Dose Optimization of Combined Linezolid and Fosfomycin against
            <i>Enterococcus</i>
            by Using an
            <i>In Vitro</i>
            Pharmacokinetic/Pharmacodynamic Model

Mao, Jun; Li, Ting; Zhang, Na; Wang, Shuaishuai; Li, Yaowen; Peng, Yu; Liu, Huiping; Guang, Yang; Yan, Yisong; Jiang, Lifang; Liu, Yanyan; Li, Jiabin; Huang, Xiaohui

doi:10.1128/spectrum.00871-21

Cited by 5 publications

(4 citation statements)

References 46 publications

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“…Another promising approach is the drug combination that has been used for several diseases including those of infection origin. Combos may act on different and/or complementary targets, allowing the use of lower drug concentrations and thus reducing toxic events (Wiwanitkit, 2012 ; Hendrickx et al ., 2017 ; Gaibani et al ., 2019 ; Ianevski et al ., 2021 ; Mao et al ., 2021 ).…”

Section: Discussionmentioning

confidence: 99%

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Present,

Girão,

Lin

et al. 2024

Parasitology

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Leishmania is a trypanosomatid parasite that causes skin lesions in its cutaneous form. Current therapies rely on old and expensive drugs, against which the parasites have acquired considerable resistance. Trypanosomatids are unable to synthesize purines relying on salvaging from the host, and nucleoside analogues have emerged as attractive antiparasitic drug candidates. 4-Methyl-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]pyrimidine (CL5564), an analogue of tubercidin in which the amine has been replaced by a methyl group, demonstrates activity against Trypanosoma cruzi and Leishmania infantum. Herein, we investigated its in vitro and in vivo activity against L. amazonensis. CL5564 was 6.5-fold (P = 0.0002) more potent than milteforan™ (ML) against intracellular forms in peritoneal mouse macrophages, and highly selective, while combination with ML gave an additive effect. These results stimulated us to study the activity of CL5564 in mouse model of cutaneous Leishmania infection. BALB/c female and male mice infected by L. amazonensis treated with CL5564 (10 mg kg−1, intralesional route for five days) presented a >93% reduction of paw lesion size likely ML given orally at 40 mg kg−1, while the combination (10 + 40 mg kg−1 of CL5564 and ML, respectively) caused >96% reduction. The qPCR confirmed the suppression of parasite load, but only the combination approach reached 66% of parasitological cure. These results support additional studies with nucleoside derivatives.

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Section: Discussionmentioning

confidence: 99%

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Present,

Girão,

Lin

et al. 2024

Parasitology

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“…In rare cases of infections caused by linezolid-resistant Staphylococcus spp. or Enterococcus spp., and in absence of valid alternatives, some associations have been proposed, although they are supported only by exploratory and mostly in vitro data [91,92]. The use of higher doses, to the contrary, is generally not recommended, because of safety concerns [93].…”

Section: Linezolid and Tedizolidmentioning

confidence: 99%

Antibiotic Resistance to Molecules Commonly Prescribed for the Treatment of Antibiotic-Resistant Gram-Positive Pathogens: What Is Relevant for the Clinician?

Tebano,

Zaghi,

Baldasso

et al. 2024

Pathogens

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Antibiotic resistance in Gram-positive pathogens is a relevant concern, particularly in the hospital setting. Several antibiotics are now available to treat these drug-resistant pathogens, such as daptomycin, dalbavancin, linezolid, tedizolid, ceftaroline, ceftobiprole, and fosfomycin. However, antibiotic resistance can also affect these newer molecules. Overall, this is not a frequent phenomenon, but it is a growing concern in some settings and can compromise the effectiveness of these molecules, leaving few therapeutic options. We reviewed the available evidence about the epidemiology of antibiotic resistance to these antibiotics and the main molecular mechanisms of resistance, particularly methicillin-resistant Sthaphylococcus aureus, methicillin-resistant coagulase-negative staphylococci, vancomycin-resistant Enterococcus faecium, and penicillin-resistant Streptococcus pneumoniae. We discussed the interpretation of susceptibility tests when minimum inhibitory concentrations are not available. We focused on the risk of the emergence of resistance during treatment, particularly for daptomycin and fosfomycin, and we discussed the strategies that can be implemented to reduce this phenomenon, which can lead to clinical failure despite appropriate antibiotic treatment. The judicious use of antibiotics, epidemiological surveillance, and infection control measures is essential to preserving the efficacy of these drugs.

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“…When the linezolid-fosfomycin combination was used at clinical isolates of Enterococcus, it prevented the emergence of resistant mutants in lower drug concentrations and was synergistic in a hollow fiber model; another in vitro study demonstrated a reduction in linezolid MIC when co-administered with fosfomycin, even though MICs for fosfomycin were relatively high (≥64 mg/L) [171][172][173]. The simulated fosfomycin regimen in this work, however, was higher than the levels achievable by oral administration [171]. In addition, an in vitro study showed that the fosfomycin-cefixime combination has synergistic killing properties against E. coli, even in half the MIC concentrations for each drug [174].…”

Section: The Potential Utility Of Oral Fosfomycin Against Endocarditi...mentioning

confidence: 99%

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives

Eleftheriotis,

Marangos,

Lagadinou

et al. 2023

Microorganisms

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Bacteremia and endocarditis are two clinical syndromes that, for decades, were managed exclusively with parenteral antimicrobials, irrespective of a given patient’s clinical condition, causative pathogen, or its antibiotic susceptibility profile. This clinical approach, however, was based on low-quality data and outdated expert opinions. When a patient’s condition has improved, gastrointestinal absorption is not compromised, and an oral antibiotic regimen reaching adequate serum concentrations is available, a switch to oral antibacterials can be applied. Although available evidence has reduced the timing of the oral switch in bacteremia to three days/until clinical improvement, there are only scarce data regarding less than 10-day intravenous antibiotic therapy in endocarditis. Many standard or studied oral antimicrobial dosages are smaller than the approved doses for parenteral administration, which is a risk factor for treatment failure; in addition, the gastrointestinal barrier may affect drug bioavailability, especially when the causative pathogen has a minimum inhibitory concentration that is close to the susceptibility breakpoint. A considerable number of patients infected by such near-breakpoint strains may not be potential candidates for oral step-down therapy to non-highly bioavailable antibiotics like beta-lactams; different breakpoints should be determined for this setting. This review will focus on summarizing findings about pathogen-specific tailoring of oral step-down therapy for bacteremia and endocarditis, but will also present laboratory and clinical data about antibiotics such as beta-lactams, linezolid, and fosfomycin that should be studied more in order to elucidate their role and optimal dosage in this context.

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Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

Cited by 5 publications

References 46 publications

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Antibiotic Resistance to Molecules Commonly Prescribed for the Treatment of Antibiotic-Resistant Gram-Positive Pathogens: What Is Relevant for the Clinician?

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives

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Dose Optimization of Combined Linezolid and Fosfomycin against Enterococcus by Using an In Vitro Pharmacokinetic/Pharmacodynamic Model

Cited by 5 publications

References 46 publications

N6-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

N6-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

Antibiotic Resistance to Molecules Commonly Prescribed for the Treatment of Antibiotic-Resistant Gram-Positive Pathogens: What Is Relevant for the Clinician?

Oral Antibiotics for Bacteremia and Infective Endocarditis: Current Evidence and Future Perspectives

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N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model

N⁶-methyltubercidin gives sterile cure in a cutaneous Leishmania amazonensis mouse model