Compendium of the most significant studies with reference to properties, intake, effects.

Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–. Amoxicillin and Clavulanic Acid. 2018 Oct 31.

Abstract.  Limited information indicates that adverse reactions in infants are uncommon during the use of amoxicillin-clavulanic acid during nursing, with restlessness, diarrhea and rash occurring occasionally. Amoxicillin-clavulanic acid is acceptable in nursing mothers.

Karolyi M, Pawelka E, Kelani H, Funk GC, Lindner B, Porpaczy C, Publig S, Omid S, Seitz T, Traugott M, Turner M, Zoufaly A, Wenisch C. Management of hospitalized influenza A patients during the season 2018/19 : Comparison of three medical departments and the effect on outcome and antibiotic usage. Wien Klin Wochenschr. 2021 Oct 6. doi: 10.1007/s00508-021-01950-8.

Abstract. Diagnosis and treatment of influenza patients are often provided across several medical specialties. We compared patient outcomes at an infectious diseases, a rheumatology and a pulmonology department. 

Saudagar PS, Survase SA, Singhal RS. Clavulanic acid: a review. Biotechnol Adv. 2008 Jul-Aug;26(4):335-51. doi: 10.1016/j.biotechadv.2008.03.002.

Abstract. The review discusses the biosynthetic pathway, fermentative production, downstream processing and applications of Clavulanic acid.

Ser HL, Law JW, Chaiyakunapruk N, Jacob SA, Palanisamy UD, Chan KG, Goh BH, Lee LH. Fermentation Conditions that Affect Clavulanic Acid Production in Streptomyces clavuligerus: A Systematic Review. Front Microbiol. 2016 Apr 22;7:522. doi: 10.3389/fmicb.2016.00522 

Abstract. Overall, these findings provide vital knowledge and insight that could assist media optimization and fermentation design for clavulanic acid production in S. clavuligerus.

Neu HC, Wilson AP, Grüneberg RN. Amoxycillin/clavulanic acid: a review of its efficacy in over 38,500 patients from 1979 to 1992. J Chemother. 1993 Apr;5(2):67-93. doi: 10.1080/1120009x.1993.11739213.

Abstract. Clinical efficacy rates (cure or improved) with amoxycillin/clavulanic acid were 88% and 92% in comparative and uncontrolled trials, respectively. Gastro-intestinal side effects are the most common adverse event but have been relatively infrequent. Amoxycillin/clavulanic acid should continue to be a useful antibiotic for upper and lower respiratory tract infections, skin structure infections, dental, head and neck infections, and selected urinary tract infections.

Carlier M, Noë M, De Waele JJ, Stove V, Verstraete AG, Lipman J, Roberts JA. Population pharmacokinetics and dosing simulations of amoxicillin/clavulanic acid in critically ill patients. J Antimicrob Chemother. 2013 Nov;68(11):2600-8. doi: 10.1093/jac/dkt240.

Abstract. Although vast pharmacokinetic variability exists for both amoxicillin and clavulanic acid in intensive care unit patients, current dosing regiments are appropriate for most patients, except those with very high creatinine clearance.

Lacroix JM, Lamothe F, Malouin F. Role of Bacteroides bivius beta-lactamase in beta-lactam susceptibility. Antimicrob Agents Chemother. 1984 Nov;26(5):694-8. doi: 10.1128/AAC.26.5.694.

Abstract.  The susceptibility of 46 clinical isolates of Bacteroides bivius to amoxicillin, cefotaxime, cefoxitin, ceftizoxime, cephaloridine, cephalothin, moxalactam, penicillin G, amoxicillin plus clavulanic acid in a ratio of 2:1, carbenicillin, cefamandole, and ceftazidime was determined by an agar dilution technique.

Becopoulos T, Georgoulias D, Constantinides C, Stathakis H, Kosmidis J. Acute prostatitis: which antibiotic to use first. J Chemother. 1990 Aug;2(4):244-6. doi: 10.1080/1120009x.1990.11739024.

Abstract.  The obtained ratios of prostatic tissue to serum concentrations and the relative antimicrobial activity to local pathogens of each agent indicate that the agent of choice for prostatic disease is netilmicin followed by aztreonam, cefuroxime and the ticarcillin-clavulanic acid combination.

Clavulanic acid is an antibiotic isolated in 1974 from a gram-positive bacterium, Streptomyces clavuligerus and is always used in combination with amoxicillin and in its saline form clavulanate potassium for the treatment of infections that affect

• lower respiratory tract
• urinary tract
• some skin infections
• sinusitis
• otitis media
• soft tissues caused by organisms such as H. influenzae, M. catarrhalise S. aureus

and is used in surgical antimicrobial prophylaxis and postoperative infections in urology as a beta-lactamase inhibitor (which can inhibit the activity of most penicillins) by preventing degradation of the β-lactam ring, thereby ensuring that these damaging microorganisms are eradicated. Clavulanic acid reduces the susceptibility of beta-lactamase-positive strains to beta-lactamase-negative strains.

Clavulanic acid, which is found in liquid or solid form, does not possess its own specific antibacterial effects, but must always be accompanied by amoxicillin.

Applications

This study collected and analyzed clinical, laboratory, and therapeutic data from children with acute hematogenous osteomyelitis admitted to an Italian children's hospital between 2010 and 2019. The results suggest that amoxicillin-clavulanic acid could be an option for oral antibiotic therapy in children with acute hematogenous osteomyelitis (1).

This study collected and analyzed clinical, laboratory, and therapeutic data from children with acute hematogenous osteomyelitis admitted to an Italian children's hospital between 2010 and 2019. The results suggest that amoxicillin-clavulanic acid could be an option for oral antibiotic therapy in children with acute hematogenous osteomyelitis (2).

The amoxicillin/clavulanic acid combination is a broad-spectrum antibacterial treatment in pediatric patients against penicillin-resistant S. pneumoniae intermedia and against beta-lactamase-producing strains of Haemophilus influenzae and Moraxella catarrhalis that cause acute otitis media (3).

Breastfeeding is considered the gold standard for infant nutrition.Data from this research suggest that amoxicillin/clavulanic acid and cefuroxime may be safe during breastfeeding. Larger studies are needed to confirm these findings (4).

For transrectal ultrasound-guided biopsy of the prostate (TRUBP) lacombination of pivmecillinam and amoxicillin/clavulanic acid has been shown to be clinically, bacteriologically, and ecologically attractive prophylaxis compared with ciprofloxacin (5).

This study evaluated the clinical and microbiological outcomes of amoxicillin/clavulanic acid administration in urinary tract infections, and the results confirmed the validity and efficacy of oral administration, although some strains may develop resistance during therapy (6).

Clavulanic acid studies

Typical optimal characteristics of the commercial product clavulanic acid

• Molecular Formula: C₈H₉NO₅
• Molecular Weight: 199.162 g·mol⁻¹
• CAS: 58001-44-8
• UNII 23521W1S24
• EC Number: 261-069-2
• DSSTox Substance ID: DTXSID2022830
• MDL number  
• PubChem Substance ID  5280980 
• InChl=1S/C8H9NO5/c10-2-1-4-7(8(12)13)9-5(11)3-6(9)14-4/h1,6-7,10H,2-3H2,(H,12,13)/b4-1-/t6-,7-/m1/s1
• InChI Key      HZZVJAQRINQKSD-PBFISZAISA-N
• SMILES    C1C2N(C1=O)C(C(=CCO)O2)C(=O)O
• IUPAC (2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
• ChEBI    48947

Synonyms: 

• BRL 14151
• Clavulanate
• Clavulanic Acid, Monosodium Salt
• Clavulanic Acid, Monopotassium Salt
• Clavulanate Potassium

References______________________________________________________________________

(1) Tonelli F, Mazzei T, Novelli A, Mazzoni P, Ficari F; Italian Cooperative Group. Amoxicillin/clavulanic acid versus cefotaxime for antimicrobial prophylaxis in abdominal surgery: a randomized trial. J Chemother. 2002 Aug;14(4):366-72. doi: 10.1179/joc.2002.14.4.366. 

(2) Serrano E, Ferri I, Galli L, Chiappini E. Amoxicillin-Clavulanic Acid Empirical Oral Therapy for the Management of Children with Acute Haematogenous Osteomyelitis. Antibiotics (Basel). 2020 Aug 18;9(8):525. doi: 10.3390/antibiotics9080525.

(3) Easton J, Noble S, Perry CM. Amoxicillin/clavulanic acid: a review of its use in the management of paediatric patients with acute otitis media. Drugs. 2003;63(3):311-40. doi: 10.2165/00003495-200363030-00005.

(4) Benyamini L, Merlob P, Stahl B, Braunstein R, Bortnik O, Bulkowstein M, Zimmerman D, Berkovitch M. The safety of amoxicillin/clavulanic acid and cefuroxime during lactation. Ther Drug Monit. 2005 Aug;27(4):499-502. doi: 10.1097/01.ftd.0000168294.25356.d0. 

(5) Antsupova V, Nørgaard N, Bisbjerg R, Nygaard Jensen J, Boel J, Jarløv JO, Arpi M. Antibiotic prophylaxis for transrectal prostate biopsy-a new strategy. J Antimicrob Chemother. 2014 Dec;69(12):3372-8. doi: 10.1093/jac/dku293.

(6) Beytur A, Yakupogullari Y, Oguz F, Otlu B, Kaysadu H. Oral amoxicillin-clavulanic Acid treatment in urinary tract infections caused by extended-spectrum Beta-lactamase-producing organisms. Jundishapur J Microbiol. 2014 Dec 6;8(1):e13792. doi: 10.5812/jjm.13792.