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International Journal of Antimicrobial... Jul 2018Polymyxin B (PMB) and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms...
Polymyxin B (PMB) and fosfomycin are two 'old' antibiotics that consistently maintain activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms based on in vitro susceptibility testing. However, the use of each antibiotic in monotherapy has been associated with high rates of treatment failure. Therefore, the objective of this study was to investigate the combinatorial pharmacodynamics of PMB and fosfomycin against KPC-producing K. pneumoniae (KPC-Kp). PMB front-loading (3.33 mg/kg for one dose, followed by 1.43 mg/kg every 12 h starting 12 h later) and burst (5.53 mg/kg for one dose, with no subsequent doses) simulated dosing regimens were explored in combination with fosfomycin (4 g every 8 h) against KPC-2-producing K. pneumoniae ST258 in a hollow-fibre infection model over 120 h. Population analysis profiles were used to track the temporal PMB and fosfomycin resistance profiles. Against isolate KPC-Kp 9A (PMB MIC = 0.5 mg/L; fosfomycin MIC ≤ 8 mg/L), monotherapies resulted in >3 log CFU/mL killing within 3 h but re-growth and proliferation of resistant subpopulations within 48 h. PMB combinations with fosfomycin demonstrated rapid bacterial killing (>6 log CFU/mL reductions) while preventing propagation of PMB and fosfomycin resistance. Against isolate KPC-Kp 24A with a higher fosfomycin MIC (polymyxin B MIC = 0.5 mg/L; fosfomycin MIC = 32 mg/L), a PMB burst and fosfomycin combination caused a >6 log CFU/mL reduction within 1 h, although bacterial re-growth occurred with the amplification of fosfomycin-resistant subpopulations. PMB in combination with fosfomycin may provide a practicable treatment strategy against KPC-Kp and warrants further investigation.
Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Multiple, Bacterial; Drug Therapy, Combination; Fosfomycin; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Polymyxin B; beta-Lactamases
PubMed: 29486233
DOI: 10.1016/j.ijantimicag.2018.02.010 -
Pharmacology Research & Perspectives Oct 2022In recent years, polymyxin B-associated acute kidney injury (PB-AKI) in critically ill patients has been reported frequently, but polymyxin B (PB) is mainly cleared...
In recent years, polymyxin B-associated acute kidney injury (PB-AKI) in critically ill patients has been reported frequently, but polymyxin B (PB) is mainly cleared through non-renal pathways, and the reasons of PB-AKI remain unclear. The aim of this study was to investigate the relationship between the serum concentration of PB and PB-AKI. We conducted a prospective cohort study in an intensive care unit between May 2019 and July 2021. Over the study period, 52 patients were included and divided into an AKI group (n = 26) and a non-AKI group (n = 26). The loading dose of PB in the AKI group was significantly higher than that in the non-AKI group. The C , C , and estimated area under the concentration-time curve (AUC) of PB in the AKI group were dramatically increased compared with those in the non-AKI group, but the C between the two groups showed no differences. Upon obtaining the ROC curve, the areas for the C , C , and estimated AUC were 0.742, 0.710, and 0.710, respectively. The sensitivity was ascertained to be 61.54%, and the specificity was 76.92% when the cutoff value for the estimated AUC of 97.72 mg·h/L was used preferentially. The incidence of PB-AKI is high and related to the loading dose of PB. PB-AKI could be predicted when the estimated AUC of PB was greater than 97.72 mg·h/L.
Topics: Acute Kidney Injury; Critical Illness; Humans; Intensive Care Units; Polymyxin B; Prospective Studies
PubMed: 36206131
DOI: 10.1002/prp2.1010 -
International Journal of Antimicrobial... Jun 2020Lack of effective treatment for multidrug-resistant Klebsiella pneumoniae (MDR-Kp) necessitates finding and optimising combination therapies of old antibiotics. The aims...
Combination of polymyxin B and minocycline against multidrug-resistant Klebsiella pneumoniae: interaction quantified by pharmacokinetic/pharmacodynamic modelling from in vitro data.
Lack of effective treatment for multidrug-resistant Klebsiella pneumoniae (MDR-Kp) necessitates finding and optimising combination therapies of old antibiotics. The aims of this study were to quantify the combined effect of polymyxin B and minocycline by building an in silico semi-mechanistic pharmacokinetic/pharmacodynamic (PKPD) model and to predict bacterial kinetics when exposed to the drugs alone and in combination at clinically achievable unbound drug concentration-time profiles. A clinical K. pneumoniae strain resistant to polymyxin B [minimum inhibitory concentration (MIC) = 16 mg/L] and minocycline (MIC = 16 mg/L) was selected for extensive in vitro static time-kill experiments. The strain was exposed to concentrations of 0.0625-48 × MIC, with seven samples taken per experiment for viable counts during 0-28 h. These observations allowed the development of the PKPD model. The final PKPD model included drug-induced adaptive resistance for both drugs. Both the minocycline-induced bacterial killing and resistance onset rate constants were increased when polymyxin B was co-administered, whereas polymyxin B parameters were unaffected. Predictions at clinically used dosages from the developed PKPD model showed no or limited antibacterial effect with monotherapy, whilst combination therapy kept bacteria below the starting inoculum for >20 h at high dosages [polymyxin B 2.5 mg/kg + 1.5 mg/kg every 12 h (q12h); minocycline 400 mg + 200 mg q12h, loading + maintenance doses]. This study suggests that polymyxin B and minocycline in combination may be of clinical benefit in the treatment of infections by MDR-Kp and for isolates that are non-susceptible to either drug alone.
Topics: Anti-Bacterial Agents; Drug Resistance, Multiple, Bacterial; Drug Synergism; Drug Therapy, Combination; Humans; Klebsiella Infections; Klebsiella pneumoniae; Microbial Sensitivity Tests; Minocycline; Models, Biological; Polymyxin B
PubMed: 32171741
DOI: 10.1016/j.ijantimicag.2020.105941 -
BMC Pharmacology & Toxicology Jul 2018Polymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial... (Review)
Review
BACKGROUND
Polymyxin B (PMB), which is regarded as the ultimate antibacterial treatment against some intractable gram-negative bacteria with its outstanding anti-bacterial activities, inflicts several adverse effects on patients. However, skin hyperpigmentaion (SH) induced by PMB is very rare. Here, we report a case of polymyxin B-induced skin hyperpigmentation (PMB-iSH) in a 21-year-old female. To the best of our knowledge, this is the first case of PMB-iSH in China.
CASE PRESENTATION
A 21-year-old female patient with sepsis received the administration of PMB by intravenous injection for the treatment of multi-drug resistant Klebsiella pneumoniae (MDR-KP) infection. She later suffered from a rare adverse drug reaction (ADR), namely PMB-iSH, after 5-day PMB administration during her treatment. There were multiple red rashes spread on the whole body skin at first. With the rashes fading away, SH with dark round spots appeared, associated with no pain or pruritus. The skin of the head and neck was darkened evidently, and dark brown spots were spread on the skin of trunk and limbs. About a month after her admission, urged by the relatives, the patient was transferred back to the local hospital for further treatment in the end, and her skin color didn't recover to the previous state at that time.
CONCLUSION
Both our case and the literature review highlight that PMB can give rise to SH indeed. Clinicians and pharmacists should attach great importance to this rare pigmentary disorder and further investigation is warranted.
Topics: Adult; Anti-Bacterial Agents; Female; Humans; Hyperpigmentation; Klebsiella Infections; Klebsiella pneumoniae; Polymyxin B; Young Adult
PubMed: 29973293
DOI: 10.1186/s40360-018-0226-1 -
Antimicrobial Agents and Chemotherapy Nov 2020Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of...
Polymyxin B, used to treat infections caused by antibiotic-resistant Gram-negative bacteria, produces nephrotoxicity at its current dosage. We show that a combination of nonbactericidal concentration of this drug and lysophosphatidylcholine (LPC) potently inhibits growth of and at least two other Gram-negative bacteria This combination makes bacterial membrane porous and causes degradation of DnaK, the regulator of protein folding. Polymyxin B-LPC combination may be an effective and safer regimen against drug-resistant bacteria.
Topics: Anti-Bacterial Agents; Gram-Negative Bacteria; Lysophosphatidylcholines; Microbial Sensitivity Tests; Polymyxin B
PubMed: 32988824
DOI: 10.1128/AAC.01337-20 -
Journal of Global Antimicrobial... Mar 2021The epidemic dimensions of the emergence of multidrug-resistant (MDR) Gram-negative bacterial infections have led to the revival of old antibiotics, including the... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVES
The epidemic dimensions of the emergence of multidrug-resistant (MDR) Gram-negative bacterial infections have led to the revival of old antibiotics, including the polymyxins.
METHODS
We performed a review and meta-analysis to evaluate the current literature data regarding the effectiveness and safety of intravenous polymyxin B in patients with MDR Gram-negative bacterial infections and the overall mortality and nephrotoxicity in patients treated with intravenous polymyxin B either as monotherapy or combination therapy.
RESULTS
A total of 5 prospective and 28 retrospective studies, 1 cross-sectional study, 2 retrospective case series and 7 case reports provided data regarding the effectiveness and/or toxicity of intravenous polymyxin B. All-cause mortality of 2910 patients (from 27 studies) who received intravenous polymyxin B was 41.2% (95% CI 35.5-47.0%). All-cause nephrotoxicity of 2994 patients (from 28 studies) treated with intravenous polymyxin B was 40.7% (95% CI 35.0-46.6%). Renal failure among 2111 patients (from 14 studies) was 11.2% (95% CI 8.7-13.9%).
CONCLUSION
Mortality of patients treated with intravenous polymyxin B is similar to the literature-reported mortality of patients treated with intravenous colistin, while nephrotoxicity associated with polymyxin B use is possibly milder compared with colistin use based on literature data. Head-to-head prospective studies would help to clarify the benefit of polymyxin B over colistin. However, a critical evaluation of the existing worldwide literature data supports the need for availability of the intravenous formulation of polymyxin B as a potentially useful option for the treatment of patients with MDR and extensively drug-resistant (XDR) Gram-negative bacterial infections.
Topics: Cross-Sectional Studies; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Polymyxin B; Prospective Studies; Retrospective Studies
PubMed: 33486122
DOI: 10.1016/j.jgar.2020.12.026 -
Critical Care (London, England) Jun 2023Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We... (Randomized Controlled Trial)
Randomized Controlled Trial Observational Study
BACKGROUND
Polymyxin B hemadsorption (PMX-HA) reduces blood endotoxin levels, but characteristics of patients with sepsis likely to benefit from PMX-HA are not well known. We sought to identify patient subgroups likely to benefit from PMX-HA.
METHODS
We retrospectively identified 1911 patients with sepsis from a retrospective observational study in Japan (the JSEPTIC-DIC study) and 286 patients with endotoxemic septic shock from a randomized controlled trial in North America that restricted patients to those with high endotoxin activity (the EUPHRATES trial). We applied the machine learning-based causal forest model to the JSEPTIC-DIC cohort to investigate heterogeneity in treatment effects of PMX-HA on 28-day survival after adjusting for potential confounders and ascertain the best criteria for PMX-HA use. The derived criteria for targeted therapy by PMX-HA were validated using the EUPHRATES trial cohort.
RESULTS
The causal forest model revealed heterogeneity in treatment effects of PMX-HA. Since patients having higher treatment effects were more likely to have severe coagulopathy and hyperlactatemia, we identified the potential treatment targets of PMX-HA as patients with PT-INR > 1.4 or lactate > 3 mmol/L. In the EUPHRATES trial cohort, PMX-HA use on the targeted subpopulation (75% of all patients) was significantly associated with higher 28-day survival (PMX-HA vs. control, 68% vs. 52%; treatment effect of PMX-HA, + 16% [95% CI + 2.2% to + 30%], p = 0.02).
CONCLUSIONS
Abnormal coagulation and hyperlactatemia in septic patients with high endotoxin activity appear to be helpful to identify patients who may benefit most from PMX-HA. Our findings will inform enrollment criteria for future interventional trials targeting patients with coagulopathy and hyperlactatemia.
Topics: Humans; Polymyxin B; Anti-Bacterial Agents; Retrospective Studies; Hemadsorption; Hyperlactatemia; Sepsis; Shock, Septic; Endotoxins; Hemoperfusion
PubMed: 37344804
DOI: 10.1186/s13054-023-04533-3 -
International Journal of Molecular... Jan 2023The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and...
The emergence and growth of bacterial resistance to antibiotics poses an enormous threat to humanity in the future. In this regard, the discovery of new antibiotics and the improvement of existing ones is a priority task. In this study, we proposed the synthesis of new polymeric conjugates of polymyxin B, which is a clinically approved but limited-use peptide antibiotic. In particular, three carboxylate-bearing polymers and one synthetic glycopolymer were selected for conjugation with polymyxin B (PMX B), namely, poly(α,L-glutamic acid) (PGlu), copolymer of L-glutamic acid and L-phenylalanine (P(Glu--Phe)), copolymer of N-vinyl succinamic acid and N-vinylsuccinimide (P(VSAA--VSI)), and poly(2-deoxy-2-methacrylamido-D-glucose) (PMAG). Unlike PGlu and PMAG, P(Glu--Phe) and P(VSAA--VSI) are amphiphilic and form nanoparticles in aqueous media. A number of conjugates with different polymyxin B loading were synthesized and characterized. In addition, the complex conjugates of PGLu or PMAG with polymyxin B and deferoxamine (siderophore) were obtained. A release of PMX B from Schiff base and amide-linked polymer conjugates was studied in model buffer media with pH 7.4 and 5.8. In both cases, a more pronounced release was observed under slightly acidic conditions. The cytotoxicity of free polymers and PMX B as well as their conjugates was examined in human embryonic kidney cells (HEK 293T cell line). All conjugates demonstrated reduced cytotoxicity compared to the free antibiotic. Finally, the antimicrobial efficacy of the conjugates against was determined and compared. The lowest values of minimum inhibitory concentrations (MIC) were observed for polymyxin B and polymyxin B/deferoxamine conjugated with PMAG. Among the polymers tested, PMAG appears to be the most promising carrier for delivery of PMX B in conjugated form due to the good preservation of the antimicrobial properties of PMX B and the ability of controlled drug release.
Topics: Humans; Polymyxin B; Deferoxamine; Glutamic Acid; Anti-Bacterial Agents; Polymers
PubMed: 36768160
DOI: 10.3390/ijms24031832 -
MSphere Feb 2023Outer membrane vesicles (OMVs) secreted by Gram-negative bacteria serve as transporters for the delivery of cargo such as virulence and antibiotic resistance factors....
Outer membrane vesicles (OMVs) secreted by Gram-negative bacteria serve as transporters for the delivery of cargo such as virulence and antibiotic resistance factors. OMVs play a key role in the defense against membrane-targeting antibiotics such as the polymyxin B. Herein, we conducted comparative proteomics of OMVs from paired Klebsiella pneumoniae ATCC 700721 polymyxin-susceptible (polymyxin B MIC = 0.5 mg/L) and an extremely resistant (polymyxin B MIC ≥128 mg/L), following exposure to 2 mg/L of polymyxin B. Comparative profiling of the OMV subproteome of each strain revealed proteins from multiple perturbed pathways, particularly in the polymyxin-susceptible strain, including outer membrane assembly (lipopolysaccharide, -antigen, and peptidoglycan biosynthesis), cationic antimicrobial peptide resistance, β-lactam resistance, and quorum sensing. In the polymyxin-susceptible strain, polymyxin B treatment reduced the expression of OMV proteins in the pathways related to adhesion, virulence, and the cell envelope stress responses, whereas, in the polymyxin-resistant strain, the proteins involved in LPS biosynthesis, RNA degradation, and nucleotide excision repair were significantly overexpressed in response to polymyxin B treatment. Intriguingly, the key polymyxin resistance enzymes 4-amino-4-deoxy-l-arabinose transferase and the PhoPQ two-component protein kinase were significantly downregulated in the OMVs of the polymyxin-susceptible strain. Additionally, a significant reduction in class A β-lactamase proteins was observed following polymyxin B treatment in the OMVs of both strains, particularly the OMVs of the polymyxin-susceptible strain. These findings shed new light on the OMV subproteome of extremely polymyxin resistant K. pneumoniae, which putatively may serve as active decoys to make the outer membrane more impervious to polymyxin attack. OMVs can help bacteria to fight antibiotics not only by spreading antibiotic resistance genes but also by acting as protective armor against antibiotics. By employing proteomics, we found that OMVs have a potential role in shielding K. pneumoniae and acting as decoys to polymyxin attack, through declining the export of proteins (e.g., 4-amino-4-deoxy-l-arabinose transferase) involved in polymyxin resistance. Furthermore, polymyxin B treatment of both strains leads to shedding of the OMVs with perturbed proteins involved in outer membrane remodeling (e.g., LPS biosynthesis) as well as pathogenic potential of K. pneumoniae (e.g., quorum sensing). The problematic extended spectrum beta-lactamases SHV and TEM were significantly reduced in both strains, suggesting that polymyxin B may act as a potentiator to sensitize the bacterium to β-lactam antibiotics. This study highlights the importance of OMVs as "molecular mules" for the intercellular transmission and delivery of resistance and cellular repair factors in the bacterial response to polymyxins.
Topics: Polymyxin B; Polymyxins; Klebsiella pneumoniae; Pharmaceutical Preparations; Lipopolysaccharides; Proteomics; Anti-Bacterial Agents
PubMed: 36622250
DOI: 10.1128/msphere.00537-22 -
Nigerian Journal of Clinical Practice Sep 2023Polymyxin B was widely used to treat drug-resistant gram-negative bacteria and showed a better antibacterial effect. However, it is associated with some side effects. It...
Polymyxin B was widely used to treat drug-resistant gram-negative bacteria and showed a better antibacterial effect. However, it is associated with some side effects. It should be remembered that polymyxin B may cause hyperpigmentation, albeit rare. This is a case report of a 68-year-old male patient who developed hyperpigmentation following treatment of a chest infection with polymyxin B. He was a known patient with chronic kidney diasease and chronic obstructive pulmonary disease followed up in the intensive care unit due to acute exacerbation of COPD. Later, polymyxin B treatment was started due to the development of pneumonia caused by the multidrug-resistant Acinetobacter baumannii. On the second day of polymyxin B treatment, hyperpigmentation developed in the face and neck region. The fact that the patient had chronic kidney disease possibly facilitated the development of skin hyperpigmentation due to the cumulative effect of polymyxin B. Hyperpigmentation which a rare side effect of polymyxin B may occur in those with underlying kidney disease.
Topics: Male; Humans; Aged; Polymyxin B; Anti-Bacterial Agents; Pneumonia; Hyperpigmentation; Acinetobacter baumannii; Microbial Sensitivity Tests
PubMed: 37794556
DOI: 10.4103/njcp.njcp_185_23