Optimal Empiric Polymyxin B Treatment of Patients Infected with Gram-Negative Organisms Detected Using a Blood Antimicrobial Surveillance Network in China.

BACKGROUND: Few pharmacodynamics studies to date have evaluated the efficacy and safety of polymyxin B (PMB) in treating patients with bloodstream infections (BSIs) in China. METHODS: Patients with BSIs were identified using an antimicrobial surveillance network, and their pathogens were isolated. Patients were treated with a loading dose of PMB followed by either a weight-based or weight-independent maintenance dose. Monte Carlo simulation was utilized to calculate the probability of target attainment (PTA) and cumulative fraction of response (CFR) against Gram-negative organisms in patients with normal or decreased renal function. RESULTS: A total of 10,066 Gram-negative organisms, including 5500 Escherichia coli (Eco), 2519 Klebsiella pneumoniae (Kpn), 501 Acinetobacter baumannii (Aba), were isolated from patients with BSIs. Although these strains were highly resistant to carbapenem, they remained susceptible to PMB. Among patients with renal impairment (mean CrCL, 42 mL/min), a PMB 2.5 mg/kg loading dose followed by a maintenance dose of 60 mg q12h reached ≥90% PTA against isolates with an MIC of 2 mg/L, with a low risk of toxicity. Among patients with normal renal function (mean CrCL, 123 mL/min), all simulated regimens showed PTAs of 25-80%. A weight-based loading dose followed by either a weight-based or weight-independent maintenance dose showed a promising CFR, especially in patients with renal impairment, with CFRs ≥90% against carbapenem-resistant Eco, Kpn, and Aba. Simulated regimens showed a disappointing CFR (<80%) against carbapenem-resistant Pae in patients with normal renal function. Based on the optimal balance of efficacy and toxicity, a fixed maintenance dose of 60 mg q12h among patients with renal impairment yielded a CFR similar to regimens based on total body weight and was associated with a probability of toxicity (12.5%) significantly lower than that of simulations based on total body weight. Among patients with normal renal function, a weight-based maintenance dose of 1.25 mg/kg q12h achieved a higher CFR than a fixed maintenance dose, without significantly increasing toxicity. CONCLUSION: A 2.5 mg/kg loading dose of PMB is optimal, regardless of renal function. A fixed maintenance dose of 60 mg q12h is recommended for empirical treatment of patients with renal impairment infected with Eco, Kpn, and Aba, whereas a weight-based maintenance dose of 1.25 mg/kg is recommended for patients with normal renal function.

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.

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.

An alternative strategy for combination therapy: Interactions between polymyxin B and non-antibiotics.

Antimicrobial resistance is increasing and few new antibiotics are in the development pipeline. Alternative strategies to treat infectious diseases, such as combination therapy, are urgently needed. Polymyxin B is a neglected and disused antibiotic with moderate antibacterial activity. In this study, we aimed to find synergistic interactions between polymyxin B and a wide range of non-antibiotics (non-ABs) to improve its efficacy. Thirty non-AB compounds from various drug classes were screened for synergistic potential with sub-minimum inhibitory concentrations (MICs) of polymyxin B in an agar diffusion assay against Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa (3 isolates per species). Potential candidates were further studied in in vitro checkerboard assays, up to 5 isolates per species, using optical density to assess growth. Interactions were assessed with fractional inhibitory concentration index (FICi) analysis and surface response analysis with Loewe, Bliss and Highest Single Agent analysis using the Combenefit program. Twenty non-ABs enhanced polymyxin B activity in the agar diffusion test in one or more species. Of these, three showed a consistent synergistic effect (FICi ≤ 0.5) in the checkerboard assay for at least one species: citalopram, sertraline and spironolactone. Surface response analyses were largely in concordance, and further assessment showed only spironolactone was synergistic with polymyxin B at clinically relevant levels. The screening strategy used showed consistent synergism in vitro between polymyxin B and some non-ABs for A. baumannii, E. coli and K. pneumoniae. The synergistic interactions found merit further exploration as alternative strategies for difficult-to-treat infections.

Efficacy of intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B for post-neurosurgical intracranial infections due to MDR/XDR Acinectobacter baumannii: a retrospective cohort study.

Background: Post-neurosurgical intracranial infections caused by multidrug-resistant or extensively drug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality. In this study, we analyzed the therapeutic efficacy of intravenous combined with intrathecal/intracerebral ventricle injection of polymyxin B for this type of intracranial infection. Methods: This retrospective study was conducted from January 2013 to September 2017 at the Second Affiliated Hospital, Zhejiang University School of Medicine (Hangzhou,China) and included 61 cases for which cerebrospinal fluid (CSF) cultures were positive for multidrug-resistant or extensively drug-resistant A. baumannii after a neurosurgical operation. Patients treated with intravenous and intrathecal/intracerebral ventricle injection of polymyxin B were assigned to the intrathecal/intracerebral group, and patients treated with other antibiotics without intrathecal/intracerebral injection were assigned to the intravenous group. Data for general information, treatment history, and the results of routine tests and biochemistry indicators in CSF, clinical efficiency, microbiological clearance rate, and the 28-day mortality were collected and analyzed. Results: The rate of multidrug-resistant or extensively drug-resistant A. baumannii infection among patients who experienced an intracranial infection after a neurosurgical operation was 33.64% in our hospital. The isolated A. baumannii were resistant to various antibiotics, and most seriously to carbapenems (100.00% resistance rate to imipenem and meropenem), cephalosporins (resistance rates of 98.38% to cefazolin, 100.00% to ceftazidime, 100.00% to cefatriaxone, and 98.39% to cefepime). However, the isolated A. baumannii were completely sensitive to polymyxin B (sensitivity rate of 100.00%), followed by tigecycline (60.66%) and amikacin (49.18%). No significant differences in basic clinical data were observed between the two groups. Compared with the intravenous group, the intrathecal/intracerebral group had a significantly lower 28-day mortality (55.26% vs. 8.70%, P = 0.01) and higher rates of clinical efficacy and microbiological clearance (95.65% vs. 23.68%, P < 0.001; 91.30% vs. 18.42%, P < 0.001, respectively). Conclusions: Intravenous plus intrathecal/intracerebral ventricle injection of polymyxin B is an effective regimen for treating intracranial infections caused by multidrug-resistant or extensively drug-resistant A. baumannii.

Triple combination antibiotic therapy for carbapenemase-producing Klebsiella pneumoniae: a systematic review.

BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.

Aerosolized Polymyxin B for Treatment of Respiratory Tract Infections: Determination of Pharmacokinetic-Pharmacodynamic Indices for Aerosolized Polymyxin B against Pseudomonas aeruginosa in a Mouse Lung Infection Model.

Pulmonary administration of polymyxins is increasingly used for the treatment of respiratory tract infections caused by multidrug-resistant Gram-negative bacteria, such as those in patients with cystic fibrosis. However, there is a lack of pharmacokinetics (PK), pharmacodynamics (PD), and toxicity data of aerosolized polymyxin B to inform rational dosage selection. The PK and PD of polymyxin B following pulmonary and intravenous dosing were examined in neutropenic infected mice, and the data were analyzed by a population PK model. Dose fractionation study was performed for total daily doses between 2.06 and 24.8 mg base/kg of weight against Pseudomonas aeruginosa ATCC 27853, PAO1, and FADDI-PA022 (MIC of 1 mg/liter for all three strains). Histopathological examination of the lung was undertaken at 24 h posttreatment in both healthy and neutropenic infected mice. A two-compartment PK model was required for both epithelial lining fluid (ELF) and plasma drug exposure. The model consisted of central and peripheral compartments and was described by bidirectional first-order distribution clearance. The ratio of the area under the curve to the MIC (AUC/MIC) was the most predictive PK/PD index to describe the antimicrobial efficacy of aerosolized polymyxin B in treating lung infections in mice (R2 of 0.70 to 0.88 for ELF and 0.70 to 0.87 for plasma). The AUC/MIC targets associated with bacteriostasis against the three P. aeruginosa strains were 1,326 to 1,506 in ELF and 3.14 to 4.03 in plasma. Histopathological results showed that polymyxin B aerosols significantly reduced lung inflammation and preserved lung epithelial integrity. This study highlights the advantageous PK/PD characteristics of pulmonary delivery of polymyxin B over intravenous administration in achieving high drug exposure in ELF.

Clinical translation of polymyxin-based combination therapy: Facts, challenges and future opportunities.

The emergence and spread of multidrug resistant Gram-negative bacteria has led to a resurgence in the clinical use of polymyxin antibiotics. However, the prevalence of polymyxin resistance is on the rise at an alarming rate, motivating the idea of combination therapy to sustain the revival of these "old" antibiotics. Although ample evidence in favor of combination therapy has emerged, it seems impracticable and confusing to find a promising combination from the diverse reports or gain adequate information on the efficacy and safety profile. With a stagnating discovery pipeline of novel antimicrobials, there is a clear need to fill the knowledge gaps in translating these basic research data to beneficial clinical practice. In this review, we examined the factors and ambiguities that stand as major hurdles in bringing polymyxin combination therapy to bedside care, highlighting the importance and urgency of incorporating translational research insights into areas of difficulty. We also discussed future research priorities that are essential to gather the necessary evidence and insights for promoting the best possible use of polymyxins in combination therapy.

Limewater and Polymyxin B Associated with NaOCl for Endotoxin Detoxification in Root Canal with Necrotic Pulp.

This clinical study investigated the effects of endodontic treatment by using different irrigants (limewater + NaOCl and polymyxin B + NaOCl) and intracanal medication on endotoxins in teeth with primary endodontic infection and radiographically visible apical periodontitis. Thirty-three teeth with necrotic pulp and periapical lesions from different patients were selected for this study. Samples were collected after the coronal opening (S1) and after instrumentation (S2). Root canals were divided in 3 groups (n = 11) according to the irrigant combination used: NaOCl + LW: 2.5% NaOCl + calcium hydroxide solution (0.14%, limewater); NaOCl + PmB: 2.5% NaOCl + 10.000 UI/mL polymyxin B; 2.5% NaOCl (control). The third sampling (S3) was performed after ethylenediaminetetraacetic acid and the fourth (S4) after samples got 14 days with intracanal medication with 2% chlorhexidine gel + calcium hydroxide. Endotoxins (lipopolysaccharide) were quantified by chromogenic Limulus amebocyte lysate (LAL). Endotoxins were detected in all root canals after the coronal opening (S1). NaOCl + PmB group presented the greatest endotoxin reduction after instrumentation (76.17%), similar to NaOCl + LW group (67.64%, p<0.05) and different from NaOCl group (42.17%, p<0.05). After intracanal medication period (S4), there was significant increase of endotoxins neutralization. It was concluded that NaOCl + PmB promoted the greatest reduction of endotoxin levels, followed by NaOCl + LW. Intracanal medications had no significant complementary role in the reduction of endotoxins at the end of the treatment.

Limewater and Polymyxin B Associated with NaOCl for Endotoxin Detoxification in Root Canal with Necrotic Pulp

Abstract This clinical study investigated the effects of endodontic treatment by using different irrigants (limewater + NaOCl and polymyxin B + NaOCl) and intracanal medication on endotoxins in teeth with primary endodontic infection and radiographically visible apical periodontitis. Thirty-three teeth with necrotic pulp and periapical lesions from different patients were selected for this study. Samples were collected after the coronal opening (S1) and after instrumentation (S2). Root canals were divided in 3 groups (n = 11) according to the irrigant combination used: NaOCl + LW: 2.5% NaOCl + calcium hydroxide solution (0.14%, limewater); NaOCl + PmB: 2.5% NaOCl + 10.000 UI/mL polymyxin B; 2.5% NaOCl (control). The third sampling (S3) was performed after ethylenediaminetetraacetic acid and the fourth (S4) after samples got 14 days with intracanal medication with 2% chlorhexidine gel + calcium hydroxide. Endotoxins (lipopolysaccharide) were quantified by chromogenic Limulus amebocyte lysate (LAL). Endotoxins were detected in all root canals after the coronal opening (S1). NaOCl + PmB group presented the greatest endotoxin reduction after instrumentation (76.17%), similar to NaOCl + LW group (67.64%, p<0.05) and different from NaOCl group (42.17%, p<0.05). After intracanal medication period (S4), there was significant increase of endotoxins neutralization. It was concluded that NaOCl + PmB promoted the greatest reduction of endotoxin levels, followed by NaOCl + LW. Intracanal medications had no significant complementary role in the reduction of endotoxins at the end of the treatment

Resumo Este estudo clínico investigou os efeitos do tratamento endodôntico com uso de diferentes irrigantes (NaOCl + água de cal e NaOCl + polimixina B) e medicação intracanal sobre endotoxinas em dentes com infecção endodôntica primária e presença de lesão periapical visível radiograficamente. Foram selecionados para o estudo trinta e três dentes de pacientes que apresentavam necrose pulpar e presença de lesão periapical. As amostras foram coletadas após a abertura coronária (S1) e após a instrumentação (S2). Os canais radiculares foram divididos em 3 grupos (n = 11) de acordo com a combinação de irrigantes utilizada: NaOCl + LW:- hipoclorito de sódio 2,5% + solução de hidróxido de cálcio (água de cal 0,14%); NaOCl + PmB: hipoclorito de sódio a 2,5% + polimixina B 10.000 UI/mL; NaOCl (controle): hipoclorito de sódio a 2,5%. A terceira coleta (S3) foi realizada após aplicação do ácido etilenodiamino tetra acético (EDTA) e a quarta coleta (S4) após 14 dias de medicação intracanal de hidróxido de cálcio + clorexidina gel 2%. Endotoxinas (lipopolissacarídeos) foram quantificadas pelo ensaio cromogênico do lisado de amebócitos de Limulus (LAL). Endotoxinas foram detectadas em todos os canais radiculares após abertura coronária (S1). Grupo NaOCl + PmB apresentou a maior redução de endotoxinas após a instrumentação (76,17%), sendo similar ao grupo NaOCl + LW (67,64%, P >.05) e diferente do grupo NaOCl (42,17%, P <.05). Após o período de medicação intracanal, houve aumento significativo da neutralização de endotoxinas. Concluiu-se que NaOCl + PmB promoveu a maior redução dos níveis de endotoxinas, seguido de NaOCl + LW. A medicação intracanal não teve um papel complementar significativo na redução de endotoxinas no final do tratamento.

Clinical efficacy and safety of herbal medicine Dermidoc in the management of atopic dermatitis versus allopathic medicine PolymixinB-bacitrin ointment.

Atopic dermatitis (AD) commonly identified as eczema. AD is an inflammatory, long-lasting, highly pruritic reverting disease of the skin. AD is classified by disease of outer skin layer barrier function. AD is progress with Immunoglobulin E facilitated sensitization to food and environmental allergens. One study stated that more than 59.6% of teen-agers with AD are at high risk of develop asthma or rhinitis. Interaction between genes and environment increase the prevalence of AD. AD have three standard stages: infantile, childhood, and adulthood. AD sign and symptoms diverge extensively. AD can be present that simply affect the hand to where a patient presents with erythroderma. AD present with erythematous papules, extremely pruritic with serous exudate. Lichenified plaques and papules are symptoms of long lasting AD. Due to outer skin layer barrier dysfunction bacterial and viral infection risk is increased in AD patients. This study was directed on 100 patients in which 50 are PolymixinB-bacitrin group and 50 are Dermidoc group. Patients were selected after seeing inclusion and exclusion criteria and taking written informed consent. Dermidoc group expressively amended skin symptoms associated with AD comparing to the PolymixinB-bacitrin group. The Dermidoc cream is effective and well tolerated. The results were analysis using paired sample t-test. The p value is <0.05. Test group (Dermidoc) were significantly more effective than PolymixinB-bacitrin group.

Poly(L-lactide)/halloysite nanotube electrospun mats as dual-drug delivery systems and their therapeutic efficacy in infected full-thickness burns.

In this study, poly(L-lactide) (PLLA)/halloysite nanotube (HNT) electrospun mats were prepared as a dual-drug delivery system. HNTs were used to encapsulate polymyxin B sulphate (a hydrophilic drug). Dexamethasone (a hydrophobic drug) was directly dissolved in the PLLA solution. The drug-loaded HNTs with optimised encapsulation efficiency were then mixed with the PLLA solution for subsequent electrospinning to form composite dual-drug-loaded fibre mats. The structure, morphology, degradability and mechanical properties of the electrospun composite mats were characterised in detail. The results showed that the HNTs were uniformly distributed in the composite PLLA mats. The HNTs content in the mats could change the morphology and average diameter of the electrospun fibres. The HNTs improved both the tensile strength of the PLLA electrospun mats and their degradation ratio. The drug-release kinetics of the electrospun mats were investigated using ultraviolet-visible spectrophotometry. The HNTs/PLLA ratio could be varied to adjust the release of polymyxin B sulphate and dexamethasone. The antibacterial activity in vitro of the mats was evaluated using agar diffusion and turbidimetry tests, which indicated the antibacterial efficacy of the dual-drug delivery system against Gram-positive and -negative bacteria. Healing in vivo of infected full-thickness burns and infected wounds was investigated by macroscopic observation, histological observation and immunohistochemical staining. The results indicated that the electrospun mats were capable of co-loading and co-delivering hydrophilic and hydrophobic drugs, and could potentially be used as novel antibacterial wound dressings.

Framework for optimisation of the clinical use of colistin and polymyxin B: the Prato polymyxin consensus.

In the face of diminishing therapeutic options for the treatment of infections caused by multidrug-resistant, Gram-negative bacteria, clinicians are increasingly using colistin and polymyxin B. These antibiotics became available clinically in the 1950s, when understanding of antimicrobial pharmacology and regulatory requirements for approval of drugs was substantially less than today. At the 1st International Conference on Polymyxins in Prato, Italy, 2013, participants discussed a set of key objectives that were developed to explore the factors affecting the safe and effective use of polymyxins, identify the gaps in knowledge, and set priorities for future research. Participants identified several factors that affect the optimum use of polymyxins, including: confusion caused by several different conventions used to describe doses of colistin; an absence of appropriate pharmacopoeial standards for polymyxins; outdated and diverse product information; and uncertainties about susceptibility testing and breakpoints. High-priority areas for research included: better definition of the effectiveness of polymyxin-based combination therapy compared with monotherapy via well designed, randomised controlled trials; examination of the relative merits of colistin versus polymyxin B for various types of infection; investigation of pharmacokinetics in special patient populations; and definition of the role of nebulised polymyxins alone or in combination with intravenous polymyxins for the treatment of pneumonia. The key areas identified provide a roadmap for action regarding the continued use of polymyxins, and are intended to help with the effective and safe use of these important, last-line antibiotics.

Successful treatment of extensively drug-resistant Acinetobacter baumannii peritoneal dialysis peritonitis with intraperitoneal polymyxin B and ampicillin-sulbactam.

OBJECTIVE: To describe a case of extensively drug-resistant (XDR) Acinetobacter baumannii peritoneal dialysis (PD)-associated peritonitis successfully treated with combination antibiotics, including intraperitoneal polymyxin B, with retention of the catheter. CASE SUMMARY: A 54-year-old woman with end-stage renal disease receiving chronic PD and recent antibiotic and hospital exposure presented with abdominal pain, nausea, and vomiting. She was found to have XDR A. baumannii PD peritonitis. Treatment was initiated with intravenous and intraperitoneal ampicillin-sulbactam, followed by the addition of intraperitoneal polymyxin B based on susceptibilities. The patient recovered without the need for catheter removal or switch to hemodialysis. DISCUSSION: The frequency of XDR A. baumannii as a nosocomial pathogen is increasing, and polymyxins are being used more often as part of combination therapy for infections caused by this organism. Neither XDR A. baumannii PD peritonitis nor the use of intraperitoneal polymyxin B has been well described. In our patient, intraperitoneal dosing of polymyxin B was determined based on limited published pharmacokinetic and pharmacodynamic data. CONCLUSIONS: A case of XDR A. baumannii PD peritonitis was successfully treated with combination antibiotic therapy, including intraperitoneal polymyxin B, without major complications.

Differences in bacteriologic treatment failures in acute otitis externa between ciprofloxacin/dexamethasone and neomycin/polymyxin B/hydrocortisone: results of a combined analysis.

OBJECTIVE: To compare treatment failure rates for the two major acute otitis externa (AOE) pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, by topical therapy with ciprofloxacin 0.3%/dexamethasone 0.1% (CDex) or neomycin 0.35%/polymyxin B 10,000 IU/mL/hydrocortisone 1% (Cort) based on clinical and microbiological failure in patients positive for these pathogens at baseline. RESEARCH DESIGN AND METHODS: A combined analysis was conducted from two similar, but non-identical clinical trials involving CDex vs. Cort. Outcomes of the combined efficacy analysis were treatment failure rates and antibiotic susceptibility values for P. aeruginosa and S. aureus. The raw data for the treatment failure rates from the two studies were combined to calculate the overall treatment failure rates of each treatment group. Chi-square tests of independence were conducted to assess differences in treatment failure rates between treatment groups. RESULTS: Of the 789 patients with culture-positive ears prior to the initiation of therapy, 61.0% (n = 481) were positive for P. aeruginosa and 8.9% (n = 70) were positive for S. aureus. While treatment failure rates for S. aureus were similar for the two therapies, CDex had a significantly lower treatment failure rate than Cort (5.1 vs. 13.0%; p = 0.0044) for P. aeruginosa. All of the persisting P. aeruginosa and S. aureus isolates were susceptible to fluoroquinolones and neomycin/polymyxin B. LIMITATIONS: The analysis strength is dependent on pooled data from similar studies. CONCLUSIONS: Ototopical ciprofloxacin 0.3%/dexamethasone 0.1% more effectively eradicates P. aeruginosa compared to Cort. Eradication of S. aureus by either drug was similar. These results favor CDex as a better first-line choice in the treatment of AOE compared to Cort.

Dietary glutamine and oral antibiotics each improve indexes of gut barrier function in rat short bowel syndrome.

Short bowel syndrome (SBS) is associated with gut barrier dysfunction. We examined effects of dietary glutamine (GLN) or oral antibiotics (ABX) on indexes of gut barrier function in a rat model of SBS. Adult rats underwent a 60% distal small bowel + proximal colonic resection (RX) or bowel transection (TX; control). Rats were pair fed diets with or without l-GLN for 20 days after operation. Oral ABX (neomycin, metronidazole, and polymyxin B) were given in some RX rats fed control diet. Stool secretory immunoglobulin A (sIgA) was measured serially. On day 21, mesenteric lymph nodes (MLN) were cultured for gram-negative bacteria. IgA-positive plasma cells in jejunum, stool levels of flagellin- and lipopolysaccharide (LPS)-specific sIgA, and serum total, anti-flagellin- and anti-LPS IgG levels were determined. RX caused gram-negative bacterial translocation to MLN, increased serum total and anti-LPS IgG and increased stool total sIgA. After RX, dietary GLN tended to blunt bacterial translocation to MLN (-29%, P = NS) and significantly decreased anti-LPS IgG levels in serum, increased both stool and jejunal mucosal sIgA and increased stool anti-LPS-specific IgA. Oral ABX eliminated RX-induced bacterial translocation, significantly decreased total and anti-LPS IgG levels in serum, significantly decreased stool total IgA and increased stool LPS-specific IgA. Partial small bowel-colonic resection in rats is associated with gram-negative bacterial translocation from the gut and a concomitant adaptive immune response to LPS. These indexes of gut barrier dysfunction are ameliorated or blunted by administration of dietary GLN or oral ABX, respectively. Dietary GLN upregulates small bowel sIgA in this model.

A multicenter comparison of polymyxin B sulfate/trimethoprim ophthalmic solution and moxifloxacin in the speed of clinical efficacy for the treatment of bacterial conjunctivitis.

PURPOSE: To compare the speed of clinical efficacy for two currently available topical antibiotics: polymyxin B sulfate/trimethoprim (polymyxin/trimethoprim) and 0.5% moxifloxacin ophthalmic solution. METHODS: Eighty-four eyes of 56 patients younger than 18 years with a clinical diagnosis of bacterial conjunctivitis were enrolled in this multicenter study. Patients were randomly assigned to receive either 1 drop of polymyxin/trimethoprim four times daily for 7 days or 1 drop of 0.5% moxifloxacin three times daily for 7 days. Ocular signs and symptoms were evaluated at baseline and 24 and 48 hours after the start of dosing. Microbiological cultures were collected at baseline and 48 hours. Patients rated ocular symptoms and adverse events on day 7 via telephone interview. Primary efficacy assessment included relief of all signs and symptoms of bacterial conjunctivitis. RESULTS: All patients but one completed all visits. At the 48-hour visit, complete resolution of ocular signs and symptoms was observed in 81% of the patients treated with moxifloxacin and 44% of the patients treated with polymyxin/trimethoprim (P = .001). No adverse events were reported. CONCLUSION: Moxifloxacin 0.5% administered three times daily is safe and cures bacterial conjunctivitis more effectively and significantly faster than polymyxin/trimethoprim dosed four times daily. The majority of patients were cured and symptom-free by 48 hours. Therefore, moxifloxacin is cost-effective and significantly more efficacious than polymyxin/trimethoprim in the speed by which it reduces the symptoms and disease transmission.

Comparison of efficacy and safety of ciprofloxacin otic solution 0.2% versus polymyxin B-neomycin-hydrocortisone in the treatment of acute diffuse otitis externa*.

OBJECTIVE: To compare the efficacy and safety of ciprofloxacin otic solution 0.2% to polymyxin B-neomycin-hydrocortisone (PNH) otic solution in the treatment of acute diffuse otitis externa in children, adolescents, and adults. METHODS: This was a randomized, parallel-group, evaluator-blind, active-controlled, multicenter, noninferiority study. The primary efficacy endpoint was clinical cure of otitis symptoms at the test-of-cure (TOC) visit. Clinical cure at the end-of-treatment (EOT) visit and percentages of patients with clinical improvement and resolution and/or improvement of otalgia at EOT and TOC visits were secondary efficacy endpoints. RESULTS: A total of 630 patients were randomized to ciprofloxacin twice daily (n = 318) or PNH 3 times daily (n = 312) for 7 days. Ciprofloxacin was shown to be noninferior to PNH. The percentage of patients with clinical cure at the TOC visit was 86.6% with ciprofloxacin and 81.1% with PNH; the treatment difference was 5.6% in favor of ciprofloxacin (95% CI: -0.9 to 12.1). At the EOT visit, clinical cure was achieved in 70.0% and 60.5% of patients, respectively, with a treatment difference in favor of ciprofloxacin (9.5%, 95 CI: 1.2 to 17.9). In all secondary efficacy variables, ciprofloxacin and PNH showed similar results, including pain duration and resolution. The clinical cure rate for patients with baseline cultures showing P. aeruginosa was 87.5% in the ciprofloxacin group and 78.6% in the PNH group, a treatment difference of 8.9% in favor of ciprofloxacin (95% CI: 0.6 to 17.3); for patients with baseline cultures showing S. aureus, the clinical cure rate was 72.7% for the ciprofloxacin group and 75.9% for the PNH group (treatment difference of 3.1% in favor of PNH, 95% CI: -21.1% to 27.4%). Most adverse events were mild and unrelated to study medication in both treatment groups. A limitation of this study is the assessment of signs and symptoms at baseline and after treatment, which does not provide data to evaluate the interim response. CONCLUSIONS: Ciprofloxacin otic solution 0.2% was found to be noninferior to PNH. This efficacy, good tolerability, and ease of administration make ciprofloxacin otic solution 0.2% without a topical steroid an attractive option for the treatment of acute otitis externa.

Parenteral polymyxin B use in patients with multidrug-resistant gram-negative bacteremia and urinary tract infections: a retrospective case series.

BACKGROUND: Parenteral polymyxin use declined after the 1960s, due to safety concerns. An increase in multidrug-resistant (MDR) gram-negative infections and a shortage of new agents have prompted increased use of parenteral polymyxin. OBJECTIVE: To describe our clinical experience with parenteral polymyxin B for MDR gram-negative bacteremia and urinary tract infection (UTI). METHODS: Paper pharmacy records were used to identify patients aged 18 years or older, presence of MDR gram-negative bacteremia or UTI, and use of parenteral polymyxin B for at least 48 hours. Electronic and paper patient records were then retrospectively reviewed. Polymyxin B susceptibility was evaluated using the Kirby-Bauer method. MDR isolates were defined as resistant to at least 3 antimicrobial classes, excluding polymyxin B. Microbiologic clearance was defined by 1 repeat urine or 2 repeat blood cultures that were sterile or growing different organisms. Secondary outcomes included hospital mortality and nephrotoxicity, defined as an increase in serum creatinine of 0.5 mg/dL or more, or a 50% reduction in creatinine clearance. RESULTS: Seventeen infections in 16 patients were treated with polymyxin B (1 pt. had 2 infections that were analyzed separately). Microbiologic clearance occurred in 14 of 16 (88%) cases of MDR gram-negative bacteremia or UTI in which repeat cultures were done. Ten of 16 patients died (all-cause mortality 63%). Five patients required hemodialysis prior to polymyxin B use. Six (55%) of the remaining 11 patients with baseline renal insufficiency developed nephrotoxicity, and none of them required hemodialysis. The mean +/- SD number of days from the initiation of therapy to the onset of nephrotoxicity was 7.5 +/- 2.3 (range 4-10) days. Three (50%) of 6 patients with nephrotoxicity died. CONCLUSIONS: Our data suggest that polymyxin B may be effective for MDR gram-negative infections in patients with limited therapeutic options, but precautions should be taken to avoid toxicity.

Pooled analysis of two clinical trials comparing the clinical outcomes of topical ciprofloxacin/dexamethasone otic suspension and polymyxin B/neomycin/hydrocortisone otic suspension for the treatment of acute otitis externa in adults and children.

OBJECTIVE: This study aimed to compare the clinical outcome of patients receiving topical ciprofloxacin 0.3%/dexamethasone 0.1% (CD) otic suspension with that of those receiving polymyxin B/neomycin/ hydrocortisone (PNH) otic suspension for the treatment of acute otitis externa (AOE). METHODS: Data from 2 institutional review board-approved, multicenter, observer-masked, parallel-group, randomized, noninferiority clinical trials conducted at 76 institutions across the United States between April 1998 and July 1999 were pooled together for this analysis. Patients > or =1 year of age diagnosed with AOE were considered for inclusion in the studies. Patients with AOE >4 weeks' duration, a perforated tympanic membrane, chronic suppurative otitis media, or use of either antibiotics or steroids within the previous 7 days were excluded from the studies. Patients were randomly assigned to receive CD or PNH for 7 days. CD was administered as 3 drops in children and 4 drops in patients > or =12 years of age BID. PNH was administered as 3 drops in children and 4 drops in patients > or =12 years of age TID. The clinical investigators were blinded to treatment assignment. Due to the different dosing regimens, patients were not blinded, but they also were not directly informed of their treatment assignments. Otic inflammation, tenderness, edema, and discharge were clinically assessed on days 3, 8, and 18 of the studies. Otic inflammation and edema were evaluated using a 4-point scale (none = 0; mild = 1; moderate = 2; and severe = 3). Otic tenderness and discharge were rated on a binomial scale (absent = 0 and present = 1). The clinical assessments were aggregated into a 9-point composite clinical scale (range, 0-8) to compare baseline severity between groups. For the final outcomes assessment in this study, the aggregated clinical scores were dichotomized into cured (0) versus noncured (>0) and analyzed using a Kaplan-Meier survival technique. A log-rank test was used to compare the cure curves between treatment groups. Kaplan-Meier summary statistics provide the mean and median times to cure, and the mean times to cure for the 25th and 75th patient quartiles. Tolerability was assessed by monitoring patients for adverse events at each visit. RESULTS: Data from 1072 patients (1242 ears) were included in the analysis (CD, 537 patients; PNH, 535 patients). Baseline AOE severity and demographic characteristics were similar between the 2 treatment groups. The mean patient age was 21.7 and 22.0 years in the CD and PNH groups, respectively. Both groups were similar with respect to sex, with 50.7% and 53.5% females in the CD and PNH groups, respectively. The racial composition was predominately white (88.6% vs 84.9% in the CD and PNH groups, respectively). The log-rank test revealed a significant difference in the AOE cure curves between the CD and PNH groups (P = 0.038). The proportions cured in the AOE at-risk groups at the day-3, -8, and -18 assessments in the CD and PNH treatment groups were 0.14 and 0.10, 0.75 and 0.72, and 0.98 and 0.97, respectively. The Kaplan-Meier summary statistics indicated that the mean time to cure was 0.6 day less with CD compared with PNH (9.7 vs 10.3 days). Treatment-related adverse event rates were similar between the 2 groups and occurred in 3.8% of the patients. The most common adverse events included otic pruritus (2.1%), otic congestion (0.6%), otic debris (0.5%), otic pain (0.3%), superimposed ear infection (0.3%), and erythema (0.1%). CONCLUSION: These data from 2 previous studies suggest that time to cure was significantly less with CD compared with PNH in patients with AOE.