Clinical evaluation of a thin absorbent skin adhesive dressing for wound management.

OBJECTIVE: This article assesses the use of BeneHold Thin Absorbent Skin Adhesive (TASA) wound dressings in a large UK primary care organisation. These wound dressings are thin (0.12 mm), breathable, transparent, and are able to absorb and retain wound exudate. This non-comparative evaluation was undertaken to explore the clinical advantages this differentiated combination of physical properties offered. METHOD: The dressings are CE-marked medical devices, and were used on patients with acute and chronic wounds that were assessed and classified as light to moderately exuding. Clinical performance was evaluated with respect to the dressing's ease of use (application and removal, conformability, mould-ability, rolling and edge-lift), debridement, protection of the peri-wound, wear time, fluid handling, wound bed residue, visibility of the wound, and clinical acceptability. The evaluating clinicians used an agreed audit tool to collect data from case reports to document the progression of wounds of various aetiologies, including chronic and acute, for a maximum period of four weeks. Qualitative feedback on dressing performance was also collected at the evaluation's end, both from the clinicians' and patients' perspectives Results: Some 15 patients were assessed. The wear time was up to seven days in many cases, and on average was 3.9 days longer than their previous dressings. Clinicians perceived that wounds progressed toward healing in all but two cases, where the wounds remained unchanged. Out of five cases where wounds presented with necrosis, all underwent significant autolytic debridement underneath the new dressings. Transparency was a noted benefit from both the clinicians' and patients' perspectives because it enabled continuous monitoring of the full wound bed and peri-wound skin without the need to disrupt the dressing. CONCLUSION: The dressing was well-received by both clinicians and patients in all fifteen cases. The thin absorbent skin adhesive dressing was found to be a promising new technology that could offer significant advantages to improve the quality, cost, and convenience of wound care. Further work is underway to validate these findings in larger and more homogeneous patient groups.

Effector functions are required for broad and potent protection of neonatal mice with antibodies targeting HSV glycoprotein D.

Multiple failed herpes simplex virus (HSV) vaccine candidates induce robust neutralizing antibody (Ab) responses in clinical trials, raising the hypothesis that Fc-domain-dependent effector functions may be critical for protection. While neonatal HSV (nHSV) infection results in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, supporting the hypothesis that Ab-based therapeutics could protect neonates from HSV. We therefore investigated the mechanisms of monoclonal Ab (mAb)-mediated protection in a mouse model of nHSV infection. For a panel of glycoprotein D (gD)-specific mAbs, neutralization and effector functions contributed to nHSV-1 protection. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types consistent with vaccine trial results. Effector functions are therefore crucial for protection by these gD-specific mAbs, informing effective Ab and vaccine design and demonstrating the potential of polyfunctional Abs as therapeutics for nHSV infections.

Antibody effector functions are required for broad and potent protection of neonates from herpes simplex virus infection.

The failure of multiple herpes simplex virus (HSV) vaccine candidates that induce neutralizing antibody responses raises the hypothesis that other activities, such as Fc domain-dependent effector functions, may be critical for protection. While neonatal HSV (nHSV) infection result in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, suggesting the potential efficacy of antibody-based therapeutics to protect neonates. We therefore investigated the mechanisms of monoclonal antibody (mAb)-mediated protection in a mouse model of nHSV infection. Both neutralization and effector functions contributed to robust protection against nHSV-1. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types that is consistent with vaccine trial results. Together, these results emphasize that effector functions are crucial for optimal mAb-mediated protection, informing effective Ab and vaccine design, and demonstrating the potential of polyfunctional Abs as potent therapeutics for nHSV infections.

Maternally transferred mAbs protect neonatal mice from HSV-induced mortality and morbidity.

Neonatal herpes simplex virus (nHSV) infections often result in significant mortality and neurological morbidity despite antiviral drug therapy. Maternally transferred herpes simplex virus (HSV)-specific antibodies reduce the risk of clinically overt nHSV, but this observation has not been translationally applied. Using a neonatal mouse model, we tested the hypothesis that passive transfer of HSV-specific human mAbs can prevent mortality and morbidity associated with nHSV. The mAbs were expressed in vivo via vectored immunoprophylaxis or recombinantly. Through these maternally derived routes or through direct administration to pups, diverse mAbs to HSV glycoprotein D protected against neonatal HSV-1 and HSV-2 infection. Using in vivo bioluminescent imaging, both pre- and post-exposure mAb treatment significantly reduced viral load in mouse pups. Together these studies support the notion that HSV-specific mAb-based therapies could prevent or improve HSV infection outcomes in neonates.

Cannabis dependence as a primary drug use-related problem: the case for harm reduction-oriented treatment options.

Few studies have focused on cannabis dependence as compared to other drugs more commonly acknowledged as presenting a substantial need for treatment. This paper presents findings from a 2004-2005 study of drug user treatment clients in Southern Ontario, Canada. Clients with cannabis (n = 128) or cocaine (n = 300) as their primary drug problem were compared on psychosocial and demographic characteristics, drug effects, and clinical impairment. There are more similarities than differences between groups, with DAST and DSM scores showing high rates of "dependence" and reported symptoms of "abuse." However, cannabis consistently scored lower on these items, supporting the idea of a continuum of risk on which its rank compared with other potentially misused drugs holds across a wide range of symptoms of impairment. The less disruptive nature of cannabis use-related problems poses greater challenges for drug user treatment providers guided by strict abstinence agendas. The authors call for the expansion of harm reduction treatment options and educational initiatives beyond primary prevention that acknowledge benefits of moderate controlled use when addressing cannabis misuse.

Concurrent EGFR amplification and TP-53 mutation in glioblastomas.

Glioblastoma multiforme is the most common and most aggressive of the primary brain tumors. The mean survival of patients is 10-12 months. Conventional therapy of surgery, radiation and chemotherapy is largely palliative. Cytogenetically, karyotypes of glioblastomas are very complex with trisomy 7 and monosomy 10 as the most frequent abnormalities. A genetic alteration that is significantly more frequent in primary than in secondary glioblastomas, the latter arising from preceding low-grade gliomas, is epidermal growth factor receptor gene (EGFR) amplification, whereas TP-53 mutations are significantly more frequent in low-grade gliomas and secondary glioblastomas derived there- from. We report the histological and genetic study of two glioblastomas, one case arising de novo and the other case arising 3 years after a previously diagnosed anaplastic astrocytoma, with concurrent EGFR amplification and TP-53 mutation. These anomalies were initially deemed as mutually exclusive. However, a small percentage of cases have been found with both anomalies although at a significantly lower level than could be expected. We have analyzed these two cases cytogenetically and by molecular studies in order to detect additional alterations associated with this phenotype. Cytogenetically, both cases showed in common the monosomy of chromosomes 10 and 17. At the molecular level, a rare mutation of TP-53 was found in the secondary glioblastoma and hypermethylation of the promoter region of p16(INK4a) and p14(ARF) genes were observed in the primary and secondary glioblastoma, respectively.

Surfactant protein D in Pseudomonas aeruginosa keratitis.

PURPOSE: To determine the importance of surfactant protein D in Pseudomonas keratitis. METHODS: The surfactant D status of wild-type and surfactant D-deficient Black Swiss mice was confirmed by PCR reactions and immunoblot assay. Mouse corneas were infected with one of three strains of P. aeruginosa. At 1, 2, 3, and 6 days postinfection, eyes were scored by slit-lamp examination and bacteria per cornea quantified. RESULTS: Infected wild-type mice had slit-lamp scores on 3 and 6 days postinfection that were significantly lower than those of surfactant D-deficient mice (p

Multiple drugbinding sites on the R482G isoform of the ABCG2 transporter.

BACKGROUND & PURPOSE: Drug-resistant cancer cells frequently display efflux pumps such as P-glycoprotein (P-gp), the multidrug resistance associated protein (MRP1) or the transporter ABCG2. These transporters are each capable of mediating the active efflux of numerous anticancer drugs and display relatively distinct substrate preferences. The last, most recently discovered member, ABCG2, plays a major role in resistance in several types of cancer and the precise pharmacology of this multidrug transporter remain unresolved as does the nature of substrate binding. EXPERIMENTAL APPROACH: Plasma membranes from insect cells expressing ABCG2 were used to characterise binding of [3H]daunomycin to the multidrug transporter. The kinetics of association and dissociation for this substrate and several other compounds were also determined in this experimental system. KEY RESULTS: The dissociation constant for [3H]daunomycin binding was 564 +/- 57 nM and a Hill slope of 1.4 suggested cooperative binding. Doxorubicin, prazosin and daunomycin completely displaced the binding of radioligand, while mitoxantrone and Hoechst 33342 produced only a partial displacement. Analysis of the dissociation rates revealed that [3H]daunomycin and doxorubicin bind to multiple sites on the transporter. CONCLUSIONS: Both kinetic and equilibrium data support the presence of at least two symmetric drug binding sites on ABCG2, which is distinct from the asymmetry observed for P-gp. The data provide the first molecular details underlying the mechanism by which this transporter is capable of interacting with multiple substrates.

Cytotoxic efficacy of an anthraquinone linked platinum anticancer drug.

Platinum complexes are widely used in cancer chemotherapy; however, they are associated with toxicity, high "non-specific" reactivity and relatively poor pharmacokinetic profiles. In particular, their low cellular uptake and rapid metabolic inactivation means that the amount of "active" drug reaching the nuclear compartment is low. Our strategy to facilitate nuclear accumulation was to introduce a hydrophobic anthraquinone (1C3) moiety to the Pt-complex. Anthraquinones are known to readily intercalate into DNA strands and hence, the Pt-1C3 complex may represent an effective system for the delivery of the platinum moiety to nuclear DNA. Efficacy of the complex was determined by measuring the extent and potency of cytotoxicity in comparison to cisplatin and an anthraquinone based anticancer drug, doxorubicin. The Pt-1C3 complex generated higher levels of cytotoxicity than cisplatin, with a potency of 19 +/- 4 microM in the DLD-1 cancer cell line. However, this potency was not significantly different to that of the 1C3 moiety alone. To examine the reason for the apparent lack of platinum related cytotoxicity, the cellular distribution was characterised. Confocal fluorescence microscopy indicated that the Pt-1C3 complex was rapidly sequestered into lysosomes, in contrast to the nuclear localisation of doxorubicin. In addition, there was negligible DNA associated Pt following administration of the novel complex. Thus, the addition of a 1C3 moiety generated sequestration of the complex to lysosomes, thereby preventing localisation to the nucleus.

Collateral sensitivity of multidrug resistant cells to narcotic analgesics is due to effects on the plasma membrane.

It has previously been demonstrated that opiates interact directly with P-glycoprotein in drug resistant Chinese hamster ovary (CHO) cells (Callaghan, R. and Riordan, J.R. (1993) J. Biol. Chem. 268, 16059-16064). In this study we have examined the effects of several opiates on the growth of drug sensitive and resistant CHO and human MCF7 cell lines. The growth of P-glycoprotein expressing cells was inhibited by the opiates pentazocine, pethidine and naloxone to a greater extent than in drug sensitive cells. Since P-glycoprotein is localised at the plasma membrane the effects of opiates on membrane biophysical properties were investigated. The opiates caused a fluidizing effect in membranes from P-glycoprotein expressing cells and decreased the basal level of P-glycoprotein phosphorylation. In addition, they were able to increase the leakage of the membrane impermeant compound 6-carboxyfluorescein entrapped in model membrane vesicles. The ability to alter membrane biophysical properties correlated with the inhibitory effects on growth of drug resistant cells. These results suggest that the collateral sensitivity of P-glycoprotein expressing cell lines to opiates is mediated by the drugs' effects on the plasma membrane.

Increased accumulation of drugs in a multidrug resistant cell line by alteration of membrane biophysical properties.

Growth of CHRC5 multidrug resistant cells in media enriched in a saturated C-17 fatty acid, heptadecanoic acid, resulted in these cells accumulating vinblastine at a rate and to an extent comparable to that of the parental cell line AB1. The fatty acid-enriched growth media had no effect on the ability of AB1 cells to take up vinblastine. The action of amphiphiles on the uptake of rhodamine dyes by CHRC5 cells was compared with the increased dye accumulation affected by verapamil. Membrane rigidifying agents, such as the saturated fatty acid stearic acid, or the cholesterol derivatives, cholesteryl hemisuccinate and cholesteryl phosphorylcholine, as well as a membrane fluidizing unsaturated fatty acid, linoleic acid, could significantly increase dye uptake, although not as well as verapamil. These results taken in conjunction with other reports in the literature, demonstrate that multidrug resistance is sensitive to alterations of membrane properties. They suggest that perturbation of the membrane to either increased or to decreased membrane fluidity can lower the level of resistance.

The functional purification of P-glycoprotein is dependent on maintenance of a lipid-protein interface.

P-Glycoprotein (P-gp) is a 180-kDa membrane-bound transporter which can confer the multi-drug resistance phenotype on tumor cells. We have examined the factors required to preserve activity of P-gp during its purification. The starting material for purification was plasma membranes from Chinese hamster ovary (CHrB30) cells, overexpressing P-glycoprotein. These membranes displayed drug stimulated ATPase activity (Vm = 897 +/- 55 nmol min(-1) mg(-1); Km = 1.8 +/- 0.4 mM) and high affinity binding of [3H]vinblastine (Kd = 36 +/- 5 nM; Bm = 161 +/- 11 pmol/mg). Several non-ionic detergents which readily solubilized P-glycoprotein significantly inhibited ATPase activity and drug binding at concentrations well below their respective CMC values. This inactivation was prevented by excess crude lipid mixtures, with the greatest protection afforded against dodecyl-maltoside. Furthermore, the significantly reduced binding affinity and capacity of solubilized P-gp was partly reversed by the addition of lipids. A combination of anion-exchange and hydroxyapatite chromatography were used to purify P-gp with high yield to greater than 90%. The purified, reconstituted P-gp displayed high ATPase activity (Vm = 2137 +/- 309; Km = 2.9 +/- 0.9 mM) which was stimulated by verapamil (EC50 = 3.8 +/- 0.6 microM) and inhibited by orthovanadate (3.1 +/- 0.8 microM). Pure P-gp also displayed high affinity vinblastine binding (Kd = 64 +/- 9 nM) with a capacity of 2320 +/- 192 pmol/mg. This purification scheme yields the highest P-gp activity reported to date, and indicates a dependence of function on maintaining a lipid-protein interface.

The influence of tumour microenvironmental factors on the efficacy of cisplatin and novel platinum(IV) complexes.

The chemotherapeutic drug cisplatin is an important treatment for many types of solid tumours, in particular non-small cell lung cancer (NSCLC). Platinum(IV) complexes offer several advantages to cisplatin due to their requirement for reduction to the active platinum(II) form to elicit cytotoxicity. This should minimise non-specific effects and facilitate higher amounts of the active complexes reaching the target DNA. Hypoxia and a quiescent cell population are features of the tumour microenvironment known to lead to resistance to many chemotherapeutic agents. It is unclear how these microenvironmental factors will impact on the efficacy of novel platinum(IV) complexes. Consequently, the cytotoxicities of several platinum drugs were determined in monolayer and tumour spheroid cultures derived from NSCLC lines. Platinum(IV) reduction potential correlated well with cytotoxicity. The complex containing a chloro axial ligand demonstrated the greatest potency and the drug with the hydroxy ligand was the least effective. Although drug cytotoxicity was not enhanced under hypoxic conditions, both cisplatin and the platinum(IV) complexes retained full potency. In addition, all of the platinum drugs retained the ability to evoke apoptosis in quiescent cells. In summary, unlike many anticancer drugs, the platinum(IV) complexes retain cytotoxic potency under resistance-inducing tumour microenvironmental conditions and warrant further investigation as more selective alternatives to current platinum-based therapy for the treatment of solid tumours.

Association of chromosome 7, chromosome 10 and EGFR gene amplification in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is characterized by intratumoral heterogeneity in both histomorphological and genetic changes, displaying a wide variety of numerical chromosome aberrations, the most common of which are trisomy 7 and monosomy 10. The amplification of the epidermal growth factor receptor (EGFR) gene is the most frequently reported genetic abnormality. The associations between these parameters and their implication in the tumoral progression are poorly understood. We performed simultaneous fluorescence in situ hybridization (FISH) with centromeric DNA probes for chromosomes 7 and 10 in smear preparations, and EGFR gene amplification by PCR from 25 cases of GBM. Trisomy/ polysomy for chromosome 7 was present in 76% of cases and monosomy 10 in 68%. Both alterations were associated in 56% of cases. The EGFR gene was amplified in 52% of tumors; in 44% associated with trisomy/ polysomy 7, and in 36% with monosomy 10. The three parameters were associated together in 28% of cases. Kaplan-Meier survival rate analysis demonstrated lower survival rates in patients with monosomy 10, trisomy 7, and monosomy associated with trisomy 7. The other combinations were not different in frequency in relation to survival. In the present study, trisomy/polysomy 7 and monosomy 10 have been found to be frequently associated. The combination of both anomalies is probably important in the tumorigenesis of glioblastoma. Moreover, this association is apparently independent of EGFR gene amplification, which could be a later event in this process.

Prevalence of pharyngeal and laryngeal abnormalities in Thoroughbreds racing in Australia, and their association with performance.

REASONS FOR PERFORMING STUDY: Little information is available regarding the prevalence of abnormalities of the upper airway and their association with performance in the general population of Thoroughbred racehorses. OBJECTIVES: To describe the prevalence of selected abnormalities of the upper airway and their association with performance in Thoroughbred racehorses in Australia. HYPOTHESIS: That abnormalities of the upper airway of Thoroughbred racehorses are associated with poor race performance. METHODS: Rhinolaryngoscopy was performed after racing and presence and characteristics of abnormalities of the larynx and pharynx were recorded in a prospective cross-sectional study of Thoroughbred horses racing in Victoria, Australia. RESULTS: Rhinolaryngoscopy was performed once on each of 744 horses over 35 months. Fifty abnormalities of the upper airway were detected in 47 horses (6.3%, 95% confidence interval [CI] 4.7-83%). Epiglottic entrapment was detected in 7 horses (0.9%, 95% CI 0.4-1.9%) and was significantly (P = 0.015) associated with superior performance. Grade 2 asymmetry (4 grade scale) of the left arytenoid cartilage was detected in 9 horses (1.2%, 95% CI 0.5-2.4%) and was also associated with superior performance (P<0.001). Ulceration or erosion of the mucosa of the axial surface of one or both arytenoids was detected in 18 horses (2.4%, 95% CI 13-3.8%) and was not associated with alterations in exercise performance (P = 0.31). CONCLUSIONS: Epiglottic entrapment, Grade 2 laryngeal asymmetry and mucosal erosions detected in Thoroughbred racehorses were not associated with impaired performance; therefore, surgical correction and concern over laryngeal function in horses with Grade 2 asymmetry may not be necessary in individuals performing to expectation.

Alteration of major vault protein in human glioblastoma and its relation with EGFR and PTEN status.

Glioblastoma (GBM) is the most frequent and malignant primary brain tumor. Conventional therapy of surgical removal, radiation and chemotherapy is largely palliative. Major vault protein (MVP), the main component of the vault organelle has been associated with multidrug resistance by reducing cellular accumulation of chemotherapeutic agents. With regard to cancer, MVP has been shown to be overexpressed in drug resistance development and malignant progression. The aim of the present study was to evaluate the MVP gene dosage levels in 113 archival samples from GBM and its correlation with patients' survival and epidermal growth factor receptor (EGFR) and phosphatase and tensin homolog (PTEN) gene dosages. Fluorescent in situ hybridization revealed polysomy of chromosome 7 in 76.1% of the GBMs and EGFR amplification in a 64.6% of the tumors. Genetic status of EGFR, PTEN and MVP copies was determined by multiplex ligation-dependent probe amplification (MLPA) technique. 31% of the tumors showed the EGFR is variant III mutation (EGFRvIII) mutation and 74.3% of them presented amplification of MVP gene. Amplification of EGFR and MVP was found in a 63.7% and 56.6% of the GBM, respectively. An inverse correlation between MVP and PTEN dosage values was observed. Besides, an inverse relationship between the survival of the patients treated with chemotherapy and the levels of MVP copies was determined. In conclusion, our study reveals an important role of MVP, together with EGFRvIII and PTEN, in the progression of GBM and proposes it as a novel and interesting target for new treatment approaches.

Inhibition of P-glycoprotein function by XR9576 in a solid tumour model can restore anticancer drug efficacy.

Resistance to cancer chemotherapy involves both altered drug activity at the designated target and modified intra-tumour pharmacokinetic properties (e.g. uptake, metabolism). The membrane transporter P-glycoprotein (P-gp) plays a major role in pharmacokinetic resistance by preventing sufficient intracellular accumulation of several anticancer agents. Whilst inhibiting P-gp has great potential to restore chemotherapeutic effectiveness in blood-borne cancers, the situation in solid tumours is less clear. Therefore, the degree of resistance tumours pose to the cytotoxicity of vinblastine and doxorubicin was characterised using the multicellular tumour spheroid model. Tumour spheroids were generated from either drug-sensitive MCF7(WT) breast cancer cells or a resistant P-gp-expressing variant (NCI/ADR(Res)). Drug-induced cytotoxicity in tumour spheroids was measured using an outgrowth assay and compared with that observed in monolayer cultures. As anticipated, the 3-D organisation of MCF7(WT) in tumour spheroids was associated with a reduction in the potency of doxorubicin and vinblastine-i.e. the inherent multicellular resistance phenomenon. In contrast, tumour spheroids from NCI/ADR(Res) cells did not display multicellular resistance. However their constitutive expression of P-gp reduced the potency of both anticancer drugs. Moreover, the highly potent P-gp inhibitor, the anthranilic acid derivative, XR9576, was able to restore the cytotoxic efficacy of both drugs in tumour spheroids comprising NCI/ADR(Res) cells. The results suggest that inhibition of P-gp in solid tumours is achievable and that generation of potent inhibitors will provide a significant benefit towards restoration of chemotherapy in solid tissues.

Ciprofloxacin iontophoresis for aminoglycoside-resistant pseudomonal keratitis.

Studies using ciprofloxacin for the therapy of experimental aminoglycoside-resistant keratitis caused by Pseudomonas aeruginosa were conducted using transcorneal iontophoresis as the drug-delivery system. Corneas infected with P. aeruginosa ATCC 27853/pMG6 were treated 22 hours postinfection with ciprofloxacin delivered by iontophoresis (0.8 mA X 10 min), mock iontophoresis (eyecup with no current), or frequently applied topical drops. Iontophoresis of 10 mg/ml or 25 mg/ml of ciprofloxacin significantly reduced the number of viable bacteria per cornea by more than 5 log units compared with untreated controls (P less than 0.0001). Five hours after the initiation of treatment, mock iontophoresis (10 mg/ml or 25 mg/ml) or 11 applications of topical ciproflaxicin drops (7.5 mg/ml) decreased the viable bacteria relative to the untreated controls by 5 log units (P less than 0.0001). One treatment with an eyecup was as effective as 11 treatments with topical drops (P greater than 0.75). One hour after treatment with iontophoresis or mock iontophoresis of 10 mg/ml of ciprofloxacin, aqueous humor concentrations were 83.75 +/- 8.85 micrograms/ml and 24.87 +/- 4.0 micrograms/ml (mean +/- standard error of the mean), respectively. One hour after the last of five applications of 7.5 mg/ml of ciprofloxacin (every 15 min for 1 hr) the aqueous humor concentration was 4.2 +/- 1.14 micrograms/ml. These results show the value of ciprofloxacin in treating aminoglycoside-resistant infections caused by P. aeruginosa and suggest that ciprofloxacin can be efficiently delivered by iontophoresis.

Ciprofloxacin versus tobramycin for the treatment of staphylococcal keratitis.

PURPOSE: To compare the chemotherapeutic efficacies of ciprofloxacin (0.3%) and fortified (1.36%) tobramycin for the treatment of methicillin-sensitive and methicillin-resistant Staphylococcus aureus keratitis during early and late stages of infection. METHODS: Rabbit corneas were intrastromally injected with 10(2) colony-forming units (CFU) of methicillin-sensitive S. aureus (MSSA) or methicillin-resistant S. aureus (MRSA). Topical therapy was initiated at either 4 hours postinfection (early stage) or at 10 hours postinfection (late stage). Drops were administered every 15 minutes for 5 hours. Corneal bacterial counts and aqueous humor antibiotic concentrations were determined. RESULTS: Early administration of ciprofloxacin sterilized all MSSA-infected corneas and 83% of MRSA-infected corneas. Late administration of ciprofloxacin reduced the numbers of viable MSSA and MRSA to 3.6 and 3.7 log10 CFU per cornea, respectively, but did not sterilize any corneas. Early administration of fortified (1.36%) tobramycin sterilized all MSSA-infected corneas but none of the MRSA-infected corneas. Late administration of tobramycin reduced the viable MSSA to very low numbers (0.5 and 0.0 log10, respectively) and sterilized 33% of MSSA-infected corneas, but had little effect on MRSA-infected corneas. CONCLUSIONS: Early in infection, ciprofloxacin was highly effective against MSSA and MRSA, whereas tobramycin was effective only against MSSA. During later stages of infection, tobramycin was more effective than ciprofloxacin against MSSA, and neither antibiotic was effective against MRSA. Thus, ciprofloxacin is limited by the time of application and tobramycin is limited by the resistance of the MRSA strain.