Fortified Antibiotic eye drops

Harinder singh bhangu

Western university of health sciences

PreceptorAshwin Patel

Why do we need fortification of antibiotic eye drops…. To attain minimum inhibitory concentration

especially in the case of resistant , non healingulcers.

To treat moderate to severe corneal ulcersintensive antibiotic treatment is needed to stopthe progression of ulcer

Empirical fortified therapy

NO ORGANISM SEENBUT BACTERIASUSPECTED

Cefazolin- 50mg/ml or100mg/ml+Tobramycin -14mg/ml

Gentamicin-14mg/ml orAmikacin-10mg/ml+Vancomycin -25mg/ml(OR)Bacitracin 10000 u/ml

Drugs and their coverage Bacteria type First line option AlternativeGRAM POSITIVE COCCI ( Staphylococci, Streptococci, )

Cefazolin- 50mg/ml 0r 100mg/ml Vancomycin -25mg/mlBacitracin- 10000 u/mlCiprofloxacinOfloxacinLevofloxacin

GRAM POSITIVE BACILLI Bacillus , clostridium

Tobramycin -14mg/ml Vancomycin 25-50mg/mlBacitracin -10000 u/mlGentamicin -14mg/ml

GRAM NEGATIVE COCCI(N. meningitides, N. gonorrhoeae, Moraxella catarrhalis )

Ceftriaxone-50mg/ml or 100mg/mL OfloxacinLevofloxacinCiprofloxacin

GRAM NEGATIVE BACILLI( Psuedomonas, E.coli, Klebsella, Acinobacter, Enterobacter, Citrobacter)

Tobramycin -14mg/ml, Amikacin -10mg/ml

Gentamicin -14mg/mlPolymyxin B-50000 u/mlCiprofloxacinOfloxacinLevofloxacin

Culture identified therapy

PSEUDOMONAS Tobramycin -14mg /ml ( OR) Amikacin 10mg/ml and a quinolone

STAPHYLOCOCCUS Cefazolin -50mg/ml,Vancomycin – 25-50 mg/ml

PROTEUS/ENTEROBACTER/E.COLI/KLEBSIELLA/ACINETOBACTER

Tobramycin -14mg/ml,Gentamicin -14mg/ml,Amikacin - 10mg/ml, Ceftriaxone -50mg/ml

List of fortified antibiotic eye drops

Cefazolin 50mg/ml

Ceftazidime 50mg/ml

Vancomycin 25-50mg/ml

Tobramycin 14mg/ml

Gentamycin 14mg/ml

Linezolid 2 mg/ml (0.2%)

Colistin 0.19%

Imipenem(500mg)-Cilastin (500mg),

Common indications

Vision- threatening bacterial infection, >1.5 mm diameter ulcer

Non operative bacterial corneal ulcer

Bacterial keratitis

Preparation of Aminoglycosides

Fortified Tobramycin or gentamycin 14mg/ml(1.4%)Method

Add 2ml/80mg of parenteral tobramycin or gentamycin to commercially available tobramycin orgentamycin eye drops 0.3% 5 ml (15mg/5ml).

Efficacy of Aminoglycoside

STUDY 1

Fluoroquinolone ( Ciprofloxacin or Ofloxacin ) vs fortified tobramycin1.3%- cefazolin5%)-

Result-

• The duration of intensive therapy was less with fluoroquinolone especially in those over 60 years ofage (4 days v 6 days, p=0.01).

• Hospital stay significantly less with fluoroquinolone treatment (7 day vs 10 days, p=0.02) inpatients in the age group over 60 years old.

Conclusion

• No significant treatment difference was found between fluoroquinolone and fortified therapy interms of final visual outcome.

• However, serious complications such as corneal perforation, evisceration, of the affected eye weremore common with fluoroquinolone therapy

Efficacy of Aminoglycoside

Study 2-• Monotherapy with moxifloxacin (0.5%) or Gatifloxacin (0.3%) Vs combination therapy of cefazolin

(5%) and tobramycin (1.3%) in treatment of bacterial corneal ulcers. Method• A total of 61 patients were enrolled [cefazolin and tobramycin (n = 20), Gatifloxacin (n = 21), and

moxifloxacin (n = 20. Result• No statistically significant difference was found among all the 3 treatment groups (P = 0.98) Limitation• Author stated that 77 patients per group would be needed to find a difference greater than 15% in

treatment efficacy but only 20 patient per group was assigned• So the treatment group differences reported by author were not statistically significant has very little

meaning

Efficacy of Aminoglycoside

• Study 3- ( Meta- analysis)Method

• A comprehensive search for 16 high quality trials involving 1823 participantsincluded in the review.

Results

• No evidence of difference in comparative effectiveness between fluoroquinolonesand aminoglycoside-cephalosporin treatment

• There were differences in safety profile .• Fluoroquinolones decreased the risk of ocular discomfort and chemical

conjunctivitis but increased the risk of white corneal precipitate

Stability of Aminoglycoside

Study 1- Method

• Solutions were prepared to a final theoretical concentration of 13.6 mg/mL

• Solutions were refrigerated at 4-8 degrees C and were analyzed by fluorescence polarizationimmunoassay on days 0 (before refrigeration), 1, 2, 3, 4, 7, 14, 28, 63, and 91.

Results

• Fluorescence polarization immunoassay showed the mean concentrations of gentamicin and tobramycinon day 91 to be 104.4% and 97.4%, respectively

• HPLC validated these results; the mean concentration of gentamicin and tobramycin on day 91 was103.3% and 101.2%, respectively, of the mean day 0 concentrations.

• Gentamicin and tobramycin in ophthalmic solutions prepared by mixing ophthalmic and injectableproducts and stored in plastic bottles at 4-8 degrees C were stable for three months

Stability of Aminoglycoside

Study 2-• Potency and stability -Fortified tobramycin and moxifloxacin also maintained potency for 14

days at 24 and 35°C

• Study project did not meet the regulatory definitions of Human Subjects Research

Side effect of Aminoglycoside

Nephrotoxicity as a side effect Study 1

• Autoimmune markers and ultrasound of the urinary system were unremarkable.

• The renal function recovered dramatically after stopping the medication

• The gentamicin level was checked 2 days after it had been stopped, and the serum level was 0.34 mg/L.

• Renal function improved on supportive management without dialysis. Serum creatinine level completely normalized 2 months later.

Cephalosporins

Fortified Cefazolin Eye Drops 50mg/ml( 5%) and Fortified Ceftazidime eye drops: 50mg/ml( 5%) Method: Reconstitute parenteral Cefazolin or ceftazidime 500mg with 2ml sterile water and then

add to 8ml of artificial tears.

Storage: Refrigerate in 4 degrees C.

Efficacy of Cephalosporins

Study 1.Cefazolin-Gentamicin versus Vancomycin-Ceftazidime Eye Drops for Bacterial Corneal Ulcers (Double blind -Randomized Clinical Trial)

MethodMost common micro-organisms were S. aureus (24.7%) and Pseudomonas (14.6%)

Baseline character were not similar- Study consist of 57 (64%) male and 32 (36%) female subjectsResults

Vancomycin-ceftazidime seem to be more effective than cefazolin-gentamicin

Time for resolution of stromal infiltration, re-epithelization and clearing of the anterior chamberwas shorter in vancomycin-ceftazidime groups compare to cefazolin-gentamicin (P< 0.05)

Efficacy of Cephalosporin

Study 2 ( Tobramycin - Cefazolin vs Tobramycin- Ceftazidime) Method

The combination of topical ceftazidime and aminoglycosides in the treatment of refractory pseudomonal keratitis , who hasresponded to initial therapy of fortified aminoglycoside(14 mg/ml) combined with cefazolin (50 mg/ml).

They treated 12 patient with a topical combination of ceftazidime ophthalmic solution (50 mg/ml) and aminoglycosides (14mg/ml

Results

Substitution of cefazolin by ceftazidime achieved a remarkable clinical improvement during the first 24-48 h of administrationin all cases.

No serious side effect is detected.

Stability of Cephalosporin

Study 1. (Fortified cefazolin sodium solutions ) Method

Fortified cefazolin sodium solutions were prepared by reconstituting it with sterile water and further diluted with Tears Naturale II or Natear, 2 commercial artificial tears

Solutions were then kept at room temperature (28°C) or in the refrigerator (4°C).

Results

The formulation is physically and chemically stable for at least 28 days in the refrigerator.

Room temperature formulation showed gradual change in color and odor.

Stability of Cephalosporin

Study 2 (Ceftazidime ) Methods:

Antibiotic solutions were prepared by reconstitution and dilution of the commercially available powders and stored at -20C

Stability of various physical and chemical properties was determined by a pH meter, an osmometer, and high-performance liquid chromatography.

Results:

Solutions of 5% amikacin or ceftazidime in 0.9% sodium chloride and vancomycin in 5% dextrose were found to be physically, chemically, and microbiologically stable after storage at -20C for 190 days.

****Study is very less clinically meaningful due to freezing temperature for storage******

Vancomycin

Concentration 25 mg/mL,50mg/ml

Preparation Reconstitute 500mg Vancomycin powder with 10 ml sterile water Or artificial tears.

Storage: REFRIGERATE;

Dosing: (Adult Dose)

1 drop hourly for first 24 hours, then taper gradually according to clinical improvement

Efficacy of vancomycin

Study 1. Methods:

Vancomycin use in Non responder to Quinolone ( A) vs non- responder to Aminoglycoside-cefuroxime(B)

In group A, 73.3% showed positive response within two days to quinolones . In group B, 66.7%responded to aminoglycoside- cefuroxime.

The non responding cases in both groups; A and B, were given topical Vancomycin drops (50mg/ml)

Results: 72.7% were labeled to be good responders within the first 24 hours.

Conclusion: Topical fortified vancomycin shows positive additive effect when added to theempirical mono or dual therapy regimens ( P value <0.05) .

Limitation: Blinding was not performed and study sample was small

Stability of Vancomycin Eye Drops

Study 1 Method

A bottle fortified vancomycin 25% was stored separately at 4, 24, and 35°C, with the potency determined by microbiological assay at 0, 7, and 14 days.

Differences in potency were assessed by 2-way analysis of variance followed by a 1-way repeated-measures analysis of variance with Bonferroni post hoc testing.

Results

The concentration of fortified vancomycin remained constant at 4°C for

It declined by 38% at 24°C on day 14 and by 78% at 35°C on day 14.

Conclusion

Refrigerate at 4 Degrees C. Shelf Life: 14 days at 4 Degrees C

Stability of vancomycin

Study 2.

Purpose /Methods: Antibiotic solutions were prepared by reconstitution and dilution of the commercially available

powders and stored at -20C

Results: Solutions of vancomycin in 5% dextrose were found to be physically, chemically, and

microbiologically stable after storage at -20C for 190 days.

****Study is very less clinically meaningful due to freezing temperature for storage******

Others

Topical Linezolid 2 mg/ml (0.2%) Method: Can use directly from parenteral Linezolid (Lancure / Adlid /Rapidline) available as

200mg/100ml (2mg/ml) IV infusion.

Colistin 0.19% Method: Prepared from parenteral Colistimethate sodium powder (Xylistin) 1million IU/75mg

Added to 10ml distilled water – 7.5mg/ml (0.75%)

1ml of above solution is then added to 3ml distilled water – 0.19% Colistin drops

****** Not much data on stability and efficacy*******

Others

Topical Imipenem–Cilastin eye drops 1% Method: To parenteral Imipenem(500mg)-Cilastin (500mg), add 10ml sterile water to create a

solution of strength 50mg/ml.

Take 1 ml of this solution and add 4 ml sterile water to make topical Imipenem 1% - 1mg/ml

Storage - In amber coloured bottles Stability – 3 days at 2-8 deg C

****** Not much data on stability and efficacy*******

References

Potency and Sterility of Fortified Tobramycin, Fortified Vancomycin, and Moxifloxacin. (n.d.). Retrieved June 16, 2017, from https://www-ncbi-nlm-nih-gov.proxy.westernu.edu/pubmed/26555587

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.

Prabhasawat P, Chotikavanich S, Leelaporn A. Sterility of non preservative eye drops. J Med Assoc Thai. 2005;88:S6-10.

Karampatakis V, Papanicolaou T, Giannousis M, Goulas A et al. Stability and antibacterial potency of ceftazidime and vancomycin eye drops reconstituted in BSS against Pseudomonas aeruginosa and Staphyloccoccus aureus. Acta Ophthalmologica 2009; 87(5):555-558.

Gangopadhyay, N., Daniell, M., Weih, L., & Taylor, H. R. (2000, April 01). Fluoroquinolone and fortified antibiotics for treating bacterial corneal ulcers. Retrieved June 20, 2017, from http://bjo.bmj.com/content/84/4/378

http://ovidsp.tx.ovid.com.proxy.westernu.edu/sp-3.25.0a/ovidweb.cgi?T=JS&PAGE=fulltext&D=ovft&AN=00003226-201109000-00031&NEWS=N&CSC=Y&CHANNEL=PubMed#22

(n.d.). Retrieved June 21, 2017, from https://www-ncbi-nlm-nih-gov.proxy.westernu.edu/pubmed/24729078

(n.d.). Retrieved June 21, 2017, from https://www-ncbi-nlm-nih-gov.proxy.westernu.edu/pubmed/2028997

http://globalrph.com/antibiotic/eye.htm

https://www-ncbi-nlm-nih-gov.proxy.westernu.edu/pubmed/?term=topical+ceftazidime+and+aminoglycosides+in+the+treatment+of+refractory+pseudomonal+keratitis

Chédru-legros V, Fines-guyon M, Chérel A, et al. In vitro stability of fortified ophthalmic antibiotics stored at -20 degrees C for 6 months. Cornea. 2010;29(7):807-11.

Available at: http://www.iasj.net/iasj?func=fulltext&aId=35544. Accessed June 21, 2017.

Comparison of topical fixed-combination fortified vancomycin|[ndash]|amikacin (VA solution) to conventional separate therapy in the treatment of bacterial corneal ulcer. Eye. 2009;23(2):294.

Dehghani, A., Fazel, F., Akhlaghi, M., Ghanbari, H., Ilanloo, M., & Ahmadi-Azad, D. (2009, January). Cefazolin-Gentamicin versus Vancomycin-Ceftazidime Eye Drops for Bacterial Corneal Ulcers;aRandomized Clinical Trial. Retrieved June 21, 2017, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3448385/