The current strategy in treating multi-drug resistant gram-negative bacterial (MDR-GNB) infections is salvage therapy by using polymyxins. However, the beginning emergence of polymyxin resistance should enforce strict antimicrobial stewardship programs to preserve polymyxin efficacy. Knowledge of structural characteristics, pharmacodynamic, and pharmacokinetic profiles of polymyxins, as well as consideration of efficacy, safety, suitability, and cost, will help in the choice of the appropriate polymyxin for therapy. Polymyxin B is the recommended polymyxin for systemic use, while colistin is recommended for lower urinary tract infections, intraventricular, and intrathecal use. Either polymyxin can be used for hospital-acquired and ventilator-associated pneumonia. Combination therapy over monotherapy remains to be advantageous due to synergism and decreased resistance development. The choice of the second drug to be used should be based on full susceptibility, or if unavailable, a drug with the least minimum inhibitory concentration relative to the breakpoint set by the Clinical and Laboratory Standards Institute. Using the mnemonic ESCAPE can also guide physicians in their polymyxin prescription process: (1) Checking if the pathogen is Extensively resistant or multi-drug resistant; (2) checking the patient’s clinical status if compatible with Significant infection; (3) using Combination therapy; (4) ensuring Adequate dosing; (5) Proper preparation and administration of drug; and (6) keeping an Eye for response and adverse effects.
Polymyxin B ; Colistin ; Polymyxins

Background: Multidrug-resistant gram-negative (MDR GN) infections pose a significant threat to pediatric health. One of the treatment options in resource-limited settings is polymyxin-based combination therapy. However, evidence on the safety and clinical effectiveness of polymyxin B in children is scarce. Objectives: This study described the outcomes of mortality, bacteriologic cure and clinical response in pediatric patients with MDR GN infections treated with polymyxin-B-based combination therapy. Adverse drug events (ADE) are likewise described. Methodology: This is a retrospective descriptive study conducted at the Philippine General Hospital (PGH) among pediatric inpatients from December 2020 to June 2023 with MDR GN infections treated with polymyxin B (PmB), combined with at least one other antibiotic with gram-negative coverage for at least 48 hours. Frequency and rates of the outcomes were measured and analyzed, in relation to the bacterial groups (Enterobacterales, Acinetobacter spp., Pseudomonas aeruginosa) and combination antibiotic regimens used, i.e., meropenem- and fluoroquinolone-containing regimen (PmB+MEM vs PmB+FQ). Frequency of ADEs were measured. Results: A total of 172 cases in 136 patients were reviewed. The rates for 14-day mortality, failure in bacteriologic cure, and failure in clinical response were 26%, 15%, and 19%, respectively. In Enterobacterales infections, PmB+FQ demonstrated lower rates of mortality, failure in bacteriologic cure, and failure in clinical responses. On the other hand, in Acinetobacter infections, PmB+MEM numerically had lower rates for the same outcomes. The Pseudomonas group had conflicting data on which regimen is numerically more favorable overall. No statistically significant differences were found in the outcomes. ADEs noted were tubulopathy (5 cases), anaphylaxis (2 cases), and neurotoxicity (1 case). Conclusion Polymyxin-B-based combination therapy appears to be an acceptable treatment option for MDR GN infections in children, especially in settings where novel antibiotics are not accessible. Safety profiles indicate common but manageable adverse effects.
Polymyxin B ; Child

The effects and interactions of 4 beta-phorbol 12,13-dibutyrate(PDB) and polymyxin B(PMB) with adenosine on the electrically-evoked acetylcholine(ACh) release were studied in rat hippocampus. Slices from rat hippocampus were equilibrated with 3H-choline and the release of the labeled product, 3H-ACh, which was evoked by electrical stimulation(3Hz, 2ms, 5Vcm-1, rectangular pulses) was measured. PDB(0.3-10 micorM), a selective protein kinase C(PKC) activator, increased the evoked ACh release in a dose related fashion with an increase in the basal rate of release. The effects of 1(M PDB were significantly inhibited by 0.3 micorM tetrodotoxin(TTX) pretreatment or Ca++-free medium. PMB(0.03-1mg), a selective PKC inhibitor, decreased the ACh release in a dose dependent manner with an increase in the basal rate of release. Adenosine(1-10 micorM) decreased the ACh release without changing the basal rate or release, and this effect was significantly inhibited by 8-cyclopentyl-1,3-dipropylxanthine(2 micorM), a selective A1-receptor antagonist treatment. However, adenosine effects were not affected by PDB and PMB. These results indicate that the PKC play a role in the ACh release in the rat hippocampus but is not involved in the post-receptor mechanism of the A1-adenosine receptor.
Acetylcholine* ; Adenosine ; Animals ; Hippocampus* ; Polymyxin B ; Polymyxins ; Protein Kinase C* ; Protein Kinases* ; Rats* ; Tetrodotoxin

Peptidoglycan (PG), the gram positive bacterial pathogen-associated molecular patterns (PAMP), is detected in a high proportion in macrophage-rich atheromatous regions, and expression of chemokine CXCL8, which triggers monocyte arrest on early atherosclerotic endothelium, is elevated in monocytes/macrophages in human atherosclerotic lesion. The aim of this study was to investigate whether PG induced CXCL8 expression in the cell type and to determine cellular signaling pathways involved in that process. Exposure of THP-1 cell, human monocyte/macrophage cell line, to PG not only enhanced CXCL8 release but also profoundly induced il8 gene transcription. PG-induced release of CXCL8 and induction of il8 gene transcription were blocked by OxPAPC, an inhibitor of TLR-2/4 and TLR4, but not by polymyxin B, an inhibitor of LPS. PG-mediated CXCL8 release was significantly attenuated by inhibitors of PI3K-Akt-mTOR pathways. PKC inhibitors, MAPK inhibitors, and ROS quenchers also significantly attenuated expression of CXCL8. The present study proposes that PG contributes to inflammatory reaction and progression of atherosclerosis by inducing CXCL8 expression in monocytes/macrophages, and that TLR-2, PI3K-Akt-mTOR, PKC, ROS, and MAPK are actively involved in the process.
Atherosclerosis ; Cell Line ; Endothelium ; Humans ; Interleukin-8 ; Monocytes ; Peptidoglycan* ; Polymyxin B

BACKGROUND: Infection caused by multi-drug resistant (MDR) Gram-negative organisms such as Pseudomonas and Acinetobacter species is one of emerging important problems in modern hospitals. To treat multi-drug resistant non-fermenting Gram-negatives, polymyxins which were used in 1960s, but abandoned because of grave toxicities such as renal toxicity are reused. The objective of this study was to estimate the probability of resistance development of the clinical isolates of Pseudomonas aeruginosa to polymyxins. METHODS AND MATERIALS: Twenty-nine multidrug-resistant P. aeruginosa isolates were collected from Dankook University Hospital and Seoul National University Hospital in 2000 and tested for antimicrobial susceptibility test, minimal inhibitory concentration (MIC), mutant prevention concentration (MPC) and mutant frequency to ciprofloxacin and polymyxin B. RESULTS: The MIC50 and MIC90 of polymyxin B for the isolates were 2 and 2 microgram/mL, and those of ciprofloxacin were 0.5 and 4 microgram/mL, respectively. Thirteen of 29 isolates developed polymyxin B-resistant mutants but all 29 isolates, ciprofloxacin-resistant mutants. The MPC50 and MPC90 of polymyxin B were 32 and 64 microgram/mL, and those values of ciprofloxacin were 4 and 64 microgram/mL. Mutation frequencies of polymyxin B ranged from 2 x 10(-9) to 2 x 10(-7), and those of ciprofloxacin from 4 x 10(-10) to 5 x 10(-7). CONCLUSIONS: Mutation frequencies of polymyxin B were similar to those of ciprofloxacin, suggesting appreciable development of resistant mutants with wide usage of polymyxins.
Acinetobacter ; Ciprofloxacin ; Mutation Rate ; Polymyxin B* ; Polymyxins* ; Pseudomonas aeruginosa* ; Pseudomonas* ; Seoul

BACKGROUND: Infection caused by multi-drug resistant (MDR) Gram-negative organisms such as Pseudomonas and Acinetobacter species is one of emerging important problems in modern hospitals. To treat multi-drug resistant non-fermenting Gram-negatives, polymyxins which were used in 1960s, but abandoned because of grave toxicities such as renal toxicity are reused. The objective of this study was to estimate the probability of resistance development of the clinical isolates of Pseudomonas aeruginosa to polymyxins. METHODS AND MATERIALS: Twenty-nine multidrug-resistant P. aeruginosa isolates were collected from Dankook University Hospital and Seoul National University Hospital in 2000 and tested for antimicrobial susceptibility test, minimal inhibitory concentration (MIC), mutant prevention concentration (MPC) and mutant frequency to ciprofloxacin and polymyxin B. RESULTS: The MIC50 and MIC90 of polymyxin B for the isolates were 2 and 2 microgram/mL, and those of ciprofloxacin were 0.5 and 4 microgram/mL, respectively. Thirteen of 29 isolates developed polymyxin B-resistant mutants but all 29 isolates, ciprofloxacin-resistant mutants. The MPC50 and MPC90 of polymyxin B were 32 and 64 microgram/mL, and those values of ciprofloxacin were 4 and 64 microgram/mL. Mutation frequencies of polymyxin B ranged from 2 x 10(-9) to 2 x 10(-7), and those of ciprofloxacin from 4 x 10(-10) to 5 x 10(-7). CONCLUSIONS: Mutation frequencies of polymyxin B were similar to those of ciprofloxacin, suggesting appreciable development of resistant mutants with wide usage of polymyxins.
Acinetobacter ; Ciprofloxacin ; Mutation Rate ; Polymyxin B* ; Polymyxins* ; Pseudomonas aeruginosa* ; Pseudomonas* ; Seoul

OBJECTIVE: To observe the clinical efficacy and safety of polymyxin B sulfate in febrile neutropenia patients with hematonosis. METHODS: Clinical data of 50 patients in the department of hematology, Fujian Medical University Union Hospital from October 2019 to September 2020 were collected. All the patients developed febrile neutropenia after chemotherapy or hematopoietic stem cell transplantation. According to the results of drug susceptible test, polymyxin B sulfate was administrated mainly when the empirical antimicrobial treatments was poor and the pathogenic microbes test was positive. RESULTS: A total of 85 times of infection occurred in 50 patients. The infection sites were lung, blood flow, intestinal tract, oral cavity, perianal, soft tissue and nasal cavity. Gram negative bacteria was the main pathogenic microbe. After administration of polymyxin B sulfate when the etiology was confirmed, the total effective rate was 68%, especially the effective rate increased significantly after more than 7 days of polymyxin B sulfate treatment. Also, 24% and 8% of the patients were discharged automatically and died respectively. The effective rate of patients receiving carbapenem antibiotics changed to polymyxin B sulfate within 14 or 7 days was 80% and 70.6%, respectively, while the effective rate of patients who changed after 2 weeks was only 33.3%. The effective rate of patients receiving tigecycline changed to polymyxin B sulfate within 14 or 7 days was 80% and 66.7%, respectively. The incidence of adverse reactions of polymyxin B sulfate was low, most of which were mild, and only one patient occurred rhabdomyolysis. CONCLUSION Polymyxin B sulfate has good clinical efficacy and safety in febrile neutropenia patients with hematonosis.
Anti-Bacterial Agents/therapeutic use* ; Carbapenems ; Febrile Neutropenia/drug therapy* ; Humans ; Polymyxin B/therapeutic use* ; Tigecycline

Polymyxin B, which is a last-line antibiotic for extensively drug-resistant Gram-negative bacterial infections, became available in China in Dec. 2017. As dose adjustments are based solely on clinical experience of risk toxicity, treatment failure, and emergence of resistance, there is an urgent clinical need to perform therapeutic drug monitoring (TDM) to optimize the use of polymyxin B. It is thus necessary to standardize operating procedures to ensure the accuracy of TDM and provide evidence for their rational use. We report a consensus on TDM guidelines for polymyxin B, as endorsed by the Infection and Chemotherapy Committee of the Shanghai Medical Association and the Therapeutic Drug Monitoring Committee of the Chinese Pharmacological Society. The consensus panel was composed of clinicians, pharmacists, and microbiologists from different provinces in China and Australia who made recommendations regarding target concentrations, sample collection, reporting, and explanation of TDM results. The guidelines provide the first-ever consensus on conducting TDM of polymyxin B, and are intended to guide optimal clinical use.
Humans ; Anti-Bacterial Agents/therapeutic use* ; China ; Drug Monitoring/methods* ; Polymyxin B ; Practice Guidelines as Topic

<b>OBJECTIVEb>To investigate the mechanism of polymyxin B (PMB) antagonizing the biological activity of lipopolysaccharide (LPS).

<b>METHODSb>The affinity of PMB for LPS and lipid A was assayed by biosensor, and the neutralization of PMB for LPS (2 ng/ml) was detected by kinetic turbidimetric limulus test. The releases of TNF-alpha and IL-6 in murine peritoneal macrophages a (PMphi) after exposure to LPS (100 ng/ml) were detected, and the expression levels of TLR4, TNF-alpha and IL-6 mRNA in PMphi induced by LPS (100 ng/ml) were measured by RT-PCR.

<b>RESULTSb>PMB had high-affinity to LPS and lipid A with dissociation equilibrium constants of 18.9 nmol/L and 11.1 nmol/L, respectively, and neutralized LPS in a dose-dependent manner. Furthermore, PMB could markedly inhibit the expressions of TLR4, TNF-alpha and IL-6 mRNA and the release of cycokines in LPS-stimulated murine peritoneal macrophages.

<b>CONCLUSIONSb>PMB neutralizes LPS and inhibites the expression and release of cycokines in macrophages, in which the affinity of PMB for lipid A plays an important role.

Animals ; Cytokines ; analysis ; Limulus Test ; Lipid A ; antagonists & inhibitors ; Lipopolysaccharides ; antagonists & inhibitors ; Macrophages ; chemistry ; Mice ; Polymyxin B ; pharmacology

Conventional medical therapies have not been very successful in treating adults with refractory septic shock. The effects of direct hemoperfusion using polymyxin B and veno-arterial extracorporeal membrane oxygenation (ECMO) for refractory septic shock remain uncertain. A 66-year-old man was admitted to the emergency department and suffered from sepsis-induced hemodynamic collapse. For hemodynamic improvement, we performed direct hemoperfusion using polymyxin B. Computed tomography scan of this patient revealed emphysematous pyelonephritis (EPN), for which he underwent emergent nephrectomy with veno-arterial ECMO support. To the best of our knowledge, this is the first report of successful treatment of EPN with refractory septic shock using polymyxin B hemoperfusion and nephrectomy under the support of ECMO.
Adult ; Aged ; Emergency Service, Hospital ; Endotoxins ; Extracorporeal Membrane Oxygenation* ; Hemodynamics ; Hemoperfusion ; Humans ; Nephrectomy* ; Polymyxin B ; Pyelonephritis ; Shock, Septic*