Chemical structure of Flucloxacillin.
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Flucloxacillin

Flucloxacillin (INN) or floxacillin (USAN) is a narrow spectrum beta-lactam antibiotic. It is used to treat infections caused by susceptible Gram-positive bacteria. Notably, it is active against beta-lactamase-producing organisms such as Staphylococcus aureus, which would otherwise be resistant to most penicillins. It is very similar to dicloxacillin and these two agents are considered interchangeable. Flucloxacillin is available under a variety of trade names including Flopen (CSL) and Floxapen (GSK). more...

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Mode of action

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.

Medicinal 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 (PBPs) and inhibit peptidoglycan crosslinking, but is not bound by or inactivated by β-lactamases.

Clinical use

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.

Flucloxacillin has similar pharmacokinetics, antibacterial activity and indications to dicloxacillin and the two agents are considered interchangeable. It is believed to have higher incidence of severe hepatic adverse effects than dicloxacillin, but a lower incidence of renal adverse effects. (Rossi, 2006)

Available forms

Flucloxacillin is commercially 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 and 1000 mg per vial).

Indications

Flucloxacillin is indicated for the treatment of infections caused by susceptible bacteria. Specific approved indications include: (Joint Formulary Committee, 2005; Rossi, 2006)

  • Staphylococcal skin infections and cellulitis – including impetigo, otitis externa, folliculitis, boils, carbuncles, and mastitis
  • Pneumonia (adjunct)
  • Osteomyelitis, septic arthritis
  • Septicaemia
  • Empirical treatment for endocarditis
  • Surgical prophylaxis

Flucloxacillin has relatively poor activity, as noted above, against non-β-lactamase-producing bacteria including Streptococcus pyogenes. Therefore empirical therapy for significant cellulitis often involves dual-therapy to cover both staphylococci and streptococci, using either penicillin or ampicillin in addition to flucloxacillin. The latter is available as a standardardised combination preparation co-fluampicil (flucloxacillin+ampicillin).

Precautions/contraindications

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 those with a history of cholestatic hepatitis associated with the use of dicloxacillin or flucloxacillin. (Rossi, 2006)

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Bacterial contaminants and antibiotic prophylaxis in total hip arthroplasty
From Journal of Bone and Joint Surgery, 9/1/05 by Al-Maiyah, M

We have investigated the contaminating bacteria in primary hip arthroplasty and their sensitivity to the prophylactic antibiotics currently in use. Impressions (627) of the gloved hands of the surgical team in 50 total hip arthroplasties were obtained on blood agar. The gloves were changed after draping, at intervals of 20 minutes thereafter, and before using cement. Changes were also undertaken whenever a visible puncture was detected. The culture plates were incubated at 37 C for 48 hours. Isolates were identified and tested for sensitivity to flucloxacillin, which is a recognised indicator of sensitivity to cefuroxime. They were also tested against other agents depending upon their appearance on Gram staining.

We found contamination in 57 (9%) impressions and 106 bacterial isolates. Coagulase-negative staphylococci were seen most frequently (68.9%), but we also isolated Micrococcus (12.3%), diphtheroids (9.4%), Staphylococcus aureus (6.6%) and Escherichia coli (0.9%). Of the coagulase-negative staphylococci, only 52.1% were sensitive to flucloxacillin and therefore to cefuroxime. We believe that it is now appropriate to review the relevance of prophylaxis with cefuroxime and to consider the use of other agents.

Although infection after total hip arthroplasty (THA) may he caused by haematogcnous seeding, it is more commonly due to bacteria entering the wound at the time of surgery.1,2The mam sources of contamination are the skin flora of the patient and airborne bacteria from theatre personnel and the environment of the operating theatre.3,4 In order to address this problem, various measures have been introduced to control the operating environment. These have included the use of laminar air flow1,4 and Charnley's ultraclean air system, comprising sterile hoods and a body-exhaust system, which has reduced rates of infection from 9% to 1.3%,1,3,5 and prophylactic antibiotics.6 However, for the latter to he effective, they should he active against the pathogens most likely to contaminate surgical wounds. Many studies have demonstrated an increase in bacterial resistance against some antibiotics.8-10 Most post-operative prosthetic hip infections are caused by Gram-positive cocci, predominantly staphylococci.1,2 Recently, beta-lactam-resistant staphylococci have become increasingly common,11,14 reducing the efficacy of antibiotic prophylaxis using penicillins or cephalosporins. Our review of the available literature showed that most studies of antibiotic prophylaxis were carried out in the 1980s and 1990s.15-18

We undertook this study in order to identify the contaminating bacteria in our hip arthroplasty practice and to establish their sensitivity to prophylactic antibiotics in current use.

This work follows an earlier study carried out at our institution19 which highlighted significant levels of glove contamination in hip arthroplastyr20

Materials and Methods

During the course of JO THAs impressions of the gloved hands of the principal surgeon, first assistant and scrub nurse were obtained on sterile culture media (blood agar), immediately before the gloves were either changed or discarded. We only included the outer gloves in this study.

Gloves were changed after draping and thereafter either at intervals of 20 minutes or immediately before using cement, if this occurred before the end of a 20-minutc interval, and whenever a visible puncture was detected. Impressions of both hands were obtained on the same blood agar plate. Culture plates were sent to the microbiology department for incubation at 37°C for 48 hours and a consultant microbiologist (DH) reported the results. All isolates were identified by Gram stain and basic identification tests such as catalase, coagulase and oxidase reactions. The isolates were then tested for sensitivity to flucloxacillin, a recognised indicator of sensitivity to cefuroxime. Methicillin resistance implies clinical resistance to all heta-lactam antibiotics, including the cephalosporins.21 We also tested Gram-positive isolates against gentamicin, fusidic acid and linezolid Escherichia coli against gentamicin, cefuroxime and amoxicillin and pseudomoas species against gcntamicin, ceftazidime and piperacillin/tazobactam.

Results

Impressions of 627 pairs of gloved hands were included in the study, of which 57 (9%) were found to he contaminated. There were 106 bacterial isolates, of which coagulase-negative staphylococcus was the most common, followed by Micrococcus species and diphtheroids. Staphylococcus aureus was also identified as were Pseudomonas species and E. coli (Table I).

Only 38 (52.1%) of the isolates of coagulase-negative staphylococcus were found to be sensitive to flucloxacillin and therefore to cefuroxime, although 89.4% were sensitive to fusidic acid and 95.9% to gentamicin.

For Staph). aureus, 71.4% were sensitive to flucloxacillin and therefore to cefuroxime while 85.7% were sensitive to fusidic acid and gentamicin. For the Mirrocnccus species, 69.2% were sensitive to flucloxacillin and all to fusidic acid and gentamicin.

For the isolated diphtheroids, 80% were sensitive to flucloxacillin and fusidic acid and all to gentamicin. All Grampositive isolates (n = 103) were sensitive to linezolid.

The one isolated coliform was sensitive to all the agents tested. Both Pseudomonas species isolated were sensitive to gentamicin, piperacillin and tazohactum, although one isolate was resistant to ceftazidime.

Discussion

The role of theatre ventilation, theatre clothing and prophylactic antibiotics is undisputed in reducing the rate of deep infection after THA. The rates of infection have been reduced from 9.5% in 1964, for operations performed in unventilatcd theatres,22 to the current rate of 0.3% in Sweden23 and 1.4% in the UK24 for more modern designs of operating theatres. Our findings question whether cefuroxime is the most appropriate agent for antibiotic prophylaxis since staphylococci represented 75% of contaminating isolates, nearly half of which were resistant to it.

In a study from Wrightington Hospital, Wigan, UK, tissue samples were collected for bacteriological study during primary and revision hip surgery.12 It was found that coagulase-negative staphylococcus was the most common isolate (43.4%), 55% being methicillin-rcsistant. We can therefore confidently infer that those isolates were also resistant to cefuroxime. Coagulase-negative staphylococcus displays nearly total cross-resistance to cephalosporins, including cefuroxime.21

The proportion of coagulase-negative staphylococcus in infected THAs has varied between 5% and 70%.14 James et al11 found that 18 of 30 positive bacteriological cultures from tissue samples collected at surgery showed Staphylococcus epidermidis, 12 of which (67%) were methicillin-resistant (MRSR). In the same study, MRSE was cultured from 2.9 of 100 skin swabs collected from 100 consecutive patients at the time of admission for THA. The authors expressed their concern about the use of cefuroxime as a prophylactic agent. However, despite this, cefuroxime is still a commonly-used prophylactic antibiotic for joint replacement surgery in the UK and has been extensively studied.25-28

Patterns of bacterial resistance vary with both time29 and location.30,31 However, since 95% of our isolates were sensitive to gentamicin, it seems appropriate to continue the use of this agent in the bone cement used at THA. We also found that all our Gram-positive bacterial isolates were sensitive to linezolid, a relatively new agent, although some might argue that it should be reserved for the treatment of significant, multiresistant infections with Gram-positive organisms in order to limit the emergence of bacterial resistance to the antibiotic. We did not test our isolates against vancomycin because disc testing is known to be unreliable for this.32 However, vancomycin resistance in staphylococci is rare."

In 1999, Glenny and Song18 undertook a systematic review of antimicrobial prophylaxis in THA and concluded that the universal acceptance of a fixed antimicrobial regimen should be avoided in order to minimise the development of resistance to antibiotics. They also recommended that local guidelines, based upon available evidence should he developed by surgeons, microbiologists and pharmacists, taking into account the local sensitivities of the organisms commonly implicated in infected THAs. These guidelines should be continuously reviewed and updated since no definitive version could be established.18

From our study, it is difficult to draw firm conclusions about which prophylactic antibiotics to use since bacterial sensitivities can change over time and between different geographical areas. However, we believe that it is now appropriate to review the role of cefuroxime in prophylaxis and to consider further work in order to identify the best prophylactic agents.

Supplementary Material

e A further opinion by Mr Dietmar Konig is available with the electronic version of this article on our website at www.jbjs.org.uk

This study had been funded from Professor P J Gregg research fund and the bacteriological studies were conducted in Microbiology Department, James Cook University Hospital.

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

References

1. Charnley J. Postoperative infections after total hip replacement with special reference to air contamination in the operating room. Clin Orthop 1972:87:167-87.

2. Fitzgerald RH Jr, Nolan DR, llstrup DM, et al. Deep wound sepsis following tola hipaithroplasty. J Bone Joint Surg [Am] 1977;59-A:847-55.

3. Ha'eri GB, Wiley AM. Total hip replacement in a laminar flow environment with special reference to deep infection. Clin Orthop 1980:148:163-8.

4. Howorth FH. Prevention of airborne infection during surgery. Lancet 1985:1:386-8.

5. Charnley J, Eftekhar N. Postoperative infection in total prosthetic replacement arthroplasty of the hip joint: with special reference to the bacterial content of the air in the operating room. Br J Surg 1969:56:641 -9.

6. Carlsson AS, Lidgren L, Lindberg L Prophylactic antibiotics against early and late deep infections after total hip replacement. Acta OrthopScand 1977:48:405-10.

7. Gorbach SL, Condon RE, Conte JE Jr, et al. Evaluation of new anti-infective drugs for surgical prophylaxis: Infections Diseases Society of America and Food and Drug Administration. CHn Infect Dis 1992:15(Suppl 11:313-38.

8. Roberts NJ, Douglas RG. Gentamicin use and Pseudomonas and Serratia resistance: effect of surgical prophylaxis regimen. Antimicmb Agents Chemother 1978:13:214-20.

9. Harrison GA, Stress WP, Rubin MP, et al. Resistance in oral steptococci after repeated three-dose erythromycin prophylaxis. J Antimicmb Chemother 1985:15:471-9.

10. Kotilainen P, Nikokelainen J, Huovinen P. Emergence of ciprofloxacin-resistant congulase-negative staphylococcal skin flora in immunocompromised patients receiving ciproflaxacin. J Infect Dis 1990:161:41-4.

11. James PJ, Butcher IA, Gardner ER, Hamblen DL. Methicillin-resistant staphylococcus epidermidis in infection of hiparthropiasty. J Bone Joint Surg [Br] 1994:76-B: 725-7.

12. Mohanty SS, Kay PR. Infection during total hip replacements: why we screen MRSA when MRSE is the problem? J Bone Joint Surg [Br] 2004;86-B:266-8.

13. De LaIIa F. Antibiotic prophylaxis in orthopedic prosthetic surgery. J Chemother 2001:13:48-53.

14. Hope PG, Kristinsson KG, Norman P, Elson RA. Deep infection of cemented total hip arthroplasties caused bycoagulase-negative staphylococci. J Bone Joint Surg/Br] 1989:71-6:851-5.

15. Mauerhan D, Nelson C, Smith D, et al. Prophylaxis infection in total joint arthroplasty: one day of cefuroxime compared with three dayscefazolin. J Bone Joint Surg [Am]1994:76-A:39-45.

16. Wollinsky K, Oethinger M, Buchele M, et al. Autotransfusion: bacterial contamination during hip arthroplasty and efficacy of cefuroxime prophylaxis: a randomised controlled study of 40 patients. Acta OrthopScand 1997:68:225-30

17. Evrard J, Mazas F, Acar J, Doyon F, Flamant R. Comparison of 2 preventive antibiotic treatments in total hip arthroplasty. Rev Clin Orthop Reparatrice Appar Mot 1985:71 (Suppl2]:37 (in French].

18. Glenny AM, Song F. Antimicrobial prophylaxis in total hip replacement: a systematic review. Health Technology Assessment 1999:3:19.

19. AI-Maiyah M, Bajwa A, Mackenney P, et al. Glove perforation and contamination in primary total hip arthroplasty. J Bone Joint Surg [Br] 2005:87-6:556-9.

20. Young EJ, Sugarman B. Infections in prosthetic devices. Surg Clin North Am 1989: 68:167-80.

21. John JF Jr, McNeMIWF. Activity of cephalosporins against methicillin-susceptible and methicillin-resistant, coagulase-negative staphylococci: minimal effect of bataactmase. Ant/microb Agents Chemother 1980:17:179-83.

22. Charnley J. A clean-air operating enclosure. Br J Surg 1964:51:202-5.

23. Lidgren L Joint prosthetic infections: a success story. Acta Orthop Scand2001:72: 553-6.

24. Fender D, Harper WM, Gregg PJ. Outcome of Charnley total hip replacement across a single health care region in England. J Bone Joint Surg [BrJ 1999:81-6:577-81.

25. Wymenga A, van Horn J, Theeuwes A, Muytjens H, Slooff T. Cefurozime for prevention of postoperative coxitis: one versus three doses tested in a randomised multicenter study of 2,651 arthroplasties Acta Orthop Scand Î 992:62:19-24.

26. Hughes SP, Want S, Darrell JH, Dash CH, Kennedy M. Prophylactic cefuroxime in total joint replacement. Im Orthop 1982:6:155-61.

27. Innes A, Hughes SP, Robertson S, Dash CH. Cefuroxime in CMW bone cement: a clinical study. Im Orthop 1985:9:265-9.

28. McQueen MM, Hughes SP, May P, Verity L. Cefuroxime in total joint arthroplasty: intravenous or in bone cement. J Arthroplasty 1990;5:169-72.

29. Richardson JF, Marples RR. Changing resistance to antimicrobial drugs, and resistance typing in clinically significant strains or Staphylococcus epidermidis. J Med Microbiol 1982:15:475-84.

30. Kresken M, Wiedemann B. Development of resistance to nalidixic acid and the fluoroquinolones after the introduction of norfloxacin and ofloxacin. Antiinicrob Agents and Chemother 1988:32:1285-8.

31. Felmingham D, Robbins MJ, Dencer C, Nathwani A, Gruneberg RN. A multi centre collaborative study of the antimicrobial susceptibility of community-acquired, lower respiratory tract pathogens 1992-1993: the Alexander Project. J Antimicmb Chemother 1996:38:747-51.

32. Communicable Disease Report. Detecting vancomycin intermediate Staphyloccocus aureus. CDR Weekly 1997:7:417-20.

33. Wilcox MH, Fawley W. Extremely low prevalence of UK Staphylococcus aureus isolates with reduced susceptibility to vancomycin. J Antimicmb Chemother 2001;48:144-5.

M. Al-Maiyah, D. Hill, A. Bajwa, S. Slater, P. Patil, A. Port, P.J.Grcgg

From James Cook University Hospital, Middlesbrough, England

* M. Al-Maiyah, FRCS, FICMS, MSc, Specialist Registrar in Trauma and Orthopaedics

* D. Hill, MRCS(Path), Consultant Microbiology

* A. Bajwa, MRCS, MSc, Specialist Registrar in Trauma and Orthopaedics

* S. Slater, BSc(Hons), Research Assistant

*P. Patil, MRCS, Senior House Officer in Trauma and Orthopaedics

* A. Port, FRCS(Orth), Consultant in Trauma and Orthopaedics

* P. J. Gregg, FRCS, Professor of Trauma and Orthopaedics

James Cook University Hospital, Middlesbrough, TS4 3BW, UK.

Correspondence should be sent to Mr M. Al-Maiyah c/o MrA. Port's secretary, Orthopaedic Department, James Cook University Hospital, Middlesbrough TS43BW, UK; e-mail: mamaiyah@yahoo.co.uk

©2005 British Editorial Society of Bone and Joint Surgery

doi:10.1302/0301-620X.87B9. 15685 $2.00

J Bone Joint Surg [Br]

2005:87-6:1256-8.

Received 28 May 2004; Accepted after revision 21 April 2005

Copyright British Editorial Society of Bone & Joint Surgery Sep 2005
Provided by ProQuest Information and Learning Company. All rights Reserved

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