Flucloxacillin

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Flucloxacillin
Flucloxacillin.svg
Flucloxacillin-from-xtal-1980-3D-balls.png
Clinical data
Trade names Floxapen, others [1]
Other namesBRL-2039
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:B1
Routes of
administration 		By mouth, intramuscular, intravenous, intrapleural, intraarticular
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • EU:Rx-only [2]
Pharmacokinetic data
Bioavailability 50–70%
Metabolism Liver
Elimination half-life 0.75–1 hour [3]
Excretion Kidney [3]
Identifiers
  • (2S,5R,6R)-6-({[3-(2-chloro-5-fluorophenyl)-5-methylisoxazol-4-yl]carbonyl}amino)-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid
CAS Number
PubChem CID
DrugBank
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.023.683 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H17ClFN3O5S
Molar mass 453.87 g·mol−1
3D model (JSmol)
  • O=C(O)[C@@H]3N4C(=O)[C@@H](NC(=O)c2c(onc2c1c(F)cccc1Cl)C)[C@H]4SC3(C)C
  • InChI=1S/C19H17ClFN3O5S/c1-7-10(12(23-29-7)11-8(20)5-4-6-9(11)21)15(25)22-13-16(26)24-14(18(27)28)19(2,3)30-17(13)24/h4-6,13-14,17H,1-3H3,(H,22,25)(H,27,28)/t13-,14+,17-/m1/s1 Yes check.svgY
  • Key:UIOFUWFRIANQPC-JKIFEVAISA-N Yes check.svgY
   (verify)

Flucloxacillin, also known as floxacillin, is an antibiotic used to treat skin infections, external ear infections, infections of leg ulcers, diabetic foot infections, and infection of bone. [4] It may be used together with other medications to treat pneumonia, and endocarditis. [4] It may also be used prior to surgery to prevent Staphylococcus infections. [4] It is not effective against methicillin-resistant Staphylococcus aureus (MRSA). [5] It is taken by mouth or given by injection into a vein or muscle. [4]

Contents

Common side effects include an upset stomach. [4] Other side effects may include muscle or joint pains, shortness of breath, and liver problems. [4] [6] It appears to be safe during pregnancy and breastfeeding. [4] It should not be used in those who are allergic to penicillin. [4] It is a narrow-spectrum beta-lactam antibiotic of the penicillin class. [6] It is similar in effect to cloxacillin and dicloxacillin, being active against penicillinase forming bacteria. [7]

Flucloxacillin was patented in 1961. [8] It is not commonly used in the United States or Canada as of 2011. [9]

Medical uses

Flucloxacillin is an antibiotic used to treat skin infections, external ear infections, infections of leg ulcers, diabetic foot infections, and infection of bone. [4]

Skin

Flucloxacillin is used for both staphylococcal and streptococcal skin infections. [10] These include folliculitis, carbuncles, [11] impetigo, ecthyma, cellulitis, erysipelas, necrotising fasciitis, and infections of skin conditions such as eczema, scabies, ulcers and acne. [4] [10] [12] Due to the widespread belief that dual-therapy is needed to cover both Staphylococcus and Streptococcus in cellulitis, flucloxacillin is sometimes given with the addition of benzylpenicillin for more severe cellulitis. [3] However, support for this practice has lessened since findings in a study published in the Emergency Medicine Journal in 2005 did not show this combination to give additional clinical benefit. [13] [14] [15] In the UK, using flucloxacillin alone is the first choice for treating cellulitis. Some other countries vary. [16]

Wounds

Infections of leg ulcers can be treated with flucloxacillin. [4] With diabetic foot infections the dose is adjusted according to whether the infection appears mild, moderate or severe. [4]

Bone

Despite having a lower than optimum drug penetration into bone ratio of 10–20%, flucloxacillin appears effective in treating osteomyelitis. [17] [18]

Depending on local guidance it may be used in the treatment of infection of joints while waiting for culture results. [3] [19]

Other

It may be used in combination with other antibiotics to treat pneumonia and can be used to prevent infection before surgery, particularly heart, lung, or bone surgery. [4] [12] When used to treat endocarditis, in combination with other antibiotics or alone, the dose of flucloxacillin may need to exceed the usual dose. [4]

Resistance

Despite flucloxacillin being insensitive to beta-lactamases, some organisms have developed resistance to it and other narrow-spectrum β-lactam antibiotics including methicillin. Such organisms include methicillin-resistant Staphylococcus aureus, which has developed resistance to flucloxacillin and other penicillins by having an altered penicillin-binding protein. [20]

Side effects

Common side effects associated with the use of flucloxacillin include: diarrhoea, nausea, rash, urticaria, pain and inflammation at injection site, superinfection (including candidiasis), allergy, and transient increases in liver enzymes and bilirubin. [21]

Rarely, in fewer than 1 in 1,000 people, cholestatic jaundice (also referred to as cholestatic hepatitis) has been associated with flucloxacillin therapy. It may appear as pale stool with dark urine, and yellowish eyes and skin. [22] The reaction may occur up to several weeks after treatment has stopped, and takes weeks to resolve. The estimated incidence is one in 15,000 exposures, and is more frequent in people over the age of 55, females, and those with a treatment duration of longer than two weeks. [4] [22] [21]

Flucloxacillin is contraindicated in those with a previous history of allergy to penicillins, cephalosporins, or carbapenems. It should also not be used in the eye, or administered to those with a history of cholestatic hepatitis associated with the use of dicloxacillin or flucloxacillin. [21]

It should be used with caution in the elderly, patients with renal impairment where a reduced dose is required, and those with hepatic impairment, due to the risk of cholestatic hepatitis. [21]

It should be taken on an empty stomach, one half to one hour before food, as absorption is reduced when taken with food, [23] though some studies suggest that this does not compromise flucloxacillin plasma concentrations in most circumstances. [24]

The UK's National Health Service recommends taking at least 30 minutes before food and at least 2 hours after. [22]

Drug interactions

Flucloxacillin can reduce the excretion of methotrexate, potentially resulting in a risk of methotrexate toxicity. The level of flucloxacillin in the blood may rise in kidney failure and with the use of probenecid. [7]

Mechanism of action

Flucloxacillin is a narrow-spectrum antibiotic belonging to the penicillin group of antibiotics. [6] [25] It works by breaking down the bacterial cell wall. [25]

Like other β-lactam antibiotics, flucloxacillin acts by inhibiting the synthesis of bacterial cell walls. It inhibits cross-linkage between the linear peptidoglycan polymer chains that make up a major component of the cell wall of Gram-positive bacteria.[ citation needed ]

Flucloxacillin is more acid-stable than many other penicillins and can be given orally, in addition to parenteral routes. However, like methicillin, it is less potent than benzylpenicillin against non-β-lactamase-producing Gram-positive bacteria.[ citation needed ]

Flucloxacillin has similar pharmacokinetics, antibacterial activity, and indications to dicloxacillin, and the two agents are considered interchangeable. It is reported to have higher, though rare, incidence of severe hepatic adverse effects than dicloxacillin, [26] but a lower incidence of renal adverse effects. [21]

Chemistry

Flucloxacillin is insensitive to beta-lactamase (also known as penicillinase) enzymes secreted by many penicillin-resistant bacteria. The presence of the isoxazolyl group on the side chain of the penicillin nucleus facilitates the β-lactamase resistance, since they are relatively intolerant of side chain steric hindrance. Thus, it is able to bind to penicillin-binding proteins and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.[ citation needed ]

History

Flucloxacillin was developed in the 1960s following an increase in penicillin-resistant (beta-lactamase producing) staphylococcal infections due to the widespread use of benzylpenicillin by 1960. [27] [28] All the natural penicillins and first semi-synthetic penicillins were destroyed by staphylococcal beta-lactamase, leading Beecham (later GlaxoSmithKline) to search for more stable antibiotics. By 1962, a series of similarly structured acid-stable penicillins (oxacillin, cloxacillin, dicloxacillin and flucloxacillin), with the potential for being taken by mouth, were developed. Flucloxacillin and dicloxacillin showed particular stability against the beta-lactamase enzyme of Staph. aureus and could withstand acid. [27] [28] Beecham further developed cloxacillin and popularised flucloxacillin in the UK, while Bristol Laboratories concentrated on marketing oxacillin and dicloxacillin in the United States, leading to the difference in use in both countries. [29] [30] Flucloxacillin was first marketed in Europe in the 1970s. [6]

Available forms

Both the oral and intravenous preparations of flucloxacillin are inexpensive and are available as the sodium salt flucloxacillin sodium, in capsules (250 or 500 mg), oral suspensions (125 mg/5 ml or 250 mg/5 ml), and injections (powder for reconstitution, 250, 500, 1000 and 2000 mg per vial). [3] [31]

Flucloxacillin is not commonly used in the United States or Canada as of 2011. [6] In several other countries however, it is supplied under a variety of trade names including Floxapen, Flopen, Flubex, Flupen, Phylopen, and Staphylex. [1]

Combination

Flucloxacillin is combined with ampicillin in co-fluampicil. [4]

Related Research Articles

<span class="mw-page-title-main">Penicillin</span> Group of antibiotics derived from Penicillium fungi

Penicillins are a group of β-lactam antibiotics originally obtained from Penicillium moulds, principally P. chrysogenum and P. rubens. Most penicillins in clinical use are synthesised by P. chrysogenum using deep tank fermentation and then purified. A number of natural penicillins have been discovered, but only two purified compounds are in clinical use: penicillin G and penicillin V. Penicillins were among the first medications to be effective against many bacterial infections caused by staphylococci and streptococci. They are still widely used today for different bacterial infections, though many types of bacteria have developed resistance following extensive use.

<span class="mw-page-title-main">Beta-lactam antibiotics</span> Class of broad-spectrum antibiotics

β-lactam antibiotics are antibiotics that contain a beta-lactam ring in their chemical structure. This includes penicillin derivatives (penams), cephalosporins and cephamycins (cephems), monobactams, carbapenems and carbacephems. Most β-lactam antibiotics work by inhibiting cell wall biosynthesis in the bacterial organism and are the most widely used group of antibiotics. Until 2003, when measured by sales, more than half of all commercially available antibiotics in use were β-lactam compounds. The first β-lactam antibiotic discovered, penicillin, was isolated from a strain of Penicillium rubens.

<i>Staphylococcus aureus</i> Species of Gram-positive bacterium

Staphylococcus aureus is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often positive for catalase and nitrate reduction and is a facultative anaerobe that can grow without the need for oxygen. Although S. aureus usually acts as a commensal of the human microbiota, it can also become an opportunistic pathogen, being a common cause of skin infections including abscesses, respiratory infections such as sinusitis, and food poisoning. Pathogenic strains often promote infections by producing virulence factors such as potent protein toxins, and the expression of a cell-surface protein that binds and inactivates antibodies. S. aureus is one of the leading pathogens for deaths associated with antimicrobial resistance and the emergence of antibiotic-resistant strains, such as methicillin-resistant S. aureus (MRSA), is a worldwide problem in clinical medicine. Despite much research and development, no vaccine for S. aureus has been approved.

<span class="mw-page-title-main">Methicillin</span> Antibiotic medication

Methicillin (USAN), also known as meticillin (INN), is a narrow-spectrum β-lactam antibiotic of the penicillin class.

<span class="mw-page-title-main">Cephalosporin</span> Class of pharmaceutical drugs

The cephalosporins are a class of β-lactam antibiotics originally derived from the fungus Acremonium, which was previously known as Cephalosporium.

<span class="mw-page-title-main">Cefazolin</span> Antibiotic medication

Cefazolin, also known as cefazoline and cephazolin, is a first-generation cephalosporin antibiotic used for the treatment of a number of bacterial infections. Specifically it is used to treat cellulitis, urinary tract infections, pneumonia, endocarditis, joint infection, and biliary tract infections. It is also used to prevent group B streptococcal disease around the time of delivery and before surgery. It is typically given by injection into a muscle or vein.

<span class="mw-page-title-main">Cloxacillin</span> Beta-lactam antibiotic

Cloxacillin is an antibiotic useful for the treatment of a number of bacterial infections. This includes impetigo, cellulitis, pneumonia, septic arthritis, and otitis externa. It is not effective for methicillin-resistant Staphylococcus aureus (MRSA). It can be used by mouth and by injection.

<span class="mw-page-title-main">Cefalexin</span> Beta-lactam antibiotic

Cefalexin, also spelled cephalexin, is an antibiotic that can treat a number of bacterial infections. It kills gram-positive and some gram-negative bacteria by disrupting the growth of the bacterial cell wall. Cefalexin is a β-lactam antibiotic within the class of first-generation cephalosporins. It works similarly to other agents within this class, including intravenous cefazolin, but can be taken by mouth.

<span class="mw-page-title-main">Cefuroxime axetil</span> Chemical compound

Cefuroxime axetil, sold under the brand name Ceftin among others, is a second generation oral cephalosporin antibiotic.

<span class="mw-page-title-main">Piperacillin</span> Antibiotic medication

Piperacillin is a broad-spectrum β-lactam antibiotic of the ureidopenicillin class. The chemical structure of piperacillin and other ureidopenicillins incorporates a polar side chain that enhances penetration into Gram-negative bacteria and reduces susceptibility to cleavage by Gram-negative beta lactamase enzymes. These properties confer activity against the important hospital pathogen Pseudomonas aeruginosa. Thus piperacillin is sometimes referred to as an "anti-pseudomonal penicillin".

<span class="mw-page-title-main">Dicloxacillin</span> Chemical compound

Dicloxacillin is a narrow-spectrum β-lactam antibiotic of the penicillin class. It is used to treat infections caused by susceptible (non-resistant) Gram-positive bacteria. It is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. Dicloxacillin is available under a variety of trade names including Diclocil (BMS).

<span class="mw-page-title-main">Oxacillin</span> Chemical compound

Oxacillin is a narrow-spectrum beta-lactam antibiotic of the penicillin class developed by Beecham.

Antistaphylococcal penicillins are a chemical compound. They are a class of Beta lactam antibiotics used to treat infections caused by bacteria.

<span class="mw-page-title-main">Cefoxitin</span> Chemical compound

Cefoxitin is a second-generation cephamycin antibiotic developed by Merck & Co., Inc. from Cephamycin C in the year following its discovery, 1972. It was synthesized in order to create an antibiotic with a broader spectrum. It is often grouped with the second-generation cephalosporins. Cefoxitin requires a prescription and as of 2010 is sold under the brand name Mefoxin by Bioniche Pharma, LLC. The generic version of cefoxitin is known as cefoxitin sodium.

β-Lactamase inhibitor Family of enzymes

Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-lactam antibiotics. In bacterial resistance to beta-lactam antibiotics, the bacteria have beta-lactamase which degrade the beta-lactam rings, rendering the antibiotic ineffective. However, with beta-lactamase inhibitors, these enzymes on the bacteria are inhibited, thus allowing the antibiotic to take effect. Strategies for combating this form of resistance have included the development of new beta-lactam antibiotics that are more resistant to cleavage and the development of the class of enzyme inhibitors called beta-lactamase inhibitors. Although β-lactamase inhibitors have little antibiotic activity of their own, they prevent bacterial degradation of beta-lactam antibiotics and thus extend the range of bacteria the drugs are effective against.

<span class="mw-page-title-main">Benzylpenicillin</span> Antibiotic medication

Benzylpenicillin, also known as penicillin G (PenG) or BENPEN, is an antibiotic used to treat a number of bacterial infections. This includes pneumonia, strep throat, syphilis, necrotizing enterocolitis, diphtheria, gas gangrene, leptospirosis, cellulitis, and tetanus. It is not a first-line agent for pneumococcal meningitis. Due to benzylpenicillin's limited bioavailability for oral medications, it is generally taken as an injection in the form of a sodium, potassium, benzathine, or procaine salt. Benzylpenicillin is given by injection into a vein or muscle. Two long-acting forms benzathine benzylpenicillin and procaine benzylpenicillin are available for use by injection into a muscle only.

mecA is a gene found in bacterial cells which allows them to be resistant to antibiotics such as methicillin, penicillin and other penicillin-like antibiotics.

<span class="mw-page-title-main">Ceftaroline fosamil</span> Chemical compound

Ceftaroline fosamil (INN), brand name Teflaro in the US and Zinforo in Europe, is a cephalosporin antibiotic with anti-MRSA activity. Ceftaroline fosamil is a prodrug of ceftaroline. It is active against methicillin-resistant Staphylococcus aureus (MRSA) and other Gram-positive bacteria. It retains some activity of later-generation cephalosporins having broad-spectrum activity against Gram-negative bacteria, but its effectiveness is relatively much weaker. It is currently being investigated for community-acquired pneumonia and complicated skin and skin structure infection.

Cephalosporins are a broad class of bactericidal antibiotics that include the β-lactam ring and share a structural similarity and mechanism of action with other β-lactam antibiotics. The cephalosporins have the ability to kill bacteria by inhibiting essential steps in the bacterial cell wall synthesis which in the end results in osmotic lysis and death of the bacterial cell. Cephalosporins are widely used antibiotics because of their clinical efficiency and desirable safety profile.

References

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  2. ↑ List of nationally authorised medicinal products. European Medicines Agency. November 2020
  3. 1 2 3 4 5 Hitchings A, Lonsdale D, Burrage D, Baker E (2015). The Top 100 Drugs e-book: Clinical Pharmacology and Practical Prescribing. Churchill Livingstone; Elsevier. p. 181. ISBN   978-0-7020-5516-4.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "5.2 Bacterial Infection". British National Formulary (BNF) (80 ed.). BMJ Group and the Pharmaceutical Press. September 2020 – March 2021. pp. 582–587. ISBN   978-0-85711-369-6.
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  7. 1 2 Weller RB, Hunter HJ, Mann MW (2014). Clinical Dermatology. John Wiley & Sons. p. 411. ISBN   978-1-118-85097-8.
  8. ↑ Alapi EM, Fischer J (2006). "Part III. Table of Selected Analogue Classes". In Fischer J, Ganellin CR (eds.). Analogue-based Drug Discovery. Wiley-VCH. p. 491. ISBN   978-3-527-31257-3.
  9. ↑ Devereaux BM, Crawford DH, Purcell P, Powell LW, Roeser HP (1995). "Flucloxacillin associated cholestatic hepatitis. An Australian and Swedish epidemic?". European Journal of Clinical Pharmacology. 49 (1–2): 81–85. doi:10.1007/BF00192363. PMID   8751026. S2CID   1259750.
  10. 1 2 Stanway, Amy. "Streptococcal skin infection – DermNet New Zealand". www.dermnetnz.org.
  11. ↑ Gould K (2016). "1.6 Applied surgical microbiology". In Thomas WE, Reed MW, Wyatt MG (eds.). Oxford Textbook of Fundamentals of Surgery. Oxford University Press. pp. 176–177. ISBN   978-0-19-966554-9.
  12. 1 2 "Flucloxacillin 125mg/5ml Oral solution – Summary of Product Characteristics (SmPC) – (emc)". medicines.org.uk. Archived from the original on 2 March 2021. Retrieved 16 December 2020.
  13. ↑ Leman P, Mukherjee D (May 2005). "Flucloxacillin alone or combined with benzylpenicillin to treat lower limb cellulitis: a randomised controlled trial". Emergency Medicine Journal. 22 (5): 342–6. doi:10.1136/emj.2004.019869. PMC   1726763 . PMID   15843702.
  14. ↑ Sarkar R, Nair V, Sinha S, Garg VK, Rodriguez DA (2011). "7. Infectious diseases". In Taylor S, Gathers RC, Callender VD, Rodriguez DA, Badreshia-Bansal SC (eds.). Treatments for Skin of Color E-Book. Saunders Elsevier. p. 121. ISBN   978-1-4377-0859-2.
  15. ↑ Cox NH (2009). "41. Streptococcal Cellulitis/Erysipelas of the lower leg". In Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B (eds.). Evidence-Based Dermatology (2nd ed.). Blackwell Publishing. p. 409. ISBN   978-1-4051-4518-3.
  16. ↑ Sullivan T, de Barra E (March 2018). "Diagnosis and management of cellulitis". Clinical Medicine. 18 (2): 160–163. doi:10.7861/clinmedicine.18-2-160. PMC   6303460 . PMID   29626022.
  17. ↑ Preiss H, Kriechling P, Montrasio G, Huber T, Janssen İ, Moldovan A, et al. (1 January 2020). "Oral Flucloxacillin for Treating Osteomyelitis: A Narrative Review of Clinical Practice". Journal of Bone and Joint Infection. 5 (1): 16–24. doi:10.7150/jbji.40667. PMC   7045523 . PMID   32117685.
  18. ↑ Thabit AK, Fatani DF, Bamakhrama MS, Barnawi OA, Basudan LO, Alhejaili SF (April 2019). "Antibiotic penetration into bone and joints: An updated review". International Journal of Infectious Diseases. 81: 128–136. doi: 10.1016/j.ijid.2019.02.005 . PMID   30772469.
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