge of linking the side chain with the ring system. High resemblance is found in phenoxyacetic acid. Now a days, penicillin V is produced via semisynthesis, therefore, it is considered as a semisynthetic penicillin as well. Pen. V is used mostly as K salt. K-salt is more absorbed orally > Ca > Na salt. CH3 O O H H H H H S SH H 2C C N CH3 H 2N H 2N CH3 H2C C OH N CH3 OH COOH Phenylacetic acid from phenylacetic O O acid COOH Cysteine Valine from cysteine from valine 0 Benzylpenicillin (Penicillin G) H H CH3 SH O O H H H 2N H 2N CH3 H S O H2C C OH O H 2C C N CH3 OH COOH N CH3 Phenoxyacetic acid O Cysteine Valine so O COOH stable Penicillin V is relatively more acid-stable thanInstable pen. G, so it can be used orally. It is the first 0 Phenoxymethylpenicillin (Penicillin V) orally active penicillin to be introduced. What are the chemical bases behind this acid- stability? O H H O H2C C HN S CH3 inductive effect N CH3 O COOH O resonance H H H H O O H2C C HN S CH S 3 O H2C C HN CH3 Ewar O N CH 3 N CH3 resonance effect COOH its e-withdrawing O properties increases COOH This is due to 2 reasons. The side chain contains oxygen atom (electron withdrawing atom), Ewar so due to inductive effect, electron density on the amide C=O decreases and, thus, minimizing the intramolecular nucleophilic reaction. Moreover, the mesomeric or resonance effect electron density on the amide C=O the intramolecular nucleophilic reaction acid stability. 9|Page  Ph 1100-116 Penicillins Orabi – AY 2024-2025 b) Semisynthetic Penicillins: These penicillins were semi-synthesized starting with a natural compound, i.e., 6- amniopenicillianic acid (the pharmacophore). This compound is obtained via one of the seinen following methods: acid i) Starving: growing P. chrysogenum on a medium lacking phenylacetic acid. ii) Hydrolysis: of pen. G and by amidase enzyme. This cleaves off the side chain. iii) Mutation: using a mutant P. chrysogenum that lacks the needed enzyme to incorporate phenylacetic acid. After that, this 6-aminopenicillanic acid reacts with the acid chloride of the needed corresponding penicillin. O O H H 1 R HN S CH3 H 2N 6-APA 2 NaHCO3 6 5 2 R Cl + NaCl 7 N 3 CH3 4 O COONa Semisynthetic Penicillin Groups of Semisynthetic Penicillins: 1) Penicillinase-Resistant Penicillins (PRP) 2) Broad Spectrum Penicillins 3) Mega Spectrum Penicillins 1) Penicillinase-Resistant Penicillins (PRP): For penicillinase enzymes to work, the side chain should fit first inside the active site of the enzyme which looks like a hollow tube: inset O H H H S H 2C C N CH3 N CH3 O COONa Penicillin G: penicillinase-sensitive However, if the side chain fulfills the following structural requirements, the chain won't fit inside the active site and, consequently, the -lactam ring is protected. These requirements are: - The ring (alicyclic or aromatic) should attach directly to the C=O of the side chain, AND - The two ortho-positions of the ring should be substituted. 10 | P a g e  Ph 1100-116 Penicillins Orabi – AY 2024-2025 These requirements ensure a frozen conformation of the side chain, i.e., doesn't rotate and can't be squeezed. Therefore, e.g., methicillin, doesn’t fit in the active site because the two o-positions are substituted bulky side chain. However, if the substituents are on o- and p- or m- the compound squeezes itself and fits in the active site and activity is lost due to hydrolysis. eT ERG OCH3 O H H ifthebae.relase B H S lactamaseo.the acidunstable C N CH3 drugshouldbe given likemethicillin a 111 OCH3 O N CH3 COONa Methicillin: penicillinase-resistant o r Methoxy groups (OCH3) provide maximum penicillinase-resistance activity. This is fulfilled in Methicillin. However, since these groups are electron-donating groups ERG methicillin is acid-unstable and can’t be given orally. I EDG 6am Isoxazole PRP: these are eliminated via renal and hepatic routes. a) Oxacillin: It is orally active, because in the presence of acid the N atom of the isoxazole ring N- + H, i.e., isoxazole nitrogen has some basicity. This will electron density of the side chain C=O and, therefore, will the intramolecular hydrolysis, i.e., they are acid-stable. The 2 o-positions are substituted penicillinase-resistant. ii O H H H S N C N CH3 O a N O CH3 O N CH3 COONa Oxazole ring system ancientH Oxacillin b) Cloxacillin: 1 It has a chlorine atom; Cl lipophilicity absorption (blood level concentration is 2x of oxacillin) oral dose. Cl canbetakenorally O H H butwith smallest H S C N CH3 N N CH3 O CH3 O COONa Cloxacillin 11 | P a g e Ph 1100-116 Penicillins Orabi – AY 2024-2025 2 01 c) Dicloxacillin: It has two chlorine atoms lipophilicity even more absorption more (BLC is 2x of cloxacillin) oral dose more. Toxacin Cl O H H H S C N CH3 Cl N N CH3 O CH3 O COONa Dicloxacillin d) Flucloxacillin: It is not used in US. It is similar to dicloxacillin. F O H H H S C N CH3 Cl N N CH3 O CH3 O COONa Flucloxacillin Nafcillin: It is used as Na-salt IV and IM. Resembles methicillin, acid-unstable. OEt O H H H S C N CH3 N CH3 O COONa Nafcillin The ring system here is bulkier than that of methicillin, so the acid-instability here is of a less magnitude. Therefore. It can be given orally at high doses. 2) Broad Spectrum Penicillins: They are characterized by having polar side chains. a i) Ampicillin: NHz t It is amino penicillin G. In solution and at pH ≈ 7 it is found as a zwitterion. zero O H H O H H H H S H H S C C N CH3 C C N CH3 NH2 N CH3 NH3 N CH3 O O COOH COO ammonium gp Ampicillin Ampicillin zwitterion 12 | P a g e Ph 1100-116 Penicillins Orabi – AY 2024-2025 This charged ammonium group gives ampicillin properties that are not in penicillin G: 1) Acid stable, therefore, it is used orally. However, it is still penicillinase-sensitive! 2) Highly polar: this gives it the following characteristics: a) active against Gr-ve bacteria (broad spectrum). How? Ampicillin is less lipophilic than penicillin G, so some of it dissolves in the cell wall and the remainder penetrates into the inner layer (murien) of the cell wall, so the penetration power of ampicillin in Gr-ve bacteria is higher than that of penicillin G. b) Protein binding is less (so BLC is high). c) GIT absorption is retarded. Ampicillin is always charged in the GIT, so absorption doesn’t exceed 30-55%. O H H O H H O H H H H S H H S H H C C N CH3 C C N CH3 C C N S CH3 NH3 N CH3 NH3 N CH3 NH2 N CH3 O O O COO COOH COONa pH= 7 (polar) in stomach (acidic), polar in intestine (basic), polar In intestine, it is believed that ampicillin is actively transported as an amino acid (phenylalanine) and not as a drug. The consequence of this similarity is that large meals (rich o in phenylalanine) absorption of ampicillin, so ampicillin should be given one hour before meal or 2 hours after meal. O H H H H S C C N CH3 CH2 CH COOH NH2 N CH3 NH2 O COOH Ampicillin a Phenylalanine Ampicillin rash: It is a specific allergenicity due to ampicillin structure. Since it is similar to an amino acid, the nucleophilic NH2 group attacks the -lactam ring of another ampicillin molecule and, then, the NH2 group of the 2nd molecule attacks a 3rd one, and so on dimer trimer ….. polymer. This polymer looks like a polypeptide and has antigenic properties initiates body immunity to form antibodies Ag/Ab reaction rash! O H H H H S C C N CH3 NH2 N CH3 O COOH Ampicillin resembles an amino acid 13 | P a g e Ph 1100-116 Penicillins Orabi – AY 2024-2025 ii) Amoxicillin (Amoxycillin): OH a It is hydroxyampicillin and resembles tyrosine. HO O H H H H S HO C C N CH3 CH2 CH COOH NH2 N CH3 O NH2 COOH no Tyrosine Amoxicillin All antibiotics with acidic polar group (OH) on the side chain, e.g., amoxicillin, are retained longer in the polar tissues of the body longer it is given 3x/day and not 4x/day as ampicillin. tin Amoxicillin is more absorbed than ampicillin because it is absorbed like tyrosine amino acid. The system involved in tyrosine absorption works better (active transportation). Also, food does not interfere with the absorption, because the carrier proteins transport both tyrosine and amoxicillin efficiently absorption is about 75% less incidence of diarrhea and pseudomembranous colitis (PMC) and, also, can be taken on a full stomach. iii) Ticarcillin: __2C It is an example of carboxypenicillins. It has two carboxylic acid moieties, thus, highly polar. This high polarity ensures higher penetration power of Gram-negative bacterial wall, e.g., Pseudomonas aeruginosa. It is acid-unstable, due to the presence of a C=O group - to the carboxylic acid moiety. This sitting allows rapid decarboxylation the product is very similar to penicillin G and, thus, acid-unstable. Therefore, it is given via IV infusion. O H H O H H H H S HC C N S CH3 - CO2 H 2C C N CH3 COONa N CH3 N CH3 S in acid S O O COONa COONa Ticarcillin Decarboxylated ticarcillin acid-unstable Ticarcillin, like most antipseudomonal -lactam antibiotics, is not suitable as a monotherapy treatment of P. aeruginosa infections. It should be combined with an aminoglycoside antibiotic, like gentamicin, to potency and resistance development. However, ticarcillin 14 | P a g e Ph 1100-116 Penicillins Orabi – AY 2024-2025 should not be physically admixed with the acidic salt of any aminoglycoside. This would result in the immediate precipitation of the water insoluble ticarcillin free diacid. Moreover, NH2 groups of the aminoglycoside will nucleophilic add to the -lactam inactive adduct! Here, ticarcillin (2 gm) retains the majority of the activity, however, gentamicin (80 mg) is totally lost. O H H O H H H S H S CH HC C N CH3 CHC N 3 COONa N CH3 COONa HN CH3 S O S O COONa NH COONa Ticarcillin H2N Gentamicin Inactive Gentamicin (2 gm) (80 mg) So, they should be administered separately. This interaction doesn’t happen in vivo (assume normal renal function), but in renal failure, drugs stay long time in the body chance of this interaction. Ticarcillin is subjected to hydrolysis by penicillinases, so it is hard to find it alone, it is usually combined with the penicillinase inhibitor clavulanate and marketed as Timentin®. 3) Megaspectrum Penicillins (Ureidopenicillins): All -lactams exert their action by binding to Penicillin binding Proteins (transpeptidases). The presence of the NH-CO group in the side chain of the ureidopenicillins enables them to bind stronger with transpeptidases and, also, with a larger number of them, more than say, other types of penicillins. This structural feature improves the potency and broadens the spectrum of them. All members are ampicillin derivatives with a urea moiety (-NH-CO-NH) in the side chain, instead of amino group, hence the name “ureidopenicillins”. Example: Piperacillin and (mezlocillin, azlocillin), the last two are no longer in use. Piperacillin: O H H H S CH CH C N 3 NH N CH3 Urea moiety C O O COONa N O N O Piperacillin CH2CH3 15 | P a g e  Ph 1100-116 Penicillins Orabi – AY 2024-2025 Piperacillin is too polar and bulky to be orally absorbed, therefore, it is only used parenterally. Penicillinase Enzymes Inhibitors: In order to preferentially bind to penicillinase enzymes, these irreversible inhibitors should be structurally similar to penicillin’s core structure, i.e., the penam ring system. Three inhibitors are known and used in combination with different penicillins. These combinations are used against penicillinase-producing bacteria. The main factor in selecting which inhibitor goes with which penicillin is “similar pharmacokinetic parameters”, i.e., similar absorption, distribution and excretion. w̅ 1) Tazobactam: (the most potent penicillinase inhibitor) O O H N N S CH N 2 N CH3 O COOH Tazobactam Zosyn® = Piperacillin Na + Tazobactam Na, IV. 2) Sulbactam: O O H H S CH 3 N CH3 O COOH Sulbactam Unasyn®: (una=one, syn=together) = Ampicillin Na + Sulbactam Na Since the absorption of ampicillin from the GIT is erratic and unpredictable, this preparation is used IM or IV injection only. 3) K-Clavulanate: H H O CH2OH N H O COOK K-clavulanate 16 | P a g e Ph 1100-116 Penicillins Orabi – AY 2024-2025 Augmentin® (co-amoxiclav) = K-clavulanate + amoxicillin Amoxicillin is used with K-clavulanate and not ampicillin, because both (amoxicillin and clavulanate) have the same pharmacokinetics (same absorption, distribution and excretion). Clavulanate is a weaker inhibitor than the sulbactam used in Unasyn®. However, the main advantage of Augmentin® is that it is used orally and by injection. Timentin® = K-clavulanate + ticarcillin. It is used as IV. 17 | P a g e