Intravitreal Antibiotics


Drug

Class of drug

Mechanism of action

Susceptible organisms

Amikacin

Aminoglycoside

Inhibits protein synthesis by binding to 30S subunit of ribosomes

Aerobic GNBs, Pseudomonas aeruginosa

Amphotericin B

Polyene antibiotics

Binds to ergosterol and alter the permeability of the cell wall

Yeasts, filamentous fungi (resistance for various species of Aspergillus)

Ceftazidime

Third-generation cephalosporin

Inhibits peptide cross-linking of polysaccharide chains of peptidoglycan; affects cell wall synthesis

Aerobic GNBs, GPBs including Pseudomonas

Cefazolin

First-generation cephalosporin

Inhibits peptide cross-linking of polysaccharide chains of peptidoglycan; affects cell wall synthesis

GPC, GPB, E. coli, Proteus, H. influenzae

Ciprofloxacin

Fluoroquinolones

Topoisomerase II inhibitors (DNA gyrase)

Broad-spectrum activity against aerobic gram-positive and gram-negative bacteria, Actinomyces, Nocardia sp.

Imipenem

Carbapenem

Inhibits cell wall synthesis, prevents cross-linking of peptidoglycan during cell wall synthesis

MDR GPB, GNBs including Pseudomonas aeruginosa, therapeutic option for infections caused by MDR pathogens

Piperacillin/tazobactam

Beta-lactam antibiotics

Inhibit cell wall synthesis, binding to penicillin-binding proteins

GNBs, Staphylococcus epidermidis, and Pseudomonas aeruginosa; therapeutic option for infections caused by MDR pathogens

Vancomycin

Glycopeptide

Inhibits the synthesis of precursor units of bacterial cell wall; inhibits RNA synthesis

GPC—MRSA and MDR Staphylococcus epidermidis

Voriconazole

Triazoles

Inhibition of ergosterol synthesis which increases membrane permeability

Broad-spectrum activity against molds and yeasts


GPC Gram-positive cocci, GPB gram-positive bacilli, GNB gram-negative bacilli, GNC gram-negative cocci, MDR multidrug resistant, MRSA methicillin-resistant Staphylococcus aureus, VRSA vancomycin-resistant Staphylococcus aureus





Ocular Factors Influencing Intravitreal Antibiotics


Intravitreal injection bypasses the various anatomical and physiological ocular barriers and diffuses freely in the vitreous cavity to reach the retinal surface. The following factors influence the drug distribution, concentration, and clearance from the vitreous cavity [10]:


  1. 1.


    Route of exit: large molecules like vancomycin, aminoglycosides, and macrolides are known to leave the eye predominantly by the passive diffusion through the anterior chamber, while small molecules such as beta-lactams, clindamycin, and fluoroquinolones are cleared by active transport via the blood-retinal barrier [11] (Fig. 21.1).

     

  2. 2.


    Ionic nature: anionic drugs like beta-lactams, cephalosporins, and clindamycin primarily undergo clearance rapidly via the posterior route across the blood-retinal barrier, while cationic drugs like vancomycin, aminoglycosides, and erythromycin have a comparatively longer half-life as they undergo clearance by passive diffusion into the aqueous and exit via the anterior chamber [9, 12, 13]. Fluoroquinolones which are zwitterions have the shortest half-life as they are cleared via both anterior and posterior routes (Fig. 21.2) [14, 15].

     

  3. 3.


    Solubility coefficient of the drug: lipophilic antibiotics like fluoroquinolones and chloramphenicol are cleared by passive diffusion, while water-soluble antibiotics like beta-lactams leave the eye via active transport [9, 12].

     

  4. 4.


    Status of ocular inflammation: In an inflamed eye, the drug clearance through the anterior route is faster, while the clearance via the posterior route is delayed due to a compromise RPE pump. Thus in an inflamed eye, antibiotics that are routinely eliminated through the anterior route are cleared faster, while the drug clearance by the posterior route is retarded, thus increasing their half-life [9, 13, 16–18].

     

  5. 5.


    Surgical status of the eye: In aphakic eyes, the clearance of antibiotics that leave the eye through the anterior route is fast, while in vitrectomized eyes the drugs that leave via the posterior route are increased. In an experimental study, retinal toxicity to routinely used doses of intravitreal antibiotics in silicone oil-filled eyes was noted. This was due to confinement of the drug in the reduced preretinal space causing its delayed clearance [19].

     

  6. 6.


    Molecular weight: the retention of the drug in the vitreous cavity increases with its increase in molecular weight as it becomes relatively impermeable to the blood-retinal barrier. As most drugs have a molecular weight of <500 Da, their half-life is <72 h [17].

     

  7. 7.


    Vitreous liquefaction: the half-life of the drug is reduced in presence of liquefied vitreous in the anterior and posterior few millimeters of the globe [17].

     

  8. 8.


    Solution density: If the density of the injected solution is greater than vitreous, it may settle down with gravity and cause localized retinal toxicity. To avoid this complication, intermittent repositioning of the patients head is required [20].

     

  9. 9.


    Frequency of intravitreal antibiotic administration: The need for repeated intravitreal antibiotic injection depends on the clinical response, half-life of the drug, and surgical status of the eye. The aim of repeat dosing is to maintain the drug concentrations above the MIC, rather than to attain higher peak levels. Thus, adequate and safe antibiotic levels can be better achieved by frequent rather than higher dosages [16].

     


A427662_1_En_21_Fig1_HTML.jpg


Fig. 21.1
Common antibiotic clearance from the eye


A427662_1_En_21_Fig2_HTML.jpg


Fig. 21.2
Depicting the routes of exit for various intravitreal antibiotics. (a) Epithelial barrier, (b) aqueous-vitreous barrier, (c) blood-aqueous barrier, (d) outer retinal barrier, (e) inner retinal barrier (Adapted from Cunha Vaz JG, et al. Doc Ophthalmol 1997; 93:149–57)


Intravitreal Antibiotic Dose


The efficacy of intravitreal antibiotics is based on the duration the intraocular drug level exceeds the MIC of a particular drug against the implicated organism. The safe and therapeutic intravitreal doses of commonly used antibiotics have been determined in experimental and clinical studies. The recommended doses and frequency of repeated injections have been mentioned in Table 21.2.


Table 21.2
Pharmacokinetics of intravitreal antimicrobials: dose, route of exit and half-life in non-vitrectomized and vitrectomized eyes, and frequency of repeated injections




















































































































































































#
Drug
Recommended dose (μg/0.1 ml)
Route of clearance
Half-life (t 1/2) in vitreous Noninflamed phakic eyes
Aphakic vitrectomized eyes
Frequency of repeat injections (h)

1
Amikacin [25, 49, 50]
400
Anterior
25.5 h
NA
24–48

2
Amphotericin-B [51]
5–10
Posterior
8.9 days
1.8 h
NA

3
Aztreonam [52]
100
Posterior
7.5 h
NA
12

4
Cefazolin [9, 21]
2
Posterior
6.5 h
NA
24

5
Ceftazidime [25, 53]
2
Posterior and anterior
13.8 h
NA
48–72

6
Ciprofloxacin [14, 16]
100
Anterior and posterior
3.5–5.5 h
1.2 h
12

7
Clindamycin [54]
1000
Posterior
40 h
NA
72

8
Daptomycin [55]
200
Posterior
42 h
NA
Single dose

9
Dalfopristin/quinupristin [56]
400
Posterior
NA
NA
48

10
Gentamicin [57, 58]
100
Anterior
40–60 h
<40 h
72–96 h

11
Imipenem [59]
50–100
Posterior
NA
NA
NA

12
Linezolid [60, 61]
400
NA
2 h
NA
NA

13
Moxifloxacin [12]
200
Anterior and posterior
1.72 h
NA
12

14
Ofloxacin [15]
200–500
Anterior and posterior
5.6 h
NA
24

15
Penicillin [6]
2–4000 units
Posterior
NA
NA
48

16
Piperacillin/tazobactam [26–28]
225

<250
Posterior
NA
NA
NA

17
Sulfamethoxazole/trimethoprim [12]
1600 trimethoprim
Anterior
NA
NA
NA

18
Vancomycin [13]
1000
Anterior
25.5–56 h
9.8 h
72

19
Voriconazole [62]
50–200
Posterior
2.5–6.5 h
NA
NA

20
Meropenem [63]
  
Posterior
2.6 h
NA
NA


Preparation of Intravitreal Antibiotics


According to various experimental and clinical studies, the recommended therapeutic dosage of intravitreal antibiotics is very small compared to its systemic dosing and is carefully titrated to prevent retinal toxicity. Thus, it is important that an accurate dose is maintained each time an injection is prepared [21]. The injections should be prepared following standard protocols by trained personnel under strict aseptic conditions in a certified laminar flow area. Also a printed drug preparation reference display sheet should be consulted while preparing injections to prevent dilution errors. Preparation of important intravitreal antibiotics is shown in Table 21.3. Though the expiry of various drugs prepared for intavitreal use is not known, an experimental study reported that vancomycin, ceftazidime, and moxifloxacin when prepared in single-use polypropylene syringes and stored at −20 °C or −80 °C retain their potency, sterility, and stability up to 24 weeks [22].


Table 21.3
Preparation of intravitreal antibiotics































#
Injection
Add distilled water
Take
Add to Ringer’s lactate
Dosage in 0.1 ml
 
Antibacterial antibiotic

1
Amikacin 100 mg
  
0.1 ml
0.9 ml
400 μg

2
Cefazolin 500 mg

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Mar 1, 2018 | Posted by in OPHTHALMOLOGY | Comments Off on Intravitreal Antibiotics

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