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Amoxicillin

Amoxicillin, is an broad spectrum semisynthetic antibiotic useful for the treatment of a number of bacterial infections. It is similar to AMPICILLIN except that its resistance to gastric acid permits higher serum levels with oral administration.

Therapeutic use

For the treatment of infections of the ear, nose, and throat, the genitourinary tract, the skin and skin structure, and the lower respiratory tract due to susceptible (only b-lactamase-negative) strains of Streptococcus spp. (a- and b-hemolytic strains only), S. pneumoniae, Staphylococcus spp., H. influenzae, E. coli, P. mirabilis, or E. faecalis. Also for the treatment of acute, uncomplicated gonorrhea (ano-genital and urethral infections) due to N. gonorrhoeae (males and females).

Amoxicillin is a moderate-spectrum antibiotic active against a wide range of Gram-positive, and a limited range of Gram-negative organisms. It is usually the drug of choice within the class because it is better absorbed, following oral administration, than other b-lactam antibiotics. Amoxicillin is susceptible to degradation by β-lactamase-producing bacteria, and so may be given with clavulanic acid to increase its susceptability. The incidence of β-lactamase-producing resistant organisms, including E. coli, appears to be increasing. Amoxicillin is sometimes combined with clavulanic acid, a β-lactamase inhibitor, to increase the spectrum of action against Gram-negative organisms, and to overcome bacterial antibiotic resistance mediated through β-lactamase production.

Dosage and Administration

 

Toxicology

Side-effects are similar to those for other b-lactam antibiotics, including nausea, vomiting, rashes, and antibiotic-associated colitis. Loose bowel movements (diarrhea) may also occur. Rarer side-effects include mental changes, lightheadedness, insomnia, confusion, anxiety, sensitivity to lights and sounds, and unclear thinking. Immediate medical care is required upon the first signs of these side-effects.

Organism Test Type Route Reported Dose (Normalized Dose) Effect Source
child TDLo oral 300mg/kg (300mg/kg) KIDNEY, URETER, AND BLADDER: "CHANGES IN TUBULES (INCLUDING ACUTE RENAL FAILURE, ACUTE TUBULAR NECROSIS)"

KIDNEY, URETER, AND BLADDER: HEMATURIA

KIDNEY, URETER, AND BLADDER: OTHER CHANGES IN URINE COMPOSITION
Clinical Pediatrics Vol. 32, Pg. 735, 1993.
child TDLo oral 682mg/kg (682mg/kg) KIDNEY, URETER, AND BLADDER: HEMATURIA

KIDNEY, URETER, AND BLADDER: URINE VOLUME DECREASED

KIDNEY, URETER, AND BLADDER: "CHANGES IN TUBULES (INCLUDING ACUTE RENAL FAILURE, ACUTE TUBULAR NECROSIS)"
Clinical Pediatrics Vol. 32, Pg. 735, 1993.
man TDLo oral 7143ug/kg (7.143mg/kg) SKIN AND APPENDAGES (SKIN): "DERMATITIS, OTHER: AFTER SYSTEMIC EXPOSURE" Allergy. Vol. 52(Suppl,
man TDLo oral 40mg/kg/4D (40mg/kg) GASTROINTESTINAL: "HYPERMOTILITY, DIARRHEA"

GASTROINTESTINAL: OTHER CHANGES
Lancet. Vol. 2, Pg. 707, 1978.
mouse LD50 intracrebral > 500mg/kg (500mg/kg) BRAIN AND COVERINGS: RECORDINGS FROM SPECIFIC AREAS OF CNS Chemotherapy Vol. 26, Pg. 196, 1980.
mouse LD50 intraperitoneal 3590mg/kg (3590mg/kg)   Drugs in Japan Vol. -, Pg. 59, 1990.
mouse LD50 oral > 25gm/kg (25000mg/kg)   Drugs in Japan Vol. 6, Pg. 38, 1982.
mouse LD50 subcutaneous > 20mg/kg (20mg/kg)   Drugs in Japan Vol. -, Pg. 59, 1990.
rat LD50 intraperitoneal 2870mg/kg (2870mg/kg)   Drugs in Japan Vol. -, Pg. 59, 1990.
rat LD50 oral > 15gm/kg (15000mg/kg)   Drugs in Japan Vol. 6, Pg. 38, 1982.
rat LD50 subcutaneous > 8gm/kg (8000mg/kg)   Drugs in Japan Vol. -, Pg. 59, 1990.

The onset of an allergic reaction to amoxicillin can be very sudden and intense; emergency medical attention must be sought as quickly as possible. The initial phase of such a reaction often starts with a change in mental state, skin rash with intense itching (often beginning in fingertips and around groin area and rapidly spreading), and sensations of fever, nausea, and vomiting. Any other symptoms that seem even remotely suspicious must be taken very seriously. However, more mild allergy symptoms, such as a rash, can occur at any time during treatment, even up to a week after treatment has ceased. For some people allergic to amoxicillin, the side-effects can be deadly.

Use of the amoxicillin/clavulanic acid combination for more than one week has caused mild hepatitis in some patients. Young children having ingested acute overdoses of amoxicillin-manifested lethargy, vomiting, and renal dysfunction [1-2].

Nonallergic amoxicillin rash

Between 3 and 10% of children taking amoxicillin (or ampicillin) show a late-developing (>72 hours after beginning medication and having never taken penicillin-like medication previously) rash, which is sometimes referred to as the "amoxicillin rash". The rash can also occur in adults.

The rash is described as maculopapular or morbilliform (measles-like; therefore, in medical literature, it is called "amoxicillin-induced morbilliform rash" [3]). It starts on the trunk and can spread from there. This rash is unlikely to be a true allergic reaction, and is not a contraindication for future amoxicillin usage, nor should the current regimen necessarily be stopped. However, this common amoxicillin rash and a dangerous allergic reaction cannot easily be distinguished by inexperienced persons, so a healthcare professional is often required to distinguish between the two [4-5].

A nonallergic amoxicillin rash may also be an indicator of infectious mononucleosis. Some studies indicate about 80-90% of patients with acute Epstein Barr virus infection treated with amoxicillin or ampicillin develop such a rash [6].

Nonallergic amoxicillin rash eight days after first dose, 24 hours after rash began.

Eight hours after first photo, individual spots have grown and begun to merge.

At 23 hours after first photo, the color appears to be fading, and much of rash has spread to confluence.

Pharmacokinetic

 

Bioavailability  
Protein binding 20%
Metabolism hepatic <30%
Half-life 61 minutes
Cmax (mg/ml)  
tmax (hrs)  
Distribution volume Vd  
Clearance  
Excretion urinary

Absorption

Rapidly absorbed after oral administration.

Distribution


Excretion

 

Metabolism

 

Mechanism of Action

Amoxicillin binds to penicillin-binding protein 1A (PBP-1A) located inside the bacterial cell well. Penicillins acylate the penicillin-sensitive transpeptidase C-terminal domain by opening the lactam ring. This inactivation of the enzyme prevents the formation of a cross-link of two linear peptidoglycan strands, inhibiting the third and last stage of bacterial cell wall synthesis. Cell lysis is then mediated by bacterial cell wall autolytic enzymes such as autolysins; it is possible that amoxicllin interferes with an autolysin inhibitor.

Antibacterial activity

In general, Streptococcus, Bacillus subtilis, Enterococcus, Haemophilus, Helicobacter, and Moraxella are susceptible to amoxicillin, whereas Citrobacter, Klebsiella and Pseudomonas aeruginosa are resistant to it. Some E. coli and most clinical isolates of Staphylococcus aureus have developed resistance to amoxicillin to varying degrees.

Microorganism Concentration Range (μg/ml)
Aggregatibacter actinomycetemcomitans 1 - 16
Bacillus cereus 4 - 31.25
Bacillus pumilu 1
Bacillus subtilis 0.05 - 412
Bacteroides distasonis 2 - >128
Bacteroides fragilis ≤0.25 ≥512
Bacteroides ovatus 16 >128
Bacteroides thetaiotaomicron 16 >128
Bacteroides uniformis 16 >128
Bacteroides vulgatus 8 >128
Bifidobacterium spp. ≤0.125 - 0.5
Borrelia burgdorferi S.L. 0.03 - 2
Burkholderia cepacia (8Q) >18
Burkholderia mallei (Pakistan) 128
Campylobacter gracilis (ATCC 33236)  1
Campylobacter helveticus (ATCC 51209) 4
Campylobacter jejuni  0.5 - 2
Campylobacter rectus (ATCC 33238) 1
Campylobacter showae (ATCC 51146) 0.5
Capnocytophaga gingivalis (ATCC 33624) 0.5
Capnocytophaga ochracea (ATCC 27872) 1
Capnocytophaga spp.  1
Capnocytophaga sputigena (ATCC 33612) 1
Citrobacter diversus >1000
Citrobacter freundii 2 - 2048
Clostridium bifermentans ≤0.125 - 0.5
Clostridium cadaveris ≤0.125 - 0.5
Clostridium difficile 1 - 4
Clostridium histolyticum ≤0.125 - 0.5
Clostridium perfringens ≤0.03 - 0.5
Clostridium ramosum  ≤0.125 - 0.5
Clostridium sordellii ≤0.125 - 0.5
Clostridium spiroforme 0.032 - 0.5
Clostridium spp. ≤0.125 - 0.5
Clostridium tertium  ≤0.125 - 0.5
Corynebacterium matruchotii (ATCC 14266)  0.5
Corynebacterium spp. (HEGP 1006) >256
Edwardsiella hoshinae  0.13 - 0.25
Edwardsiella ictaluri 0.13 - 1
Edwardsiella tarda  0.13 - 64
Eikenella corrodens  2 - 8
Enterobacter cloacae 4 - >500
Enterobacteriaceae 0.25 - 128
Enterococci 0.12 - 128
Enterococcus faecalis  0.25 - 7
Enterococcus faecium  32 - >256
Escherichia coli 2 - >500
Eubacterium saburreum (ATCC 33271) 0.5
Eubacterium spp.  1
Eubacterium sulci (ATCC 35585) 0.5
Fusobacterium mortiferum  1 - >128
Fusobacterium necrophorum ≤0.125 - 0.5
Fusobacterium nucleatum ≤0.125 - 16
Fusobacterium periodonticum (ATCC 33693) 32
Fusobacterium spp. ≤0.125 - >128
Fusobacterium varium 1 - 2
Gemella morbillorum (ATCC 27824)  0.5 - ?
Haemolytic streptococci  0.008 - 0.12
Haemophilus ducreyi 9
Haemophilus influenzae <0.07 - >64
Haemophilus parasuis 0.6 - 310
Haemophilus spp. 0.06 - 128
Helicobacter bilis (ATCC 51630) 4
Helicobacter mustelae(ATCC 43772) 4
Helicobacter pullorum (ATCC 51864) 4
Helicobacter pylori 0.0002 - 8
Klebsiella pneumoniae 2 - >500
Lactobacillus acidophilus ≤0.125 - 2
Lactobacillus buchneri 0.25 - 1
Lactobacillus plantarum ≤0.125 - 2
Lactobacillus reuteri ≤0.125 - 4
Lactobacillus rhamnosus 0.5 - 2
Lactobacillus salivarius ≤0.125 - 0.5
Lactobacillus spp. 0.5 - 129
Lactococcus lactis ≤0.125 - 1
Leptotrichia buccalis (ATCC 14201) 0.5
Leuconostoc ≤0.125 - 1
Micrococcus <0.24 - >40
Moraxella catarrhalis (BC1) <0.07
Morganella morganii >100 - 512
Mycoplasma hyopneumoniae 0.09 - 737.3
Mycoplasma hyorhinis  0.09 - 737.3
Neisseria gonorrhoeae 0.3
Neisseria meningitidis (N2) <0.07
Neisseria mucosa (ATCC 19696) 2
Neisseria spp. 0.004 - 32
Nocardia asteroides 6.2 - ≥400
Ochrobactrum anthropi (SLO74) ≥28
Pasteurella multocida 128 - 1240
Pediococcus ≤0.125 - 1
Peptostreptococcus anaerobius ≤0.125 - 32
Peptostreptococcus asaccharolyticus ≤0.125 - 32
Peptostreptococcus magnus ≤0.125 - 32
Peptostreptococcus micros ≤0.125 - 32
Peptostreptococcus prevotii ≤0.125 - 32
Peptostreptococcus spp. <1 - 8
Peptostreptococcus tetradius ≤0.125 - 32
Pneumococci 0.008 - 4
Porphyromonas asaccharolytica ≤0.0125 - 64
Porphyromonas endodontalis (ATCC 35406) 4
Porphyromonas gingivalis ≤0.0125 - 64
Porphyromonas spp. ≤0.125 - 128
Prevotella bivia ≤0.125 - 128
Prevotella buccae ≤0.0125 - 64
Prevotella corporis ≤0.0125 - 64
Prevotella disiens ≤0.0125 - 64
Prevotella intermedia ≤0.0125 - 64
Prevotella loescheii ≤0.0125 - 64
Prevotella melaninogenica ≤0.125 - 128
Prevotella nigrescens 0.5
Prevotella oralis (group) ≤0.0125 - 64
Prevotella oris ≤0.0125 - 64
Prevotella spp. ≤0.125 - 128
Propionibacterium acnes ≤0.125 - 0.25
Proteus mirabilis (1287) 0.39
Proteus vulgaris 1 - 1024
Providencia rettgeri (NIH 96) 3.13
Pseudomonas aeruginosa 1 - 1024
Ralstonia pickettii 64
Salmonella spp. 1
Salmonella typhi 6.25 - 32
Selenomonas noxia 0.5
Serratia marcescens 16 - >256 ?
Shigella flexneri 2
Staphylococci 0.03 - 128
Staphylococcus aureus <0.0625 - >128
Staphylococcus aureus (methicillin-resistant) 0.2 - 512
Staphylococcus epidermidis 0.78 - 1
Staphylococcus faecalis 1.22 - 1.95
Streptococcus agalactiae 0.094
Streptococcus anginosus 0.5
Streptococcus bovis ≤0.125 - 1
Streptococcus constellatus (ATCC 27823) 0.5
Streptococcus equi 0.03 - 0.06
Streptococcus faecalis (ATCC 29212) 412
Streptococcus gordonii (ATCC 10558) 0.5
Streptococcus infantarius ≤0.125 - 1
Streptococcus intermedius (ATCC 27335) 1
Streptococcus mitis (ATCC 49456) 0.5
Streptococcus oralis (ATCC 35037) 0.5
Streptococcus pneumoniae ≤0.008 - 31.25
Streptococcus pyogenes 32
Streptococcus sanguinis 1
Streptococcus spp. 32 - 128
Streptococcus suis 78 - 1240
Tannerella forsythia 8
Veillonella parvula 0.5
Weissella spp. ≤0.125 - 0.25
Xanthomonas oryzae 18

The data above is sourced from The Antimicrobial Index. www.toku-e.com

Other pharmacological effects

 


Medicinal Chemistry

CAS number: 26787-78-0  EINECS: 248-003-8

Molecular Formula:  C16H19N3O5S

Average mass: 365.404205 Da

Monoisotopic mass:  365.104553 Da

Systematic name: (2S,5R,6R)-6-{[(2R)-2-Amino-2-(4-hydroxyphenyl)acetyl]amino}-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

SMILES: CC1([C@@H](N2[C@H](S1)[C@@H](C2=O)NC(=O)[C@@H](c3ccc(cc3)O)N)C(=O)O)C

Std. InChI: 1S/C16H19N3O5S/c1-16(2)11(15(23)24)19-13(22)10(14(19)25-16)18-12(21)9(17)7-3-5-8(20)6-4-7/h3-6,9-11,14,20H,17H2,1-2H3,(H,18,21)(H,23,24)/t9-,10-,11+,14-/m1/s1

ACD/LogP: 0.610.33 # of Rule of 5 Violations: 1
ACD/LogD (pH 5.5): -1.91 ACD/LogD (pH 7.4): -2.59
ACD/BCF (pH 5.5): 1.00 ACD/BCF (pH 7.4): 1.00
ACD/KOC (pH 5.5): 1.00 ACD/KOC (pH 7.4): 1.00
#H bond acceptors: 8 #H bond donors: 5
#Freely Rotating Bonds: 6 Polar Surface Area: 158.26 2
Index of Refraction: 1.702 Molar Refractivity: 91.50.4 cm3
Molar Volume: 236.25.0 cm3 Polarizability: 36.30.5 10-24cm3
Surface Tension: 85.35.0 dyne/cm Density: 1.50.1 g/cm3
Flash Point: 403.332.9 C Enthalpy of Vaporization: 113.73.0 kJ/mol
Boiling Point: 743.260.0 C at 760 mmHg Vapour Pressure: 0.02.6 mmHg at 25C

Major Impurities:

Appearance: Off-white crystalline powder

Melting point: 194C

Optical rotation: [a]D20 +246 (c = 0.1)

Solubility (mg/ml): water 4.0; methanol 7.5; abs ethanol 3.4. Insol in hexane, benzene, ethyl acetate, acetonitrile.

Absorption maximum: uv max (ethanol): 230, 274 nm (e 10850, 1400); (0.1N HCl): 229, 272 nm (e 9500, 1080); (0.1N KOH): 248, 291 (e 2200, 3000)

logP: 0.87

pKa: 3.23

Caco2 permeability: -6.1

Stability:

 


1. Cundiff, J., Joe, S. "Amoxicillin-clavulanic acid-induced hepatitis". Amer. J. Otolaryngol. 28 (1): 2830,(2007).

2. Baselt, R.  "Disposition of Toxic Drugs and Chemicals in Man" (8th ed.). Foster City, CA: Biomedical Publications. pp. 8183, (2008).

3. Barabaud, A. M., Bene M.-C., Schultz J.-L., Ehlinger A., Weber M., Faure G. C. "Role of delayed cellular hypersensitivity and adhesion molecules in amoxicillin-induced morbilliform rashes". Archives of dermatology 133, (4), 481-486, (1997).

4. Pichichero, M.E. "A review of evidence supporting the American Academy of Pediatrics recommendation for prescribing cephalosporin antibiotics for penicillin-allergic patients". Pediatrics 115 (4): 104857, (2005).

5. Schmitt, Barton D. "Your child's health: the parents' one-stop reference guide to symptoms, emergencies, common illnesses, behavior problems, healthy development" (2nd ed.). New York: Bantam Books, (2005).

6. Kagan, B. "Ampicillin rash". Western Journal of Medicine 126, (4): 333335, (1977).

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