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 Table of Contents  
PG CORNER
Year : 2018  |  Volume : 30  |  Issue : 2  |  Page : 152-154

Preparation of fortified antimicrobial eye drops


Department of Ophthalmology, Little Flower Hospital and Research Centre, Ernakulam, Kerala, India

Date of Web Publication28-Aug-2018

Correspondence Address:
Hilda K Nixon
M T Joseph Meleppuram, Meleppuram House, Potta P.O, Chalakudy, Thrissur - 680 722, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/kjo.kjo_63_18

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  Abstract 

Fortification means to intensify or strengthen the medication, to achieve adequate drug concentration. Fortified antimicrobials are not commercially available, thus should be, prepared of optimal constitution in a sterile pharmaceutical dispensary. This article provides guidelines on topical fortified therapy dosage concentration and methodology of preparation of drugs for patients with infectious keratitis. Acquaintance on fortified antimicrobial medication, its appropriate usage and timely intervention will help us to treat most of the resistant microbial keratitis and prevent the need for surgical intervention.

Keywords: Fortified medication, microbial keratitis, topical therapy


How to cite this article:
Nixon HK. Preparation of fortified antimicrobial eye drops. Kerala J Ophthalmol 2018;30:152-4

How to cite this URL:
Nixon HK. Preparation of fortified antimicrobial eye drops. Kerala J Ophthalmol [serial online] 2018 [cited 2018 Dec 11];30:152-4. Available from: http://www.kjophthal.com/text.asp?2018/30/2/152/239986


  Fortified Antimicrobial Eyedrops Top


Most of our available ophthalmic antibiotic preparations are in 0.3% concentration, which is not sufficient to attain minimum inhibitory concentration to halt the progression of resistant keratitis.[1]

Fortification means to intensify or strengthen the medication to achieve adequate drug concentration. Fortified medications have better inhibitory effect on pathogens than the commercially available topical medications.

Fortified antimicrobials are not commercially available, thus should be prepared of optimal constitution in a sterile pharmaceutical dispensary. For preparation of fortified antibiotics, a standard parenteral or lyophilized antibiotic preparation is combined with a compatible vehicle such that the antibiotic does not precipitate.[2]


  The Need for Fortification of Antibiotics Top


  • For resistant microbial keratitis, to attain appropriate drug concentration and to stop the fulminant rapid progression of keratitis
  • For moderate-to-severe corneal ulcers
  • For pediatric patients as ocular surface bacterial infections affect with a high frequency in newborns and children [3]
  • For drugs that are available only in parenteral form. For example - vancomycin and amphotericin B.


Limitations

  • High cost
  • Contamination risk
  • Since it is a preservative-free preparation, they have short shelf-life
  • Need for refrigeration.



[Table 1]">  List of Fortified Drugs [Table 1] Top
Table 1: Drugs and their coverage[1],[9]

Click here to view


Aminoglycosides

  1. Fortified tobramycin: 14 mg/ml (1.4%)
  2. Fortified gentamicin eyedrops: 14 mg/ml (1.4%)
  3. Fortified amikacin eyedrops: 40 mg/ml


Cephalosporins

  1. Fortified cefazolin eyedrops: 50 mg/ml (5%)
  2. Fortified ceftazidime eyedrops: 50 mg/ml (5%)
  3. Topical vancomycin eyedrops: 50 mg/ml (5%)
  4. Topical linezolid 2 mg/ml (0.2%)
  5. Topical colistin (0.19%)
  6. Topical imipenem–cilastatin eyedrops (1%).


Antifungals

  • Topical amphotericin B (0.15%)
  • Topical voriconazole eyedrops (1%).


General guidelines

  • Selection of fortified antimicrobials must be adapted to the type of bacteria suspected for safe and effective treatment
  • Fortified drops should be prepared by a doctor or a pharmacist inside a laminar air hood/operation room under aseptic precautions
  • Disposable syringe should be used
  • Date of preparation and date of expiry should be mentioned in prepared drops
  • Frequency of application with storage instructions should be explained to the patient
  • Short shelf-life (preservative free)
  • Since there is a risk for contamination and also it is preservative free, it should be refrigerated and can be kept up to 7 days at 4°C
  • Shake well before instillation.


Preparation of aminoglycosides

Fortified tobramycin or fortified gentamycin 14 mg/ml (1.4%)

  • Method: Take 2 ml from an injectable vial of intravenous (IV) tobramycin or gentamicin (40 mg/ml). Add the injected 2 ml to a 5-ml bottle of commercially available tobramycin or gentamycin eyedrops (0.3%)[1],[5]
  • Shelf-life: Refrigerate and shake well before instillation.


Fortified amikacin 40 mg/ml

  • Method: IV formulation can be used (80 mg/2 cc ampules)[1],[5]
  • Shelf-life: Refrigerate and shake well before instillation.


Preparation of cephalosporins

Fortified cefazolin eyedrops: 50 mg/ml (5%) or fortified ceftazidime: 50 mg/mL (5%)

  • Method: Add 9.2 ml of artificial tears to a vial of cefazolin 1 g (powder for injection) and dissolve. Take 5 ml of this solution and add it to 5 ml of artificial tears [1],[5]
  • Shelf-life: Refrigerate and shake well before instillation.


Topical vancomycin eyedrops: 15 mg/ml, 25 mg/ml, or 50 mg/ml (5%)

  • Method: To a 500 mg vial of vancomycin:[1],[5]


    1. Add 33 ml of 0.9% sodium chloride for injection USP (no preservatives) or artificial tears to produce a solution of 15 mg/ml.
    2. Add 20 ml of 0.9% sodium chloride for injection USP (no preservatives) or artificial tears to produce a solution of 25 mg/ml.
    3. Add 10 ml of 0.9% sodium chloride for injection USP (no preservatives) or artificial tears to produce a solution of 50 mg/ml.


  • Storage: Refrigerate and shake well before instillation.


Topical linezolid 2 mg/ml (0.2%)

Method: Can be used directly from parenteral linezolid available as 200 mg/100 ml (2 mg/ml) IV infusion.[6]

Topical colistin (0.19%)

  • Indication: Multiple drug-resistant Pseudomonas aeruginosa bacterial keratitis
  • Method: It is prepared from parenteral colistimethate sodium powder (Xylistin) 1 million IU/75 mg and added to 10 ml of distilled water to obtain 7.5 mg/ml (0.75%). 1 ml of the above solution is then added to 3 ml of distilled water to obtain 0.19% colistin drops.[7]


Topical imipenem–cilastatin eyedrops (1%)

  • Method: To parenteral imipenem (500 mg)–cilastatin (500 mg), add 10 ml sterile water to create a solution of strength 50 mg/ml. Take 1 ml of this solution and add 4 ml of sterile water to make topical imipenem 1% to obtain 1 mg/ml [7]
  • Storage: In amber-colored bottles.


Preparation of antifungals

Topical amphotericin B (0.15%)

  • Method: Add 10 ml of distilled or sterile water to parenteral 50 mg of amphotericin B powder for injection. Draw 3 ml of this and add to 7 ml of artificial tear eyedrops [1],[5]
  • Shelf-life: Refrigerate and shake well before instillation
  • Storage: should not be exposed to light. The drops should be inspected at each visit for any turbidity, which may indicate contamination or drug precipitation.


Topical voriconazole eyedrops (1%)

  • Method: Voriconazole powder (200 mg) was reconstituted with 19 ml of water for injections in order to obtain 20ml of a 10-mg/ml voriconazole solution: Voriconazole eyedrops (1%)[8]
  • Storage: Refrigerate at 4°C and shake well before instillation
  • Others: Trimethoprim/sulfamethoxazole
  • 16 mg/ml / 80 mg/ml commercial preparation can be used.[1],[6]



  Drawbacks of Fortified Preparations Top


The main drawback of fortified antimicrobial preparations is epithelial toxicity as epithelial-healing rate is retarded by aminoglycosides and vancomycin. When large epithelial defect or conjunctival ulcers are seen, the frequency of drug therapy must be reduced or to be thought of as an alternative drug regimen.[1],[2]


  Conclusion Top


There is a rapid increase in bacterial resistance to antibiotics in both systemic and ocular infections worldwide; thus, all medications should be started based on the severity of disease and clinical progression.[3]

Fortified drugs should be used with appropriate indication and avoided in self-limiting cases such as conjunctivitis, which will hopefully bring down the extremes of the ever-increasing antibiotic resistance.

Acquaintance on fortified antimicrobial medication, its appropriate usage and timely intervention will help us to treat most of the resistant microbial keratitis and prevent the need for surgical intervention.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Gokhale NS. Medical management approach to infectious keratitis. Indian J Ophthalmol 2008;56:215-20.  Back to cited text no. 1
[PUBMED]  [Full text]  
2.
Chiquet C, Romanet JP. Prescribing fortified eye drops. J Fr Ophtalmol. 2007;30:423-30.  Back to cited text no. 2
    
3.
Bremond-Gignac D, Chiambaretta F, Milazzo S. A European perspective on topical ophthalmic antibiotics: Current and evolving options. Ophthalmol Eye Dis 2011;3:29-43.  Back to cited text no. 3
    
4.
Tas T, Kucukbayrak A, Hakyemez IN, Mengeloglu FZ, Simavli H, Ozyalvacli G, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus keratitis in rabbits. Cornea 2013;32:1052-7.  Back to cited text no. 4
    
5.
Available from: https://www.aao.org/preferred-practice-pattern/bacterial-keratitis-ppp--2013. [Last accessed on 2018 Jul 20].  Back to cited text no. 5
    
6.
Tas T, Kucukbayrak A, Hakyemez IN, Mengeloglu FZ, Simavli H, Ozyalvacli G, et al. Linezolid versus vancomycin for the treatment of methicillin-resistant Staphylococcus aureus keratitis in rabbits. Cornea 2013;32:1052-7.  Back to cited text no. 6
    
7.
Jain R, Murthy SI, Motukupally S. Clinical outcomes of corneal graft infections caused by Multi-drug resistant Pseudomonas aeruginosa keratitis. Cornea 2014;33: 22-26.  Back to cited text no. 7
    
8.
Dupuis A, Tournier N, Le Moal G, and Venisse N. Preparation and Stability of Voriconazole Eye Drop Solution. Antimicrobial Agents and Chemotherapy, 2008;53: pp.798-9.  Back to cited text no. 8
    
9.
Jay H. Krachmer, Mark J Mannis, Edward J Holland. Cornea. Vol 1. 3rd ed. St Louis, United States: Elsevier - Health Sciences Division; 2010. Chapter 77: Bacterial keratitis. [Table 77].4; p.934.  Back to cited text no. 9
    



 
 
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