Activity of Cefiderocol and Comparators against Isolates from Cancer Patients.

Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤4 mg/liter. It had potent activity against extended-spectrum ß-lactamase-positive Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae (CRE), and nonfermenting Gram-negative bacilli, including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter species isolates. Amikacin, ceftazidime-avibactam, and meropenem had appreciable activity against non-CRE Enterobacteriaceae No comparators were active against multidrug-resistant P. aeruginosa isolates. Only trimethoprim-sulfamethoxazole had appreciable activity against S. maltophilia isolates. Overall, cefiderocol was associated with the lowest level of resistance.

High Rates of Nonsusceptibility to Ceftazidime-avibactam and Identification of New Delhi Metallo-ß-lactamase Production in Enterobacteriaceae Bloodstream Infections at a Major Cancer Center.

Resistance to the novel ß-lactam/ß-lactamase inhibitor combination ceftazidime-avibactam (CAZ-AVI) among carbapenem-resistant Enterobacteriaceae (CRE) has infrequently been reported in the United States. We report unexpectedly high rates of resistance to CAZ-AVI in CRE bloodstream isolates at our institution associated with the nonoutbreak spread of New Delhi metallo-ß-lactamase in diverse Enterobacteriaceae species.

Microbiological Assessment of Polymyxin B Components Tested Alone and in Combination.

We investigated the antimicrobial activity of four polymyxin B components, B1, B2, B3, and isoleucine (Ile)-B1, individually and in combination. B3 was the most active agent against all organisms tested except Acinetobacter baumannii, for which Ile-B1 was most active. One combination met the criteria for synergy, B3 plus Ile-B1. No combinations exhibited antagonism. The dominant components of polymyxin B products (B1 and B2) were associated with the lowest probability of improved antibacterial activity when combined.

Polymyxins: wisdom does not always come with age.

We currently face a lack of new antimicrobial therapies in an era of increasingly common multidrug-resistant (MDR) bacteria. The polymyxins have become last-line treatments for patients with MDR bacterial infections. An increasing body of published literature has attempted to answer questions about dosing, pharmacology, and susceptibility testing of these drugs, yet each takes for granted purity and potency of the 2 available polymyxin products. In the case of polymyxin B, true potency may vary by as much as 40% from the content reported in prescribing information. This poor accuracy is related to quality assurance assays established in the 1940s and currently in use, which have been shown to be significantly flawed in recent investigations. This review discusses the limitations of pharmacological knowledge about polymyxin antimicrobials, the clinical impact of these limitations, and suggestions for further study of these drugs in order to optimize their use clinically.

High-dose induction liposomal amphotericin B followed by de-escalation is effective in experimental Aspergillus terreus pneumonia.

OBJECTIVES: Aspergillus terreus is considered to be resistant to amphotericin B (AMB). However, it is unknown whether higher daily doses of liposomal AMB (L-AMB) can overcome this resistance in vivo. We evaluated the efficacy and total lung homogenate AMB concentrations of escalating intravenous doses of L-AMB (3-20 mg/kg daily) versus an induction-de-escalation dosing strategy (10 mg/kg/day ×3 days, then 3 mg/kg/day) in an experimental neutropenic murine model of A. terreus pneumonia. METHODS: BALB/c mice were rendered neutropenic with cyclophosphamide and administered cortisone acetate prior to intranasal inoculation (3.5 × 10(6) conidia) with A. terreus (Etest MIC 8 mg/L). Mice were then treated with L-AMB regimens for 5-7 days. The efficacy was assessed by animal survival and quantitative PCR lung fungal burden. Total AMB lung homogenate concentrations were determined by HPLC. RESULTS: Compared with untreated controls, 10 mg/kg/day L-AMB prolonged survival (mean >7 versus 3-4 days, P < 0.003) and reduced A. terreus lung fungal burden (median log10 conidial DNA 5.0 versus 6.7, P < 0.05). Daily L-AMB regimens >10 mg/kg/day were associated with poorer survival and higher lung fungal burden. The induction-de-escalation strategy of 10 mg/kg/day ×3 days followed by 3 mg/kg/day was as effective as 10 mg/kg daily dosing, and resulted in higher mean AMB lung homogenate concentrations compared with a continuous 10 mg/kg regimen (23.2 ±â€Š6.7 versus 16.4 ±â€Š4.4 µg/g, P = 0.09). CONCLUSIONS: A high-dose induction-de-escalation L-AMB dosing strategy was an effective treatment for experimental A. terreus pneumonia in neutropenic mice.

In vitro activity of imipenem/releactam and comparator agents against clinical bacterial isolates from patients with cancer.

OBJECTIVES: Gram-negative bacilli (GNB) are currently the predominant bacterial pathogens in patients with cancer. Many GNB have become problematic due to the widespread emergence of resistance. Imipenem/relebactam (IMI/REL) is a combination of the carbapenem imipenem with relebactam, a non-ß-lactam ß-lactamase inhibitor. It is active against most pathogenic GNB including many that are resistant to other agents. We compared its in vitro activity to six other agents against 490 GNB recovered exclusively from patients with cancer because such data are scarce. METHODS: Clinical and Laboratory Standards Institute (CLSI) microbroth dilution methods were used for susceptibility testing. Whole genome sequencing (Illumina MiSeq) was performed on 30 selected isolates. RESULTS: IMI/REL was active against 98% of Enterobacterales and 87% of non-Enterobacterales isolates (excluding Stenotrophomonas maltophilia). It had potent activity against extended spectrum ß-lactamase-producing Escherichia coli, Klebsiella pneumoniae, and other Enterobacterales (Enterobacter cloacae, Citrobacter Spp., and Serratia Spp.) and moderate activity against carbapenem-resistant Enterobacterales. IMI/REL had potent activity against Achromobacter Spp., non-multidrug resistant Pseudomonas aeruginosa, and Sphingomonas paucimobilis and moderate activity against multidrug resistant P. aeruginosa. Overall, IMI/REL was associated with the lowest number of nonsusceptible isolates compared with six other agents (imipenem, meropenem, cefepime, piperacillin/tazobactam, amikacin, and tigecycline) commonly used in patients with cancer. Whole genome sequencing performed on 30 resistant isolates (10 each of E. coli, K. pneumonia, and P. aeruginosa) did not reveal any predominant mechanism of resistance to IMI/REL. CONCLUSION: Its in vitro activity indicates that IMI/REL might have a role to play in the treatment of Gram-negative infections in patients with cancer.

Comparative in vivo dose-dependent activity of caspofungin and anidulafungin against echinocandin-susceptible and -resistant Aspergillus fumigatus.

BACKGROUND: Echinocandin resistance in Aspergillus species is rare. We examined if mutations in FKS1 would result in a complete loss of echinocandin activity in vivo in an experimental model of aspergillosis. METHODS: Neutropenic mice were infected with either an echinocandin-susceptible Aspergillus fumigatus (AF 293) or an echinocandin-resistant A. fumigatus laboratory strain harbouring 'hot-spot' substitution in Fks1p (AF Ser678Pro). Mice then received daily treatment with either anidulafungin or caspofungin at varying dosages (0.25-16 mg/kg/day) for 5 days and Aspergillus lung fungal burden was assessed by quantitative real-time PCR. RESULTS: Both strains produced histological evidence of progressive invasive pulmonary aspergillosis, but AF Ser678Pro was less virulent than AF 293, as evidenced by lower lung fungal burden and longer median survival time. At > 0.5 mg/kg/day, both anidulafungin and caspofungin reduced the lung fungal burden in neutropenic animals infected with AF 293, but had mixed efficacy against the resistant AF Ser678Pro strain. For caspofungin, the fungal burden was reduced only at doses <1 mg/kg/day. Anidulafungin also modestly reduced AF Ser678Pro lung fungal burden, but only at > 4 mg/kg/day. CONCLUSIONS: Despite a lack of appreciable antifungal activity in vitro, both anidulafungin and caspofungin were still modestly effective in vivo against a laboratory-generated A. fumigatus mutant harbouring the Ser678Pro mutation in Fks1p. This persistent activity, combined with impaired fitness of the isolate in vivo, could partially explain why microbiologically documented echinocandin-resistance in Aspergillus species remains a rare clinical occurrence.

Quantitative assessment of combination antimicrobial therapy against multidrug-resistant bacteria in a murine pneumonia model.

BACKGROUND: Combination antimicrobial therapy is clinically used as a last-resort strategy to control multidrug-resistant bacterial infections. However, selection of antibiotics is often empirical, and conventional assessment of combined drug effect has not been correlated to clinical outcomes. Here, we report a quantitative method to assess combined killing of antimicrobial agents against 2 multidrug-resistant bacteria. METHODS: Combined time-kill studies were performed using clinically achievable concentrations for each 2-agent combination against clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Bacterial burden observed at 24 h was mathematically modeled using a 3-dimensional response surface. Subsequently, a neutropenic murine pneumonia model with simulated clinical dosing exposures was used to validate our quantitative assessment of combined killing. RESULTS: Different antimicrobial combinations were found to have varying efficacy against the multidrug-resistant bacteria. As predicted by our quantitative method, cefepime plus amikacin was found to be the most superior combination, which was evidenced by a reduction in tissue bacterial burden and prolonged survival of infected animals. CONCLUSIONS: The consistency between the predictions of the mathematical model and in vivo observations substantiated the robustness of our quantitative method. These data highlighted a novel and promising method to guide rational selection of antimicrobial combination in the clinical setting.

Comparative pharmacodynamics of amphotericin B lipid complex and liposomal amphotericin B in a murine model of pulmonary mucormycosis.

We compared the kinetics of amphotericin B (AMB) lung accumulation and fungal clearance by liposomal amphotericin B (L-AMB) and amphotericin B lipid complex (ABLC) in a neutropenic murine model of invasive pulmonary mucormycosis (IPM). Immunosuppressed BALB/c mice were inoculated with 1 x 10(6) Rhizopus oryzae spores and administered L-AMB or ABLC at daily intravenous doses of 1, 5, or 10 mg/kg of body weight for 5 days starting 12 h after infection. At a dose of 10 mg/kg/day, both L-AMB and ABLC were effective at reducing the R. oryzae lung fungal burden and achieved lung tissue concentrations exceeding the isolate mean fungicidal concentration (MFC) of 8 microg/ml by 72 h. When ABLC was dosed at 5 mg/kg/day, the ABLC-treated animals had significantly higher AMB lung concentrations than the L-AMB treated animals at 24 h (6.64 and 1.44 microg/g, respectively; P = 0.013) and 72 h (7.49 and 1.03 microg/g, respectively; P = 0.005), and these higher concentrations were associated with improved fungal clearance, as determined by quantitative real-time PCR (mean conidial equivalent of R. oryzae DNA per lung, 4.44 +/- 0.44 and 6.57 +/- 0.74 log(10), respectively; P < 0.001). Analysis of the AMB tissue concentration-response relationships revealed that the suppression of R. oryzae growth in the lung required tissue concentrations that approached the MFC for the infecting isolate (50% effective concentration, 8.19 microg/g [95% confidence interval, 2.81 to 18.1 microg/g]). The rates of survival were similar in the animals treated with L-AMB and ABLC at 10 mg/kg/day. These data suggest that higher initial doses may be required during L-AMB treatment than during ABLC treatment of experimental IPM.

Pharmacodynamics of moxifloxacin against a high inoculum of Escherichia coli in an in vitro infection model.

OBJECTIVES: Escherichia coli is the leading bacterial species implicated in intra-abdominal infections. In these infections a high bacterial burden with pre-existing resistant mutants are likely to be encountered and resistance could be amplified with suboptimal dosing. Our objective was to investigate the pharmacodynamics of moxifloxacin against a high inoculum of E. coli using an in vitro hollow fibre infection model (HFIM). METHODS: Three wild-type strains of E. coli (ATCC 25922, MG1655 and EC28044) were studied by exposing approximately 2 x 10(8) cfu/mL (20 mL) to escalating dosing regimens of moxifloxacin (ranging from 30 to 400 mg, once daily). Serial samples were obtained from HFIM over 120 h to enumerate the total and resistant subpopulation. Quinolone resistance-determining regions of gyrA and parC of resistant isolates were sequenced to confirm the mechanism of resistance. RESULTS: The pre-exposure MIC of the three wild-type strains was 0.0625 mg/L. Simulated moxifloxacin concentration profiles in HFIM were satisfactory (r(2) >or= 0.94). Placebo experiments revealed natural mutants, but no resistance amplification. Regrowth and resistance amplification was observed between 30 mg/day (AUC/MIC = 47) and 80 mg/day dose (AUC/MIC = 117). Sustained bacterial suppression was achieved at >or=120 mg/day dose (AUC/MIC = 180). Point mutations in gyrA (D87G or S83L) were detected in resistant isolates. CONCLUSIONS: Our results suggest that suboptimal dosing may facilitate resistance amplification in a high inoculum of E. coli. The clinical dose of moxifloxacin (400 mg/day) was adequate to suppress resistance development in three wild-type strains. Clinical relevance of these findings warrants further in vivo investigation.

Quantitative assessment of combination antimicrobial therapy against multidrug-resistant Acinetobacter baumannii.

Treatment of multidrug-resistant bacterial infections poses a therapeutic challenge to clinicians; combination therapy is often the only viable option for multidrug-resistant infections. A quantitative method was developed to assess the combined killing abilities of antimicrobial agents. Time-kill studies (TKS) were performed using a multidrug-resistant clinical isolate of Acinetobacter baumannii with escalating concentrations of cefepime (0 to 512 mg/liter), amikacin (0 to 256 mg/liter), and levofloxacin (0 to 64 mg/liter). The bacterial burden data in single and combined (two of the three agents with clinically achievable concentrations in serum) TKS at 24 h were mathematically modeled to provide an objective basis for comparing various antimicrobial agent combinations. Synergy and antagonism were defined as interaction indices of <1 and >1, respectively. A hollow-fiber infection model (HFIM) simulating various clinical (fluctuating concentrations over time) dosing exposures was used to selectively validate our quantitative assessment of the combined killing effect. Model fits in all single-agent TKS were satisfactory (r(2) > 0.97). An enhanced combined overall killing effect was seen in the cefepime-amikacin combination (interactive index, 0.698; 95% confidence interval [CI], 0.675 to 0.722) and the cefepime-levofloxacin combination (interactive index, 0.929; 95% CI, 0.903 to 0.956), but no significant difference in the combined overall killing effect for the levofloxacin-amikacin combination was observed (interactive index, 0.994; 95% CI, 0.982 to 1.005). These assessments were consistent with observations in HFIM validation studies. Our method could be used to objectively rank the combined killing activities of two antimicrobial agents when used together against a multidrug-resistant A. baumannii isolate. It may offer better insights into the effectiveness of various antimicrobial combinations and warrants further investigations.

Aqueous and vitreous concentrations following topical administration of 1% voriconazole in humans.

OBJECTIVE: To determine the penetration of 1% voriconazole solution into the aqueous and vitreous following topical administration. METHODS: A prospective nonrandomized study of 13 patients scheduled for pars plana vitrectomy surgery. Aqueous and vitreous samples were obtained and analyzed after topical administration of 1% voriconazole every 2 hours for 24 hours before surgery. Drug concentration quantitation was performed using high-performance liquid chromatography. RESULTS: The mean (SD) sampling time after topical administration of the last voriconazole dose was 24 (14) minutes. The mean (SD) voriconazole concentrations in the aqueous and vitreous were 6.49 (3.04) microg/mL and 0.16 (0.08) microg/mL, respectively. Aqueous concentrations exceeded the minimum inhibitory concentration at which 90% of isolates are inhibited (MIC(90)) for a wide spectrum of fungi and mold, including Aspergillus, Fusarium, and Candida species. Vitreous concentrations of voriconazole exceeded the MIC(90) for Candida albicans. CONCLUSION: Topically administered voriconazole achieves therapeutic concentrations in the aqueous of the noninflamed human eye for many fungi and molds and achieves therapeutic levels in the vitreous for Candida species. Topical voriconazole may be a useful agent for the management of fungal keratitis and for prophylaxis against the development of fungal endophthalmitis.

Pharmacokinetics of polymyxin B1 in patients with multidrug-resistant Gram-negative bacterial infections.

Polymyxin B is increasingly used clinically for the treatment of multidrug-resistant Gram-negative infections, despite very limited understanding of its disposition in humans. The disposition of intravenous polymyxin B1 in 9 adult patients was characterized. Random blood samples (specifically timed in relation to the dose administered) were obtained, and the serum concentrations of polymyxin B1 were assayed using a validated methodology by liquid chromatography mass spectroscopy. The serum concentration profiles of all the patients were analyzed by a population pharmacokinetic analysis using the nonparametric adaptive grid program. The mean volume of distribution and elimination half-life were found to be 47.2 L and 13.6 h, respectively. This is the 1st case series to date in which the pharmacokinetics of polymyxin B1 after intravenous administration are described. The results of the series in conjunction with pharmacodynamic and susceptibility surveillance studies could facilitate an approach to the design of optimal dosing regimens.

In vitro activity of tedizolid and comparator agents against clinical Gram-positive isolates recovered from patients with cancer.

A total of 248 Gram-positive isolates from cancer patients were tested for in-vitro susceptibility to tedizolid and 3 comparator agents using CLSI broth microdilution methodology. Tedizolid inhibited 97% of isolates at ≤0.5µg/ml. It was active against all Gram-positive species and consistently had 8 fold lower MICs than linezolid, although based on % susceptibility using CLSI breakpoints, most isolates were also susceptible to the comparators. Tedizolid was active against MRSA isolates with vancomycin MICs of ≥1.0µg/ml.

In vitro activity of ceftaroline and comparator agents against Gram-positive and Gram-negative clinical isolates from cancer patients.

Bacterial infections are common in cancer patients. Ceftaroline (CFT) is a broad-spectrum cephalosporin with activity against most Gram-positive organisms (GPOs) and many Gram-negative organisms. In this study, the in vitro activity of CFT was compared with vancomycin (VAN), daptomycin (DAP), linezolid (LZD), trimethoprim/sulphamethoxazole (SXT) and tigecycline (TIG) against bacteria (predominantly blood culture isolates) isolated from cancer patients in 2014 and 2015. CFT was active against methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), methicillin-susceptible coagulase-negative staphylococci (MS-CoNS) and methicillin-resistant coagulase-negative staphylococci (MR-CoNS) with MIC90 values (minimum inhibitory concentration that inhibited 90% of the isolates) of 0.25, 2.0, 0.12 and 0.5 mg/L, respectively. MIC90 values for other GPOs were: Bacillus spp., >8.0 mg/L; Corynebacterium spp., 2.0 mg/L; Micrococcus spp., <0.06 mg/L; viridans group streptococci, 0.5 mg/L; Streptococcus pneumoniae, 0.25 mg/L; and Streptococcus spp., <0.06 mg/L. Among the comparator agents, VAN, DAP, TIG and LZD were active against the majority of GPOs tested. CFT also had moderate activity against common extended-spectrum ß-lactamase (ESBL)-negative Gram-negative bacilli such as Enterobacter cloacae, Escherichia coli, Klebsiella spp., Proteus mirabilis and Serratia spp.

Time-kill determination of the bactericidal activity of telavancin and vancomycin against clinical methicillin-resistant Staphylococcus aureus isolates from cancer patients.

The bactericidal activity of vancomycin and telavancin was compared against 4 clinical methicillin-resistant Staphylococcus aureus isolates recently recovered from cancer patients, using minimum bactericidal concentration (MBC):MIC ratios and time-kill studies. All 4 isolates were susceptible to both agents based on individual MIC values. The 2 methodologies for assessing bactericidal activity produced variable results. Telavancin appeared to have somewhat better bactericidal activity than vancomycin based on narrower MBC:MIC ratios. However, based on the results of the time-kill studies, neither agent demonstrated reliable bactericidal activity (defined as a ≥3 log10 reduction of the starting inoculum at the end of 24hours) against these organisms. These findings might be of some therapeutic importance in certain clinical settings and/or specific patient populations (such as febrile neutropenic patients) in whom potent bactericidal activity is either desired or preferred.

Vitreous and aqueous penetration of orally administered moxifloxacin in humans.

OBJECTIVE: To investigate intraocular penetration of moxifloxacin hydrochloride after oral administration. METHODS: Prospective study of 15 patients scheduled for vitrectomy between September and November 2004 at the Barnes Retina Institute, St Louis, MO. Aqueous, vitreous, and serum samples were analyzed from 15 patients after oral administration of 2 tablets containing 400 mg of moxifloxacin. Assays were performed using high-performance liquid chromatography. RESULTS: The mean +/- SD moxifloxacin concentrations in plasma (n = 15), vitreous (n = 13), and aqueous (n = 13) samples were 3.56 +/- 1.31 microg/mL, 1.34 +/- 0.66 microg/mL, and 1.58 +/- 0.80 microg/mL, respectively. Mean +/- SD sampling times after oral administration of the second moxifloxacin tablet for plasma, vitreous, and aqueous were 2.94 +/- 0.81 hours, 3.77 +/- 0.92 hours, and 3.71 +/- 0.89 hours, respectively. The percentages of plasma moxifloxacin concentration in the vitreous and aqueous were 37.6% and 44.3%, respectively. Minimal inhibitory concentrations against 90% levels were exceeded against a wide spectrum of gram-positive and gram-negative pathogens in the vitreous and aqueous. CONCLUSIONS: Moxifloxacin has a spectrum of coverage that encompasses the most common organisms in endophthalmitis. The pharmacokinetic findings of this investigation reveal that orally administered moxifloxacin achieves therapeutic levels in the noninflamed eye. Because of their broad spectrum of coverage, low minimal inhibitory concentration against 90% levels, good tolerability, and excellent oral bioavailability, fourth-generation fluoroquinolones may represent a major advance for managing posterior segment infections.

In vitro activity of dalbavancin and five comparator agents against common and uncommon Gram-positive organisms isolated from cancer patients.

Dalbavancin is a long acting, bactericidal lipoglycopeptide. Its in vitro activity was compared with that of vancomycin, daptomycin, linezolid, trimethoprim/sulfamethoxazole (TMP/SMX) and levofloxacin against 241 Gram-positive organisms isolated from cancer patients. The rank order of potency for the glycopeptides based on MIC90 (µg ml(-1)), that is, the concentration of antimicrobial agent required to inhibit 90% of isolates tested was dalbavancin (0.12 µg ml(-1))>daptomycin (1.0 µg ml(-1))>vancomycin (2.0 µg ml(-1)) for coagulase-negative staphylococci and Staphylococcus aureus isolates (including methicillin-susceptible (MSSA) and methicillin-resistant (MRSA) strains). Dalbavancin had potent activity against staphylococcal isolates with vancomycin MICs⩾1.0 µg ml(-1). TMP/SMX also had potent activity against staphylococci including methicillin-resistant strains, whereas levofloxacin had moderate to poor anti-staphylococcal activity. Dalbavancin also exhibited more potent activity than vancomycin and daptomycin against Bacillus spp., Corynebacterium spp., Micrococcus spp. and various streptococci (including Streptococcus pneumoniae, viridans group streptococci (VGS), beta-hemolytic streptococci and gamma-hemolytic streptococci). MBC determinations showed that dalbavancin had potent bactericidal activity against MRSA with no tolerance being detected. These data suggest that dalbavancin may be considered as an alternative to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs⩾1.0 µg ml(-1).

Penetration pharmacokinetics of topically administered 0.5% moxifloxacin ophthalmic solution in human aqueous and vitreous.

OBJECTIVE: To investigate the penetration of 0.5% moxifloxacin hydrochloride into the aqueous and vitreous after topical administration in humans. METHODS: A prospective, nonrandomized study of 20 patients scheduled for vitrectomy surgery between September 1 and December 31, 2003. Aqueous and vitreous samples were obtained and analyzed after topical administration of 0.5% moxifloxacin hydrochloride, every 2 hours (q2h) or every 6 hours (q6h), for 3 days before surgery. Assays were performed using high-performance liquid chromatography. RESULTS: Mean +/- SD moxifloxacin concentrations in the q2h group for the aqueous (n = 9) and vitreous (n = 10) were 2.28 +/- 1.23 and 0.11 +/- 0.05 microg/mL, respectively. Mean +/- SD moxifloxacin concentrations in the q6h group for the aqueous (n = 10) and vitreous (n = 9) were 0.88 +/- 0.88 and 0.06 +/- 0.06 microg/mL, respectively. The minimum inhibitory concentration for 90% of isolates (MIC(90)) was far exceeded in the aqueous for a wide spectrum of key pathogens, whereas it was not exceeded in the vitreous for several organisms. However, the minimum inhibitory concentration for 50% of the isolates was exceeded in the q2h vitreous group for Staphylococcus epidermidis, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Bacillus cereus, and other gram-negative pathogens. CONCLUSIONS: The Endophthalmitis Vitrectomy Study revealed that 94.2% of isolates from postoperative endophthalmitis are gram-positive pathogens. Moxifloxacin has a spectrum of coverage that appropriately encompasses the most common organisms in endophthalmitis. The pharmacokinetic findings of this investigation show that relatively high aqueous levels can be achieved after topical administration. Further studies will help define the precise role of 0.5% moxifloxacin ophthalmic solution in the treatment of or prophylaxis against intraocular infections.