[Advances in the diagnosis and treatment strategy of polymyxin resistant Klebsiella pneumoniae].

In recent years, the detection rate of multidrug-resistant and pandrug-resistant Klebsiella pneumoniae has increased year on year, so polymyxin has received increasing attention as an antibiotic that is still sensitive to most of the multidrug-resistant strains. However, widespread use of polymyxin is likely to lead to the emergence of polymyxin-resistant Klebsiella pneumoniae. At the same time, the polymyxin hetero-resistance has made clinical prevention and treatment difficult. In addition to relying on the combination of polymyxins with other antibiotics, the search for new antibacterial drugs has also become a research hotspot. Research into early detection methods for polymyxin resistance can also help to optimize and improve the diagnosis and treatment strategies. This article reviewed the epidemic status, mechanism, detection methods and prevention measures of polymyxin-resistant Klebsiella pneumoniae.

Clinical, biological and genome-wide comparison of carbapenem-resistant Klebsiella pneumoniae with susceptibility transformation to polymyxin B during therapy.

OBJECTIVES: The emergence of carbapenem-resistant Klebsiella pneumoniae (CRKP) is a major clinical concern, and polymyxin B (PMB) is a 'last resort' antibiotic for its treatment. Understanding the effects of drug susceptibility transformation in CRKP-infected patients undergoing PMB treatment would be beneficial to optimize PMB treatment strategies. METHODS: We retrospectively collected data from patients infected with CRKP and treated with PMB from January 2018 to December 2020. CRKPs were collected before and after PMB therapy, and patients were classified into the 'transformation' group (TG) and 'non-transformation' group (NTG) by the shift of susceptibility to PMB. We compared clinical characteristics between these groups, and further analysed the phenotypic and genome variation of CRKP after PMB susceptibility transformation. RESULTS: A total of 160 patients (37 in the TG and 123 in the NTG) were included in this study. The duration of PMB treatment before PMB-resistant K. pneumoniae (PRKP) appearance in TG was even longer than the whole duration of PMB treatment in NTG (8 [8] vs. 7 [6] days; p 0.0496). Compared with isogenic PMB-susceptible K. pneumoniae (PSKP), most PRKP strains had missense mutations in mgrB (12 isolates), yciC (10 isolates) and pmrB (7 isolates). The competition index of 82.4% (28/34) of PRKP/PSKP pairs was <67.6% (23/34), and 73.5% (25/34) of PRKP strains showed a higher 7-day lethality in Galleria mellonella and a greater ability to resist complement-dependent killing than their corresponding PSKP, respectively. CONCLUSION: Low dose with longer PMB treatment durations may be associated with the emergence of polymyxin resistance. The evolution of PRKP is predominantly mediated by an accumulation of mutations, including those in mgrB, yciC, and pmrB. Lastly, PRKP exhibited reduced growth and increased virulence compared with parental PSKP.

Real-world effectiveness of ceftazidime/avibactam versus polymyxin B in treating patients with carbapenem-resistant Gram-negative bacterial infections.

OBJECTIVES: To compare the effectiveness of ceftazidime/avibactam (CAZ/AVI) and polymyxin B against carbapenem-resistant Gram-negative bacteria (CRGNB) infections in western China. METHODS: The medical records of patients with CRGNB infections in this hospital from 2018-2022 were retrospectively reviewed. The data included demographic characteristics, laboratory results, antibiotic strategies and clinical outcomes. RESULTS: A total of 378 patients with CRGNB infections were enrolled, including 112 patients in the CAZ/AVI group and 266 patients in the polymyxin B group. The most common pathogen was carbapenem-resistant Klebsiella pneumoniae (44.44%). The rates of treatment failure at 28 days (65.04% vs. 45.54%; P = 0.000) and 28-day in-hospital mortality (20.30% vs. 9.82%; P = 0.014) in the polymyxin B group were higher than those in the CAZ/AVI group. Multivariable analysis revealed that multiple organ dysfunction syndrome (OR 2.730; P = 0.017), acute renal failure (OR 2.595; P = 0.020), higher Charlson comorbidity index (CCI) (OR 1.184; P = 0.011) and Acute Physiology And Chronic Health Evaluation (APACHE) Ⅱ scores (OR 1.149; P = 0.000) were independent risk factors for treatment failure, whereas CAZ/AVI therapy (OR 0.333; P = 0.002) had a protective effect. Multivariate Cox regression analysis revealed that CCI ≥ 5 and APACHE II score ≥ 15 were associated with a higher 28-day in-hospital mortality rate (P < 0.001). CONCLUSION: CAZ/AVI therapy was associated with treatment success among patients with CRGNB infection. However, CAZ/AVI therapy did not improve 28-day in-hospital survival compared with polymyxin B. The CCI ≥ 5 and APACHE II score ≥ 15 affected 28-day in-hospital mortality of CRGNB-infected patients.

Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study.

BACKGROUND: Polymyxin B is the first-line therapy for Carbapenem-resistant organism (CRO) nosocomial pneumonia. However, clinical data for its pharmacokinetic/pharmacodynamic (PK/PD) relationship are limited. This study aimed to investigate the relationship between polymyxin B exposure and efficacy for the treatment of CRO pneumonia in critically ill patients, and to optimize the individual dosing regimens. METHODS: Patients treated with polymyxin B for CRO pneumonia were enrolled. Blood samples were assayed using a validated high-performance liquid chromatography-tandem mass spectrometry method. Population PK analysis and Monte Carlo simulation were performed using Phoenix NLME software. Logistic regression analyses and receiver operating characteristic (ROC) curve were employed to identify the significant predictors and PK/PD indices of polymyxin B efficacy. RESULTS: A total of 105 patients were included, and the population PK model was developed based on 295 plasma concentrations. AUCss,24 h/MIC (AOR = 0.97, 95% CI 0.95-0.99, p = 0.009), daily dose (AOR = 0.98, 95% CI 0.97-0.99, p = 0.028), and combination of inhaled polymyxin B (AOR = 0.32, 95% CI 0.11-0.94, p = 0.039) were independent risk factors for polymyxin B efficacy. ROC curve showed that AUCss,24 h/MIC is the most predictive PK/PD index of polymyxin B for the treatment of nosocomial pneumonia caused by CRO, and the optimal cutoff point value was 66.9 in patients receiving combination therapy with another antimicrobial. Model-based simulation suggests that the maintaining daily dose of 75 and 100 mg Q12 h could achieve ≥ 90% PTA of this clinical target at MIC values ≤ 0.5 and 1 mg/L, respectively. For patients unable to achieve the target concentration by intravenous administration, adjunctive inhalation of polymyxin B would be beneficial. CONCLUSIONS: For CRO pneumonia, daily dose of 75 and 100 mg Q12 h was recommended for clinical efficacy. Inhalation of polymyxin B is beneficial for patients who cannot achieve the target concentration by intravenous administration.

Polymyxin combination therapy for multidrug-resistant, extensively-drug resistant, and difficult-to-treat drug-resistant gram-negative infections: is it superior to polymyxin monotherapy?

INTRODUCTION: The increasing prevalence of infections with multidrug-resistant (MDR), extensively-drug resistant (XDR) or difficult-to-treat drug resistant (DTR) Gram-negative bacilli (GNB), including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Enterobacter species, and Escherichia coli poses a severe challenge. AREAS COVERED: The rapid growing of multi-resistant GNB as well as the considerable deceleration in development of new anti-infective agents have made polymyxins (e.g. polymyxin B and colistin) a mainstay in clinical practices as either monotherapy or combination therapy. However, whether the polymyxin-based combinations lead to better outcomes remains unknown. This review mainly focuses on the effect of polymyxin combination therapy versus monotherapy on treating GNB-related infections. We also provide several factors in designing studies and their impact on optimizing polymyxin combinations. EXPERT OPINION: An abundance of recent in vitro and preclinical in vivo data suggest clinical benefit for polymyxin-drug combination therapies, especially colistin plus meropenem and colistin plus rifampicin, with synergistic killing against MDR, XDR, and DTR P. aeruginosa, K. pneumoniae and A. baumannii. The beneficial effects of polymyxin-drug combinations (e.g. colistin or polymyxin B + carbapenem against carbapenem-resistant K. pneumoniae and carbapenem-resistant A. baumannii, polymyxin B + carbapenem + rifampin against carbapenem-resistant K. pneumoniae, and colistin + ceftolozan/tazobactam + rifampin against PDR-P. aeruginosa) have often been shown in clinical setting by retrospective studies. However, high-certainty evidence from large randomized controlled trials is necessary. These clinical trials should incorporate careful attention to patient's sample size, characteristics of patient's groups, PK/PD relationships and dosing, rapid detection of resistance, MIC determinations, and therapeutic drug monitoring.

In vitro research of combination therapy for multidrug-resistant Klebsiella pneumoniae bloodstream infections.

OBJECTIVE: Multidrug-resistant Klebsiella pneumoniae (MDR KP) bloodstream infections are a serious problem. The objective of this study was to investigate the effects of appropriate combination therapies on MDR KP bloodstream infections. METHODS: MDR KP strains isolated from clinical samples were assessed for antibiotic susceptibility using the broth microdilution method. Twenty consecutive MDR KP clinical isolates from patients with bloodstream infections were examined in this study. The experiments were conducted at the Bacterial Laboratory of Tongde Hospital from March to August 2021. Antibiotic combination tests were performed using the minimum inhibitory concentration (MIC) test, and the sum of the fractional inhibitory concentration was used to assess synergy. RESULTS: Following treatment with a combination of two antibiotic agents, the MIC50 and MIC90 values decreased compared with that before treatment. MIC50 decreased by at least 50%, with one value reduced to 6.25% of the pretreatment value. None of the antibiotic combinations were antagonistic. Combination of polymyxin B with rifampicin or tigecycline had a synergistic effect on 70% and 65% of the strains, respectively. CONCLUSIONS: In vitro combination therapies with two active drug agents (polymyxin B plus rifampicin or tigecycline) had a better effect on MDR KP infections compared with that in other regimens.

Synergistic Inhibitory Effect of Polymyxin B in Combination with Ceftazidime against Robust Biofilm Formed by Acinetobacter baumannii with Genetic Deficiency in AbaI/AbaR Quorum Sensing.

Carbapenem resistance of Acinetobacter baumannii poses challenges to public health. Biofilm contributes to the persistence of A. baumannii cells. This study was designed to investigate the genetic relationships among carbapenem resistance, polymyxin resistance, multidrug resistance, biofilm formation, and surface-associated motility and evaluate the antibiofilm effect of polymyxin in combination with other antibiotics. A total of 103 clinical A. baumannii strains were used to determine antibiotic susceptibility, biofilm formation capacity, and motility. Enterobacterial repetitive intergenic consensus (ERIC)-PCR fingerprinting was used to determine the genetic variation among strains. The distribution of 17 genes related to the resistance-nodulation-cell division (RND)-type efflux, autoinducer-receptor (AbaI/AbaR) quorum sensing, oxacillinases (OXA)-23, and insertion sequence of ISAba1 element was investigated. The representative strains were chosen to evaluate the gene transcription and the antibiofilm activity by polymyxin B (PB) in combination with merapenem, levofloxacin, and ceftazidime, respectively. ERIC-PCR-dependent fingerprints were found to be associated with carbapenem resistance and multidrug resistance. The presence of blaOXA-23 was found to correlate with genes involved in ISAba1 insertion, AbaI/AbaR quorum sensing, and AdeABC efflux. Carbapenem resistance was observed to be negatively correlated with biofilm formation and positively correlated with motility. PB in combination with ceftazidime displayed a synergistic antibiofilm effect against robust biofilm formed by an A. baumannii strain with deficiency in AbaI/AbaR quorum sensing. Our results not only clarify the genetic correlation among carbapenem resistance, biofilm formation, and pathogenicity in a certain level but also provide a theoretical basis for clinical applications of polymyxin-based combination of antibiotics in antibiofilm therapy. IMPORTANCE Deeper explorations of molecular correlation among antibiotic resistance, biofilm formation, and pathogenicity could provide novel insights that would facilitate the development of therapeutics and prevention against A. baumannii biofilm-related infections. The major finding that polymyxin B in combination with ceftazidime displayed a synergistic antibiofilm effect against robust biofilm formed by an A. baumannii strain with genetic deficiency in AbaI/AbaR quorum sensing further provides a theoretical basis for clinical applications of antibiotics in combination with quorum quenching in antibiofilm therapy.

Effect of 4-Hexylresorcinol on the Efficiency of Antibiotic Treatment of Experimental Sepsis Caused by Antibiotic-Resistant Klebsiella pneumoniae Strain in Mice.

High efficiency of a combined preparation including synergistic polymyxin B and 4-hexylresorcinol was shown for treatment of experimental sepsis caused by an antibiotic-resistant highly virulent hypermucoid Klebsiella pneumoniae strain KPM9Pmr in mice. Complex therapy with polymyxin B (1 mg/kg) and 4-hexylresorcinol (30 mg/kg) led to cure in 80%; in 20% of these mice, no bacterial cells were found. After treatment with polymyxin B alone, only 50% animals survived and all of them contained bacterial cells. Comparative analysis of the results of monotherapy and combined treatment indicates that 4-hexylresorcinol not only increases the efficiency of antibiotic, but also minimizes persistence of the infection agent and therefore, the risk of development of antibiotic resistance.

Pharmacodynamic evaluation of suppression of in vitro resistance in Acinetobacter baumannii strains using polymyxin B-based combination therapy.

The emergence of polymyxin resistance in Gram-negative bacteria infections has motivated the use of combination therapy. This study determined the mutant selection window (MSW) of polymyxin B alone and in combination with meropenem and fosfomycin against A. baumannii strains belonging to clonal lineages I and III. To evaluate the inhibition of in vitro drug resistance, we investigate the MSW-derived pharmacodynamic indices associated with resistance to polymyxin B administrated regimens as monotherapy and combination therapy, such as the percentage of each dosage interval that free plasma concentration was within the MSW (%TMSW) and the percentage of each dosage interval that free plasma concentration exceeded the mutant prevention concentration (%T>MPC). The MSW of polymyxin B varied between 1 and 16 µg/mL for polymyxin B-susceptible strains. The triple combination of polymyxin B with meropenem and fosfomycin inhibited the polymyxin B-resistant subpopulation in meropenem-resistant isolates and polymyxin B plus meropenem as a double combination sufficiently inhibited meropenem-intermediate, and susceptible strains. T>MPC 90% was reached for polymyxin B in these combinations, while %TMSW was 0 against all strains. TMSW for meropenem and fosfomycin were also reduced. Effective antimicrobial combinations significantly reduced MSW. The MSW-derived pharmacodynamic indices can be used for the selection of effective combination regimen to combat the polymyxin B-resistant strain.

[Long course of polymyxin B for the treatment of brain abscess caused by carbapenem resistant Acinetobacter baumannii: a case report].

The clinical efficacy of polymyxins in severe infection caused by carbapenem resistant organism (CRO) has gradually been recognized, and the course of treatment is generally 2 to 4 weeks. The most common complications after intravenous injection are nephrotoxicity and neurotoxicity, however, there are few reports on the efficacy and safety of the long course use of polymyxins. A patient with carbapenem resistant Acinetobacter baumannii (CRAB) infection after neurosurgery was admitted to the department of neurosurgical intensive care unit (NICU) of Lanzhou University Second Hospital. As the family refused the excision of brain abscess and Ommaya reservoir placement, polymyxin B was given intravenous (3.0 mg×kg-1×d-1) combined with intrathecal (5 mg once daily) injection, and high-dose sulbactam (8 g/d) was intravenously injected for anti-infection therapy. Finally, the brain abscess was absorbed and the patient was successfully cured. The total course of polymyxin B was 69 days with a cumulative dosage of 7 500 mg. There were no complications such as polymyxin-related nephrotoxicity and neurotoxicity during the period, and no symptoms of respiratory inhibition or neuromuscular blockage were observed, but polymyxin-related skin pigmentation appeared about 1 month after intravenous administration of polymyxins B, which subsided after drug withdrawal. It is suggested that long course of polymyxins B is safe and effective for intracranial infection caused by CRAB.

Efficacy of a Novel Ophthalmic Antimicrobial Drug Combination Toward a Large Panel of Staphylococcus aureus Clinical Ocular Isolates From Around the World.

PURPOSE: Staphylococcus aureus is a leading cause of keratitis requiring urgent antimicrobial treatment. However, rising antibiotic resistance has rendered current ophthalmic antibiotics increasingly ineffective. First, a diverse, ocular S. aureus strain set was evaluated for resistance to 6 commonly used ophthalmic antibiotics. Next, a recently discovered antimicrobial drug combination containing polymyxin B/trimethoprim (PT) + rifampin that displayed impressive efficacy toward S. aureus in both in vitro and in vivo studies was evaluated as a potential novel keratitis therapeutic through testing this combination's efficacy against the clinical strain set. METHODS: A total of 163 S. aureus isolates were collected either commercially or from the Flaum Eye Institute, University of Rochester. The minimum inhibitory concentrations of moxifloxacin, levofloxacin, vancomycin, erythromycin, tobramycin, rifampin, and PT were determined for the entire strain set to establish the incidence of resistance to current treatment options among a contemporary clinical isolate set and compared with the performance of PT + rifampin. RESULTS: Among all 163 isolates tested, high rates of antibiotic resistance were found toward erythromycin (69% resistance), moxifloxacin (33%), levofloxacin (40%), and tobramycin (17%). Conversely, the entire strain set, including multidrug resistant isolates, was sensitive to PT + rifampin, demonstrating the potency of this combination. CONCLUSIONS: We established that antibiotic resistance is pervasive among clinical S. aureus isolates, underscoring the concern for the effectiveness of current ophthalmic antibiotics. The drug combination of PT + rifampin, however, eradicated 100% of isolates tested, demonstrating the ability to overcome existing circulating resistance factors, and as such, might represent a promising therapeutic for S. aureus keratitis.

Assessment of polymyxin B-doxycycline in combination against Pseudomonas aeruginosa in vitro and in a mouse model of acute pneumonia.

The increasing prevalence of antibiotic resistance in Pseudomonas aeruginosa has created an urgent need for suitable therapy. This study explored the pairing of doxycycline with other antipseudomonal antibiotics, and found that polymyxin B in combination with doxycycline had a synergistic effect against clinical strains of P. aeruginosa. This synergistic combination was studied by checkerboard assays and time-kill curve analysis. Further, in-vitro biofilm disruption, pyoverdine inhibition assays were performed. The efficacy of polymyxin B-doxycycline in combination, administered by inhalation, was evaluated using a mouse model of acute pneumonia. The combination was found to have a synergistic effect in both in-vitro and in-vivo studies. The combination decreased biofilms of P. aeruginosa and reduced the level of pyoverdine, an important siderophore of P. aeruginosa. In addition, the combination decreased the P. aeruginosa population by 3 log10 (P<0.01) in the mouse model of acute pneumonia, and showed an improvement in lung function by inhalation. To the best of the authors' knowledge, this is the first in-vivo study to evaluate the efficacy of polymyxin B in combination with doxycycline against P. aeruginosa, showing a possible promising option for acute pneumonia due to multi-drug-resistant P. aeruginosa.

[Clinical analysis of sepsis with extensively drug resistant Gram-negative bacteria in intensive care unit treated with polymyxin B-based combination therapy].

OBJECTIVE: To investigate the clinical efficacy and safety of polymyxin B in the treatment of sepsis caused by extensively-drug resistant (XDR) Gram-negative bacteria. METHODS: A retrospective analysis of 39 septic patients with XDR Gram-negative bacterial infection treated with polymyxin B in the department of critical care medicine of Xiangya Hospital of Central South University from June 2018 to September 2019 were enrolled. The clinical characteristics, bacterial culture, the sensitivity antibacterial drugs, types and courses of antibiotics, biochemical indexes, and acute physiology and chronic health evaluation II (APACHE II) before and after polymyxin B treatment were collected, to assess microbial clearance and efficacy, drug related adverse effects, and 28-day mortality in septic patients with XDR. RESULTS: Of the 39 septic patients with XDR, 32 (82.1%) were male, with the mean age of (53.6±12.6) years old. The main infection site was pulmonary infection (51.2%), and the treatment courses of polymyxin B were ≥ 5 days. A total of 66 pathogenic bacteria were detected from 39 patients. Among them, with the high estrate of detecting Acinetobacter baumannii of 51.5% (34/66). After treatment with polymyxin B, the results showed that the clearance rate of microorganisms was 65.2% (43/66), the overall effective rate was 59.0% (23/39), and the 28-day all-cause mortality was 41.0% (16/39). There were no significant differences in clinical efficacy and microbial clearance among patients with different treatment groups of polymyxin B [< 10 days, 10-15 days, and > 15 days groups: effective rates were 56.5% (13/23), 54.5% (6/11), 80.0% (4/5), χ 2 = 0.999, P = 0.728; the microbial clearance rates were 43.5% (10/23), 54.5% (6/11), and 80.0% (4/5), χ 2 = 2.141, P = 0.393]. The effective and microbial clearance rates of the polymyxin B daily doses of 150 mg and 200 mg groups were significantly higher than those of the daily dose of 100 mg [effectiveness: 85.7% (6/7), 87.5% (7/8) vs. 41.7% (10/24); microbial clearance rate: 71.4% (5/7), 87.5% (7/8) vs. 33.3% (8/24), all P < 0.05], however, there were no significant differences in the length of intensive care unit (ICU) stay and mechanical ventilation time among different daily dose groups. The APACHE II score after polymyxin B administration was significantly lower than before administration (all patients: 16.20±9.24 vs. 24.40±4.73, effective patients: 11.30±4.08 vs. 23.00±4.56, both P < 0.05). Four patients with renal injury had an increase in serum creatinine during the administration of polymyxin B, and recovered after discontinuation of the drug without other adverse reactions. CONCLUSIONS: Polymyxin B can be used as an effective treatment option for patients with severe infection of XDR Gram-negative bacteria.

Using machine learning to optimize antibiotic combinations: dosing strategies for meropenem and polymyxin B against carbapenem-resistant Acinetobacter baumannii.

OBJECTIVES: Increased rates of carbapenem-resistant strains of Acinetobacter baumannii have forced clinicians to rely upon last-line agents, such as the polymyxins, or empirical, unoptimized combination therapy. Therefore, the objectives of this study were: (a) to evaluate the in vitro pharmacodynamics of meropenem and polymyxin B (PMB) combinations against A. baumannii; (b) to utilize a mechanism-based mathematical model to quantify bacterial killing; and (c) to develop a genetic algorithm (GA) to define optimal dosing strategies for meropenem and PMB. METHODS: A. baumannii (N16870; MICmeropenem = 16 mg/L, MICPMB = 0.5 mg/L) was studied in the hollow-fibre infection model (initial inoculum 108 cfu/mL) over 14 days against meropenem and PMB combinations. A mechanism-based model of the data and population pharmacokinetics of each drug were used to develop a GA to define the optimal regimen parameters. RESULTS: Monotherapies resulted in regrowth to ~1010 cfu/mL by 24 h, while combination regimens employing high-intensity PMB exposure achieved complete bacterial eradication (0 cfu/mL) by 336 h. The mechanism-based model demonstrated an SC50 (PMB concentration for 50% of maximum synergy on meropenem killing) of 0.0927 mg/L for PMB-susceptible subpopulations versus 3.40 mg/L for PMB-resistant subpopulations. The GA had a preference for meropenem regimens that improved the %T > MIC via longer infusion times and shorter dosing intervals. The GA predicted that treating 90% of simulated subjects harbouring a 108 cfu/mL starting inoculum to a point of 100 cfu/mL would require a regimen of meropenem 19.6 g/day 2 h prolonged infusion (2 hPI) q5h + PMB 5.17 mg/kg/day 2 hPI q6h (where the 0 h meropenem and PMB doses should be 'loaded' with 80.5% and 42.2% of the daily dose, respectively). CONCLUSION: This study provides a methodology leveraging in vitro experimental data, a mathematical pharmacodynamic model, and population pharmacokinetics provide a possible avenue to optimize treatment regimens beyond the use of the 'traditional' indices of antibiotic action.

Case Commentary: the Need for Cefiderocol Is Clear, but Are the Supporting Clinical Data?

Cefiderocol is a newly approved siderophore cephalosporin that demonstrates expanded in vitro activity against multidrug-resistant Gram-negative bacteria. In two challenging cases reported here, cefiderocol shows potential utility as salvage therapy against difficult-to-treat pathogens with limited or no treatment options; however, two multicenter, randomized clinical trials have yielded mixed results among cefiderocol-treated patients. Taken together, clinicians must balance a clear need for cefiderocol in clinical practice with the uncertainties that have stemmed from the available data.

Activity of ceftazidime-avibactam alone and in combination with polymyxin B against carbapenem-resistant Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo Galleria mellonella survival model analysis.

Ceftazidime-avibactam is used clinically in combination with a polymyxin for the treatment of carbapenem-resistant Gram-negative infections; however, there are limited data to support this practice. The objective of this study was to evaluate the activity of ceftazidime-avibactam and polymyxin B alone and in combination against Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo Galleria mellonella survival model assay. Three KPC-3-producing K. pneumoniae clinical isolates were used for all experiments. All isolates harbored mutations in ompk35 and one isolate in ompk36; two isolates were susceptible to both ceftazidime-avibactam and polymyxin B, and one was resistant to both. Ceftazidime-avibactam was bactericidal against 2 of 3 strains at ≥2x minimum inhibitory concentration (MIC) whereas polymyxin B was not bactericidal against any strain at any concentration. Combinations at 1/4x or 1/2x MIC were not bactericidal or synergistic against any of the 3 isolates. In survival experiments, ceftazidime-avibactam at 4x MIC significantly improved larval survival over the untreated control strain whereas polymyxin B at 4x MIC did not. Combining polymyxin B with ceftazidime-avibactam at 4x MIC did not improve survival compared to ceftazidime-avibactam alone. This work indicates there is no improvement in in vitro bactericidal activity or in vivo efficacy when polymyxin B is combined with ceftazidime-avibactam against KPC-producing K. pneumoniae. This combination should be avoided in lieu of ceftazidime-avibactam alone or other potentially more efficacious, less toxic combination regimens.

Thermal burns of the spectacle associated with supplementary heating in native New Zealand geckos.

Case history: Gradual onset of ocular opacity was observed in three gold-striped geckos (Woodworthia chrysosiretica), and five Pacific geckos (Dactylocnemis pacificus) held in two adjacent terrariums in a zoological institution located in the North Island of New Zealand. Ultraviolet light and heat had been provided for the previous 3-4 years by a fluorescent bulb, but in the last 4 weeks of winter a ceramic heat bulb had been added, situated 10 cm above the upper mesh of the cageClinical findings: All eight geckos presented with mostly bilateral lesions of varying severity confined to the central or upper quadrant of the spectacles. These lesions ranged from variable areas of opacity within the stroma of the spectacle to similarly distributed ulcers of the surface epithelium of both spectacles. The spectacle lesions in the Pacific geckos responded well to treatment with topical combined antimicrobial therapy, within 18-29 days. The gold-striped geckos suffered complications including dysecdysis, severe spectacle ulceration and perforation, mycotic spectaculitis, and widespread mycotic dermatitis resulting in death or leading to euthanasia.Pathological findings: In the three gold-striped geckos, there were extensive areas of deep ulceration and replacement of the spectacle with a thick serocellular crust containing large numbers of fungal elements. The affected areas of the stroma were expanded by large deposits of proteinaceous and mucinous material, pyknotic cellular debris and moderate numbers of heterophils and macrophages as well as infiltrating fungal hyphae.Diagnosis: Mycotic spectaculitis with ulceration and perforation, and disseminated mycotic dermatitis likely secondary to thermal burns.Clinical relevance: This is the first report of thermal burns of the spectacle in any reptile. There was species variation in the burn severity with gold-striped geckos showing more severe lesions, possibly due to a mix of behavioural and anatomical factors. The thermal burns to the spectacles in three cases were complicated by delayed healing, perforation, dysecdysis and severe mycotic infection.

Susceptibility pattern of tracheal tube isolates from Intensive Care Unit of Fauji Foundation Hospital Rawalpindi.

OBJECTIVE: To determine the prevalence of resistant pathogens and their antimicrobial susceptibility pattern in an intensive care unit. METHODS: The cross-sectional observational study was conducted at Foundation Hospital, Rawalpindi, Pakistan, from May to September 2016, and comprised tracheal tubes which were collected in sputum culture bottles from patients with clinical findings of ventilator associated pneumonia. The tubes were cultured to locate the resistant pathogens. RESULTS: A total of 113 different strains of bacteria were isolated from 80 patients. The main isolated bacteria was acinetobacter baumannii 45(39.8%) followed by klebsiella pneumonia 14(12.3%) and methicillin-resistant staphylococcus aureus 13(11.5%). Polymyxin B was the most appropriate drug for treating patients infected with acinetobacter baumannii with a sensitivity of 64% while vancomycin and linez oli dhad 100% sensitivity for methicill in - resistant staphylococcusaureus. CONCLUSIONS: Acinetobacter baumannii was the most prevalent strain in tracheal tubes and polymyxin B was the most effective medicine.

Combination therapy with polymyxin B for carbapenemase-producing Klebsiella pneumoniae bloodstream infection.

Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) bloodstream infections (BSIs) are related to high mortality rates, and combination therapy has been associated with lower mortality in patients treated mostly with colistin. There is a paucity of studies addressing polymyxin B (PMB) treatment for KPC-KP infections. This was a retrospective cohort study of patients with monomicrobial KPC-KP BSIs. The primary outcome was 30-day mortality. Antimicrobial therapy was defined as empirical (started within the first 48 h) or definitive (initiated after >48 h) and was evaluated as follows: monotherapy (only one in vitro active agent or combination therapy of one in vitro active agent plus one or more in vitro non-active agents); and combination therapy with two or more in vitro active agents. A total of 82 KPC-KP BSIs were included; 40 patients (48.8%) died in the first 30 days. Mortality of patients treated with the combination of two in vitro active antimicrobial agents, mostly PMB plus amikacin, was significantly lower (37.5%) compared with monotherapy (64.7%) (P= 0.01). Combination therapy [adjusted hazard ratio (aHR) = 0.40, 95% confidence interval (CI) 0.22-0.83; P = 0.01] was independently associated with lower 30-day survival when controlled for non-surgical admission (aHR = 2.33, 95% CI 1.14-4.80; P = 0.02) and use of vasoactive drugs (aHR = 7.37, 95% CI 3.01-18.02; P < 0.01). In conclusion, combination therapy with two in vitro active agents, mostly PMB plus amikacin, showed a survival benefit compared with other regimens.

Polymyxin B clinical outcomes: A prospective study of patients undergoing intravenous treatment.

WHAT IS KNOWN AND OBJECTIVE: Polymyxins, especially polymyxin B, has become the last line of therapy against Gram-negative pathogens' carbapenemase producers. However, given increasing use of polymyxin B in clinical settings its therapeutic value has been evaluated worldwide due to its toxic effects. The aim of this study was to assess the efficacy and safety of antimicrobial therapy with polymyxin B in patients with multidrug-resistant bacteria in Brazil. METHODS: This was a prospective cohort study in a 403-bed academic tertiary care centre, located in the countryside of Brazil. Patients receiving polymyxin B intravenous treatment for at least 72 hours were eligible for the study. Antimicrobial susceptibility, adverse reactions and clinical outcomes were submitted for descriptive analysis. Main outcomes measure the following: Patients' conditions following treatment (Treatment Success, Mortality, Treatment Failure, Inadequate Empiric Treatment or Indeterminate Response) and toxicities induced by polymyxin B (nephrotoxicity and skin hyperpigmentation). RESULTS AND DISCUSSION: Among 247 patients, treatment success was achieved in 25.1%, while mortality was observed in 32.8%. Empirical therapy was prescribed for 26.3% of the patients. Nephrotoxicity was reported in 40.5%. The carbapenemase producer, Klebsiella pneumonia, was the bacterium most associated with mortality (22.2%). CONCLUSIONS: Even though polymyxin B is currently the main therapy against carbapenemase producers, its use demands robust criteria to lead to positive clinical outcomes.