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.

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.

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.

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.

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).

In vitro activity of telavancin compared with vancomycin and linezolid against Gram-positive organisms isolated from cancer patients.

Telavancin is a dual action, bactericidal lipoglycopeptide. Its in vitro activity was compared with vancomycin and linezolid against 392 Gram-positive isolates from cancer patients. MIC90 values (µg ml(-1)) for telavancin, vancomycin and linezolid were determined for methicillin-susceptible Staphylococcus aureus (MSSA), methicillin-resistant S. aureus (MRSA), methicillin-susceptible (MS), methicillin-resistant (MR), coagulase-negative staphylococci (CoNS), viridans group streptococci (VGS), Streptococcus pneumoniae, Bacillus species, Corynebacterium species and Micrococcus species. Telavancin had potent activity against ß-hemolytic streptococci and Staphylococcus lugdunensis. Whereas 100% of MRSA and 98% of MSSA had vancomycin MICs ⩾ 1.0 µg ml(-1) (minimum inhibitory concentrations (MICs) at which poor clinical responses have been reported), the highest telavancin MIC was 0.38 µg ml(-1). For CoNS, 95% of MS and 100% of MR isolates had vancomycin MICs ⩾ 1.0 µg ml(-1), whereas the highest telavancin MIC was 0.38 µg ml(-1). Furthermore, 48% of VGS had vancomycin MICs ⩾ 1.0 µg ml(-1), whereas the highest telavancin MIC was 0.064 µg ml(-1). A similar pattern was noticed for S. lugdunensis, Bacillus species, Corynebacterium species and ß-hemolytic streptococci. These data suggest that telavancin and linezolid have potent activity against most Gram-positive organisms that cause infections in cancer patients. Consequently, they may be considered as alternatives to vancomycin, especially in institutions wherein a substantial proportion of infections are caused by organisms with vancomycin MICs ⩾ 1.0 µg ml(-1).

Spectrum of gram-positive bacteraemia and in vitro activities of daptomycin, linezolid and vancomycin against organisms isolated from cancer patients.

Gram-positive organisms are the predominant bacterial pathogens in cancer patients. A survey indicated that coagulase-negative staphylococci (CoNS) (29.5%), Staphylococcus aureus (18.0%), Enterococcus spp. (12.1%) and viridans group streptococci (VGS) (9.1%) are isolated most often. The rate of reduced susceptibility to vancomycin (minimum inhibitory concentration ≥1.0 µg/mL) was 100% for meticillin-susceptible S. aureus and 99% for meticillin-resistant S. aureus, and 100% for meticillin-susceptible CoNS and 98% for meticillin-resistant CoNS. More than 98% of these isolates were susceptible to daptomycin and linezolid. Daptomycin and linezolid had comparable in vitro activity to vancomycin against Bacillus spp., Corynebacterium spp., Rhodococcus spp., Micrococcus spp., Stomatococcus mucilaginosus and VGS. Both agents were active against the majority (95%) of vancomycin-resistant organisms, including vancomycin-resistant enterococci, Pediococcus spp. and Leuconostoc spp. These data suggest that daptomycin and linezolid have an adequate antimicrobial spectrum and potent in vitro activity against Gram-positive isolates from cancer patients and may be considered as alternatives to vancomycin for empirical or targeted therapy in this setting.

Comparison of posaconazole versus weekly amphotericin B lipid complex for the prevention of invasive fungal infections in hematopoietic stem-cell transplantation.

BACKGROUND: Antifungal prophylaxis is shown to decrease the risk of invasive fungal infection (IFI) after hematopoietic stem-cell transplantation (HSCT). Posaconazole has been approved for prophylaxis in HSCT. However, it is only available orally given three times per day. We evaluated once weekly intravenous amphotericin B lipid complex (ABLC), given its broad-spectrum antifungal activity and prolonged half-life (172 hr), as an alternative prophylaxis in HSCT. METHODS: We prospectively randomized allogeneic HSCT patients to receive 7.5 mg/kg of intravenous ABLC weekly or 200 mg of posaconazole orally three times per day as prophylaxis for up to 6 weeks. Endpoints were the incidence of IFI and drug-related toxicities. ABLC was discontinued if creatinine level increased to two times the baseline or greater. RESULTS: A total of 46 patients were randomized; 40 received at least one dose of the drug and were included in the analysis: 19 received ABLC and 21 received posaconazole. All patients received tacrolimus. Apache II score, neutropenia, and creatinine, bilirubin, and alanine aminotransferase levels were similar in both groups at baseline. One patient in the ABLC arm and none in posaconazole arm developed IFI (5% vs. 0%, P=0.48). More patients in the ABLC arm doubled their serum creatinine (53% vs. 5%, P=0.001) necessitating discontinuation of the study drug. CONCLUSION: High-dose prophylactic ABLC in HSCT was associated with nephrotoxicity that could be aggravated by the concomitant use of other nephrotoxic agents. Further studies are needed to evaluate the role of weekly high-dose ABLC as antifungal prophylaxis in patients at lower risk for nephrotoxicity.

Escherichia coli resistance to quinolones at a comprehensive cancer center.

As part of Meropenem Yearly Susceptibility Test Information Collection/USA Surveillance Programme, we monitored the occurrence of quinolone resistance in Escherichia coli over a 10-year period. A total of 271 E. coli isolates from our institution were tested over a 10-year period. Screening for quinolone resistance (qnr) gene was performed. A decline in susceptibility of E. coli isolates to quinolones and aminoglycosides was noted over the 10-year span (P < 0.0001), which was significantly reduced compared with the average susceptibility of all sites. Introduction of quinolone prophylaxis has led to a significant decline in susceptibility of E. coli to all quinolones. The organisms remain susceptible to carbapenems, cefepime, and piperacillin/tazobactam. Periodic surveillance allows for detection of resistance patterns and adjustment of empiric antibiotic choice in patients at high risk for infection.

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.

Frequency and species distribution of gliotoxin-producing Aspergillus isolates recovered from patients at a tertiary-care cancer center.

Aspergillus isolates (n = 103) collected from cancer patients were screened to determine the taxonomic distribution and quantity of gliotoxin production. Gliotoxin was detected in 93% of Aspergillus fumigatus, 75% of A. niger, 25% of A. terreus, and 4% of A. flavus cultures. Gliotoxin concentrations were highest in cultures of A. fumigatus.

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.

Detection of gliotoxin in experimental and human aspergillosis.

Gliotoxin was measured in the lungs (mean, 3,976 +/- 1,662 ng/g of tissue) and sera (mean, 36.5 +/- 30.28 ng/ml) of mice with experimentally induced invasive aspergillosis (IA), and levels decreased with antifungal therapy. Gliotoxin could also be detected in the sera of cancer patients with documented (proven or probable) IA.

Determination of aqueous and vitreous concentration of moxifloxacin 0.5% after delivery via a dissolvable corneal collagen shield device.

PURPOSE: To determine the penetration of moxifloxacin 0.5% in the human aqueous and vitreous when delivered by a presoaked collagen shield. SETTING: University-based clinical practice. METHODS: Moxifloxacin 0.5% was administered before vitrectomy surgery in 10 patients using a 24-hour dissolvable cross-linked corneal collagen shield delivery device. Aqueous and vitreous samples were obtained after the shield was placed for 4 hours in the first 5 patients and for 24 hours in the second 5 patients. Assays were performed using high-performance liquid chromatography. RESULTS: Delivery of moxifloxacin via a collagen shield revealed a mean aqueous concentration of 0.30 microg/mL +/- 0.17 (SD) 4 hours after placement (n = 5). Vitreous levels at 4 hours and aqueous and vitreous levels at 24 hours were negligible using this route of administration. Peak aqueous moxifloxacin levels occurred soon after shield placement. This is when high concentrations of moxifloxacin are most needed to clear the aqueous of bacteria. The minimum inhibitory concentration at which 90% of the isolates were inhibited for organisms commonly responsible for endophthalmitis was exceeded in the 4-hour aqueous group. Negligible concentrations were detected at 24 hours. CONCLUSIONS: Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower than via topical drops, there are several advantages to this route of delivery that make it appealing in the immediate postoperative period. Future studies will be needed to define precisely the role of fourth-generation fluoroquinolones and presoaked collagen shields in the prophylaxis or management of intraocular infections.

Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans.

OBJECTIVE: To investigate the penetration of voriconazole, a new-generation triazole antifungal agent, into the vitreous and aqueous humor after oral administration. METHODS: A prospective, nonrandomized clinical study included 14 patients scheduled for elective pars plana vitrectomy surgery between December 1, 2002, and February 28, 2003, at the Cullen Eye Institute, Houston, Tex. Aqueous, vitreous, and plasma samples were obtained and analyzed from 14 patients after oral administration of two 400-mg doses of voriconazole taken 12 hours apart before surgery. Assays were performed by means of high-performance liquid chromatography. RESULTS: Mean +/- SD voriconazole concentrations in plasma (n = 14), vitreous (n = 14), and aqueous (n = 11) were 2.13 +/- 0.93 microg/mL, 0.81 +/- 0.31 microg/mL, and 1.13 +/- 0.57 microg/mL, respectively. Mean +/- SD sampling times after oral administration of the second voriconazole dose for plasma, vitreous, and aqueous were 2.4 +/- 0.6 hours, 3.0 +/- 0.5 hours, and 2.9 +/- 0.5 hours, respectively. The percentages of plasma voriconazole concentration achieved in the vitreous and aqueous were 38.1% and 53.0%, respectively. Mean vitreous and aqueous minimum inhibitory concentrations for 90% of isolates (MIC(90)) were achieved against a wide spectrum of yeasts and molds, including Aspergillus species and Candida species, along with many other organisms. CONCLUSIONS: Orally administered voriconazole achieves therapeutic aqueous and vitreous levels in the noninflamed human eye, and the activity spectrum appears to appropriately encompass the most frequently encountered mycotic species involved in the various causes of fungal endophthalmitis. Because of its broad spectrum of coverage, low MIC(90) levels for the organisms of concern, good tolerability, and excellent bioavailability with oral administration, it may represent a major advance in the prophylaxis or management of exogenous or endogenous fungal endophthalmitis.

Human intraocular penetration pharmacokinetics of moxifloxacin 0.5% via topical and collagen shield routes of administration.

PURPOSE: To determine penetration of moxifloxacin 0.5% into human aqueous and vitreous via topical and collagen shield routes of administration. METHODS: Moxifloxacin 0.5% was administered prior to vitrectomy surgery through one of three routes: topical drops every 2 hours for 3 days, versus topical drops every 6 hours for 3 days, versus delivery using a 24-hour dissolvable cross-linked corneal collagen shield. Aqueous and vitreous moxifloxacin concentrations were assayed using high-performance liquid chromatography. RESULTS: Mean moxifloxacin concentrations in the every-2-hour group for aqueous (n = 9) and vitreous (n = 10) were 2.28 +/- 1.23 microg/mL and 0.11 +/- 0.05 microg/mL, respectively. Mean moxifloxacin concentrations in the every-6-hour group for aqueous (n = 10) and vitreous (n = 9) were 0.88 +/- 0.88 microg/mL and 0.06 +/- 0.06 microg/mL, respectively. Levels of minimum inhibitory concentration at which 90% of isolates are inhibited (MIC90) were far exceeded in the aqueous for a wide spectrum of pathogens that most commonly cause postoperative endophthalmitis. Moxifloxacin concentration in the vitreous did not exceed the MIC90 for several key organisms. Delivery of moxifloxacin via a collagen shield revealed a mean aqueous concentration of 0.30 +/- 0.17 microg/mL 4 hours after placement (n = 5). Vitreous levels at 4 hours, as well as aqueous and vitreous levels at 24 hours, were negligible using this route of administration. CONCLUSIONS: The findings of this investigation reveal that topically administered moxifloxacin 0.5% can achieve relatively high aqueous concentrations. Although aqueous moxifloxacin levels achieved through the use of a collagen shield delivery device are lower, there are several advantages to this route of delivery that make it appealing in the immediate postoperative period. Future studies will be needed to precisely define the role of fourth-generation fluoroquinolones and presoaked collagen shields in the prophylaxis or management of intraocular infections.