Pharmacokinetics of Meropenem for Use in Bacterial Keratitis.
OBJECTIVE
To investigate the toxicity and corneal pharmacokinetics of meropenem as a potential antimicrobial for bacterial keratitis.


METHODS
Corneal epithelial cell and keratocyte toxicity was investigated using methyl thiazolyl tetrazolium (MTT) and LIVE/DEAD assays. The penetration of meropenem through the human cornea was measured using an artificial anterior chamber. In one group of corneas, the epithelial and endothelial layers were removed and in a second group these layers were left intact. We applied 50 μL (10 mg/mL) meropenem to the corneal surface and collected samples in the anterior chamber from 45 minutes up to 24 hours. Meropenem concentrations were estimated with a bioassay and HPLC.


RESULTS
Meropenem had significantly higher cellular metabolic activity (MTT assay) at both 5 mg/mL and 2.5 mg/mL compared with moxifloxacin (P = 0.029 and P = 0.018, respectively), with 96% cell viability (LIVE/DEAD assay). The measured values for meropenem concentrations in corneal and aqueous samples were significantly higher using a bioassay than with HPLC (P = 0.004). For both intact and denuded corneas, the concentrations in the anterior chamber increased from 0.48 μg/mL (SD 0.89) and 0.89 μg/mL (SD 0.81) to 6.35 μg/mL (SD 0.81) and 13.48 μg/mL (SD 14.82) using HPLC, and from 0.68 μg/mL (SD 1.50) and 1.31 μg/mL (SD 1.55) to 47.03 μg/mL (SD 5.51) and 43.69 μg/mL (SD 27.22) measured with a bioassay.


CONCLUSIONS
Meropenem has very low toxicity in vitro. It has good corneal penetration, achieving anterior chamber concentrations above MIC90 for bacteria such as Staphylococcus aureus, Pseudomonas aeruginosa, streptococci, coagulase-negative staphylococci, and the Enterobacteriaceae.
St. Paul's Eye Unit Royal Liverpool University Hospital, Liverpool, United Kingdom 2Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Henri
H
Sueke
St. Paul's Eye Unit Royal Liverpool University Hospital, Liverpool, United Kingdom 2Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Stephen
S
Kaye
Institute of Integrative Biology, University of Liverpool, Liverpool, United Kingdom.
Mark C
MC
Wilkinson
Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Stephnie
S
Kennedy
Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Victoria
V
Kearns
Department of Eye and Vision Science, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, United Kingdom.
Yalin
Y
Zheng
Department of Medical Microbiology, Royal Liverpool University Hospital, Liverpool, United Kingdom.
Paul
P
Roberts
Moorfields Eye Hospital, London, United Kingdom.
Stephen
S
Tuft
Department of Medical Microbiology, Royal Liverpool University Hospital, Liverpool, United Kingdom.
Timothy
T
Neal
D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000378:metabolism; D019573:Epithelium, Corneal / Q000187:drug effects; D015818:Eye Infections, Bacterial / Q000188:drug therapy* / Q000378:metabolism / Q000382:microbiology; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism; D007634:Keratitis / Q000188:drug therapy* / Q000382:microbiology; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000382:microbiology; D013845:Thienamycins / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem