PURPOSE:

: To study the in vitro interaction of fluoroquinolones such as levofloxacin (LVFX), gatifloxacin (GFLX), or moxifloxacin (MFLX) in combination with tobramycin (TOB) or cefmenoxime (CMX) against clinical isolates of bacteria from keratitis.

METHODS::

The activity of each drug alone was determined by an agar dilution method. Checkerboard synergy testing was then performed against 47 isolates, including Staphylococcus species, Streptococcus species, and Pseudomonas aeruginosa. Antimicrobial combinations were classified as synergistic, additive, indifferent, or antagonistic, according to their fractional inhibitory concentration.

RESULTS::

The average fractional inhibitory concentration indexes of combined use of LVFX/CMX or GFLX/CMX in Staphylococcus species and Streptococcus species, and LVFX/CMX, GFLX/CMX, MFLX/CMX in gram-negative rods were low. The additive activity of the following drug combinations were seen in more than 70% of isolates: LVFX/CMX and GFLX/CMX against gram-positive cocci and LVFX/CMX, GFLX/CMX, MFLX/CMX against gram-negative rods. No consistent synergistic or antagonistic effect was observed with the combinations used.

CONCLUSION:

: The combination of LVFX/CMX or GFLX/CMX was predominantly additive for all tested isolates.

Previous work has shown that besifloxacin, an 8-chloro-fluoroquinolone, has more potent activity against gram-positive pathogens than moxifloxacin and gatifloxacin, which carry an 8-methoxy group. This study was conducted to determine the contribution of the R7 and R8 substituent to fluoroquinolone antibacterial activity.Besifloxacin, moxifloxacin, gatifloxacin, their R8 structural analogs, and ciprofloxacin were tested against representative isolates of various gram-positive and gram-negative species and previously characterized fluoroquinolone-resistant mutants of Staphylococcus aureus. Minimum inhibitory and minimum bactericidal concentrations were determined according to Clinical and Laboratory Standards Institute (CLSI) guidelines. Reserpine was used to determine the effect of efflux pumps on antibacterial activity.In general, exchanging the R8 residue in besifloxacin slightly reduced the molecule's potency, while introducing an 8-chloro group in moxifloxacin increased its potency. A similar change in gatifloxacin had little to no effect. Substituting the R8 residues did not increase the susceptibility to the efflux pump inhibitor reserpine or result in a loss of bactericidal activity. In contrast, the positive control, ciprofloxacin, was shown to be a substrate for reserpine and lost bactericidal activity against some fluoroquinolone-resistant isolates of S. aureus.The data presented here show that, depending on the R7 substituent, replacing an 8-methoxy group with an 8-chloro substituent can improve potency or can have little-to-no effect. These findings highlight the importance of the interplay between the R7 and R8 substituents in determining antibacterial potency.

PURPOSE:

: To compare the intraocular penetration of 4 fluoroquinolone eye drops after topical instillation into rabbit eyes.

METHODS::

The tested drugs were levofloxacin 1.5% (LVFX), gatifloxacin 0.3%, moxifloxacin 0.5% (MFLX), and besifloxacin 0.6% (BFLX). Forty-eight New Zealand white rabbits were randomly assigned into 2 groups. For group 1 (40 rabbits, 80 eyes), single instillation was performed, and tissue samples were acquired after 0.5, 1, 2, 4, and 6 hours. For group 2 (8 rabbits, 16 eyes), repeated instillation was performed (4 times, every 15 minutes), and tissues were acquired 1 hour after the fourth instillation. The drug concentrations in ocular tissues (cornea, aqueous, conjunctiva, and trisected vitreous) were analyzed with high-performance liquid chromatography.

RESULTS::

The AUC0-6 h (area under the curve, in microgram.hour/gram) in group 1 and the mean concentration (in micrograms/gram) in group 2 for LVFX, gatifloxacin 0.3%, MFLX, and BFLX, respectively, were 22.97, 6.44, 13.54, and 3.29 and 22.60, 6.99, 13.69, and 1.91 in cornea; 5.66, 1.43, 3.38, and 0.42 and 5.52, 1.29, 2.47, and 0.19 in aqueous humor; 2.33, 0.91, 2.17, and 9.83 and 4.51, 0.78, 1.48, and 2.09 in bulbar conjunctiva; 0.243, 0.051, 0.134, and 0.018 and 0.182, 0.055, 0.122, and 0.015 in anterior vitreous; none of the drugs achieved enough concentration in equatorial and posterior vitreous. Repeated instillation resulted in approximately 2.1 times greater penetration than single instillation.

CONCLUSIONS::

LVFX and MFLX demonstrated good intraocular penetration particularly in cornea, aqueous humor, and anterior vitreous, and they may be considered the penetrative fluoroquinolones. BFLX showed high concentration in bulbar conjunctiva and may be considered the retentive fluoroquinolone.

The emergence of decreased ciprofloxacin susceptibility (DCS) in Salmonella enterica serovar Typhi and serovar Paratyphi A, B or C limits treatment options. We studied the impact of DCS isolates on the fate of travellers returning with enteric fever and possible alternative treatment options. We evaluated the clinical features, susceptibility data and efficacy of empirical treatment in patients with positive blood cultures of a DCS isolate compared to patients infected with a ciprofloxacin-susceptible (CS) isolate in the period from January 2002 to August 2008. In addition, the pharmacokinetic and pharmacodynamic parameters of ciprofloxacin, levofloxacin and gatifloxacin were determined to assess if increasing the dose would result in adequate unbound fraction of the drug 24-h area under the concentration-time curve/minimum inhibitory concentration (ƒAUC0-24/MIC) ratio. Patients with DCS more often returned from the Indian subcontinent and had a longer fever clearance time and length of hospital stay compared to patients in whom the initial empirical therapy was adequate. The mean ƒAUC0-24/MIC was 41.3 ± 18.8 in the patients with DCS and 585.4 ± 219 in patients with a CS isolate. For DCS isolates, the mean ƒAUC0-24/MIC for levofloxacin was 60.5 ± 28.7 and for gatifloxacin, it was 97.9 ± 28.0. Increasing the dose to an adequate ƒAUC0-24/MIC ratio will lead to conceivably toxic drug levels in 50 % of the patients treated with ciprofloxacin. Emerging DCS isolates has led to the failure of empirical treatment in ill-returned travellers. We demonstrated that, in some cases, an adequate ƒAUC0-24/MIC ratio could be achieved by increasing the dose of ciprofloxacin or by the use of alternative fluoroquinolones.

Fluoroquinolones (FQs) are important antimicrobials that exhibit activity against a wide range of bacterial pathogens and excellent tissue permeation. They exist as charged molecules in biological fluids, and thus, their disposition depends heavily on active transport and facilitative diffusion. A recent review of the clinical literature indicated that tubular secretion and reabsorption are major determinants of their half-life in plasma, efficacy, and drug-drug interactions. In particular, reported in vivo interactions between FQs and cationic drugs affecting renal clearance implicated organic cation transporters (OCTs). In this study, 13 FQs, ciprofloxacin, enoxacin, fleroxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, norfloxacin, ofloxacin, pefloxacin, prulifloxacin, rufloxacin, and sparfloxacin, were screened for their ability to inhibit transport activity of human OCT1 (hOCT1) (SLC22A1), hOCT2 (SLC22A2), and hOCT3 (SLC22A3). All, with the exception of enoxacin, significantly inhibited hOCT1-mediated uptake under initial test conditions. None of the FQs inhibited hOCT2, and only moxifloxacin inhibited hOCT3 (∼30%), even at a 1,000-fold excess. Gatifloxacin, moxifloxacin, prulifloxacin, and sparfloxacin were determined to be competitive inhibitors of hOCT1. Inhibition constants (Ki) were estimated to be 250 ± 18 μM, 161 ± 19 μM, 136 ± 33 μM, and 94 ± 8 μM, respectively. Moxifloxacin competitively inhibited hOCT3-mediated uptake, with a Ki value of 1,598 ± 146 μM. Despite expression in enterocytes (luminal), hepatocytes (sinusoidal), and proximal tubule cells (basolateral), hOCT3 does not appear to contribute significantly to FQ disposition. However, hOCT1 in the sinusoidal membrane of hepatocytes, and potentially the basolateral membrane of proximal tubule cells, is likely to play a role in the disposition of these antimicrobial agents.

To report keratitis with Elizabethkingia meningoseptica, which occurred in a healthy patient after wearing contact lenses for 6 months. A 24-year-old male patient visited our hospital with ocular pain. This patient had a history of wearing soft contact lenses for 6 months, about 10 hours per day. At initial presentation, slit lamp examination showed corneal stromal infiltrations and small epithelial defect. Microbiological examinations were performed from corneal scrapings, contact lenses, and the contact lens case and solution. The culture results from contact lenses, contact lens case and solution were all positive for Elizabethkingia meningoseptica. Thus, we could confirm that the direct cause of keratitis was contamination of the contact lenses. The patient was treated with 0.3% gatifloxacin. After treatment, the corneal epithelial defect was completely healed, and a slight residual subepithelial corneal opacity was observed. We diagnosed keratitis with Elizabethkingia meningoseptica in a healthy young male wearing soft contact lenses. We conclude that Elizabethkingia meningoseptica should be considered as a rare but potential pathogen for lens-related keratitis in a healthy host.

PURPOSE:

To investigate the spectrum of organisms causing culture-proven endophthalmitis and their susceptibilities to commonly used antimicrobial agents over 10 years.

DESIGN:

Retrospective, noncomparative, consecutive case series.

METHODS:

Medical records were reviewed of all cases with culture-proven endophthalmitis at a single institution from 2002 through 2011. The outcome measures included all intravitreal isolates identified as well as antibiotic susceptibilities.

RESULTS:

A total of 448 organisms were isolated during the study interval. The most common organisms identified were Staphylococcus epidermidis in 30.1% (135/448), Streptococcus viridians group in 10.9% (49/448), Staphylococcus aureus in 7.8% (35/448), Candida albicans in 5.8% (26/443), other coagulase-negative staphylococci in 6.0% (27/448), Propionibacterium acnes in 4.7% (21/448), and Pseudomonas aeruginosa in 3.1% (14/448). Overall, 327 (72.9%) of 448 isolates were gram-positive organisms, 48 (10.7%) of 448 isolates were gram-negative organisms, 71 (15.8%) of 448 isolates were fungi, and 2 (0.4%) of 448 isolates were viruses. For gram-positive organisms, susceptibilities were the following: vancomycin, 100%; gentamicin, 88.0%; sulfamethoxazole/trimethoprim, 77.5%; levofloxacin, 58.5%; oxacillin, 54.7%; ciprofloxacin, 51.0%; gatifloxacin, 51.0%; and moxifloxacin, 47.0%. For gram-negative organisms, susceptibilities were the following: ceftazidime, 100%; levofloxacin, 100%; ciprofloxacin, 95.0%; tobramycin, 90.6%; gentamicin, 80.6%; and sulfamethoxazole/trimethoprim, 59.4%.

CONCLUSIONS:

In the current study, no single antibiotic provided coverage for all of the microbes isolated from eyes with endophthalmitis. Combination therapy generally is the recommendation as the initial empiric treatment of suspected bacterial endophthalmitis. Appropriate history and characteristic clinical features may guide the use of initial antifungal agents.

The meta-analysis of 12 clinical research of application of antibiotics (azithromycin, roxithromycin clarithromycin, gatifloxacin) in 24 949 patients with coronary heart disease were carried out. The obtained results were shown that application of short courses of antibiotic therapy in patients with severe morphological changes in small coronary vessels were not enough effective. Contrariwise, long-term courses of antibiotic therapy could be effective in patients with initial lesions of blood vessels and presence of chronic infections.

Over the last few years a number of important drugs like rofecoxib, Rosiglitazone, and Gatifloxacin (in diabetics) have lost their position in disease management. The newest controversy revolves around Pioglitazone, a thiozolidindione, which improves insulin sensitivity and is reputed to have cardioprotective actions, but is riddled with several controversies related to weight gain, distal fractures of long bones, recent reports of bladder cancer and others. There are now new groups of drugs, which have been introduced with stringent FDA approval. These include DPP-4 inhibitors, GLP-1 analogues and bromocriptine (old wine in a new bottle). Early in 2013 we are also looking at the launch of another new agent--SGLT-2 inhibitors. These newer agents are associated with not only a significant glucose lowering effect but also positive extra-glycemic benefits principally in the areas of hypoglycemia and weight gain. This raises a very important question--do we really need such a controversial agent when such a plethora of agents are available to us with possibly better metabolic profile than Pioglitazone? This review addresses this highly contentious area dissecting the pros and cons as we see it.

Abstract

Purpose:

To determine the differences between conjunctival bacterial flora of hemodialysis patients and healthy subjects, the effect of duration of hemodialysis on conjunctival bacterial flora, and in vitro antibiotic susceptibility patterns of conjunctival bacterial flora to fluoroquinolones.

Methods:

Sixty healthy subjects (32 male, 28 female) and 60 hemodialysis patients (33 male, 27 female) who had renal failure due to reasons other than diabetic nephropathy and with no previous history of intraocular surgery participated in this study. Statistical analysis of the difference between the culture positivity of hemodialysis patients and a control group was determined using the chi-square test. Pearson's correlation test was used to quantify the correlations among culture positivity and duration of hemodialysis.

Results:

Conjunctival culture positivity of the hemodialysis patients and the control group was 58.3 and 45.0%, respectively, and there was no statistically significant difference between these groups (p = 0.144). Pearson's correlation test revealed that there was a weak but statistically significant positive correlation between culture positivity and duration of hemodialysis (r value was 0.378 [p = 0.003]). Staphylococcus aureus (28.3%) and Staphylococcus epidermidis (20.0%) were the most frequently isolated organisms in the hemodialysis patients, Staphylococcus epidermidis (26.7%) and Staphylococcus aureus (6.7%) were the most frequently isolated organisms in the control group. Resistance of most frequently isolated organisms (Staphylococcus aureus and Staphylococcus epidermidis) from control group and hemodialysis patients to ofloxacin, levofloxacin, moxifloxacin, and gatifloxacin were 20, 15, 5, and 5%, and 34.5, 20.7, 6.9, and 6.9%, respectively.

Conclusions:

As distinct from the control group, S. aureus colonization was isolated more from the hemodialysis patients. Culture positivity of the hemodialysis patients was positively correlated with the duration of hemodialysis. Antibiotic susceptibility of isolates from conjunctival bacterial flora of hemodialysis patients were less than healthy control group.