Management Of Multidrug-resistant Infections Research Articles

Phage Therapy: An Alternative Approach to Combating Multidrug-Resistant Bacterial Infections in Cystic Fibrosis.

Patients with cystic fibrosis (CF) are prone to developing life-threatening lung infections with a variety of pathogens that are difficult to eradicate, such as Burkholderia cepacia complex (Bcc), Hemophilus influenzae, Mycobacterium abscessus (Mab), Pseudomonas aeruginosa, and Staphylococcus aureus. These infections still remain an important issue, despite the therapy for CF having considerably improved in recent years. Moreover, prolonged exposure to antibiotics in combination favors the development and spread of multi-resistant bacteria; thus, the development of alternative strategies is crucial to counter antimicrobial resistance. In this context, phage therapy, i.e., the use of phages, viruses that specifically infect bacteria, has become a promising strategy. In this review, we aim to address the current status of phage therapy in the management of multidrug-resistant infections, from compassionate use cases to ongoing clinical trials, as well as the challenges this approach presents in the particular context of CF patients.

The Potential of Antibiotics and Nanomaterial Combinations as Therapeutic Strategies in the Management of Multidrug-Resistant Infections: A Review

Antibiotic resistance has become a major public health concern around the world. This is exacerbated by the non-discovery of novel drugs, the development of resistance mechanisms in most of the clinical isolates of bacteria, as well as recurring infections, hindering disease treatment efficacy. In vitro data has shown that antibiotic combinations can be effective when microorganisms are resistant to individual drugs. Recently, advances in the direction of combination therapy for the treatment of multidrug-resistant (MDR) bacterial infections have embraced antibiotic combinations and the use of nanoparticles conjugated with antibiotics. Nanoparticles (NPs) can penetrate the cellular membrane of disease-causing organisms and obstruct essential molecular pathways, showing unique antibacterial mechanisms. Combined with the optimal drugs, NPs have established synergy and may assist in regulating the general threat of emergent bacterial resistance. This review comprises a general overview of antibiotic combinations strategies for the treatment of microbial infections. The potential of antibiotic combinations with NPs as new entrants in the antimicrobial therapy domain is discussed.

Management of Multidrug Resistant Infections in Lung Transplant Recipients with Cystic Fibrosis.

Cystic fibrosis (CF) is an inherited multisystem disease characterised by bronchiectasis and chronic respiratory infections which eventually cause end stage lung disease. Lung transplantation (LTx) is a well-established treatment option for patients with CF-associated lung disease, improving survival and quality of life. Navigating recurrent infections in the setting of LTx is often difficult, where immune suppression must be balanced against the constant threat of infection. Sepsis/infections are one of the major contributors to post-LTx mortality and multiresistant organisms (eg, Burkholderia cepacia complex, Mycobacterium abscessus complex, Scedosporium spp. and Lomentospora spp.) pose a significant threat to survival. This review will summarize current and novel therapies to assist with the management of multiresistant bacterial, mycobacterial, viral and fungal infections which threaten the CF LTx cohort.

Parenteral Fosfomycin for the Treatment of Multidrug Resistant Bacterial Infections: The Rise of the Epoxide.

Fosfomycin was initially discovered in 1969 but has recently gained renewed interest for the treatment of multidrug-resistant (MDR) bacterial infections, particularly in the United States. Its unique mechanism of action, bactericidal activity, broad spectrum of activity, and relatively safe and tolerable adverse effect profile make it a great addition to the dwindling antibiotic armamentarium. Fosfomycin contains a three-membered epoxide ring with a direct carbon to phosphorous bond that bypasses the intermediate oxygen bond commonly present in other organophosphorous compounds; this structure makes the agent unique from other antibiotics. Despite nearly 50 years of parenteral fosfomycin use in Europe, fosfomycin has retained stable activity against most pathogens. Furthermore, fosfomycin demonstrated in vitro synergy in combination with other cell wall-active antibiotics (e.g., β-lactams, daptomycin). These combinations may offer respite for severe infections due to MDR gram-positive and gram-negative bacteria. The intravenous (IV) formulation is currently under review in the United States, and apropos, this review collates more contemporary evidence (i.e., studies published between 2000 and early 2019) in anticipation of this development. The approval of IV fosfomycin provides another option for consideration in the management of MDR infections. Its unique structure will give rise to a promising epoxide epoch in the battle against MDR bacteria.

Dextrin-colistin conjugates as a model bioresponsive treatment for multidrug resistant bacterial infections.

Polymer therapeutics offer potential benefits in the treatment of multidrug resistant (MDR) infections; affording targeted delivery of biologically active agents to the site of inflammation, potential decreases in systemic toxicity, and the retention of antimicrobial activity at the target site. As a prototype model, these studies developed and characterized a library of dextrin-colistin conjugates (dextrin molecular weight: 7500-48,000 g/mol) as a means of targeting the delivery of colistin. Optimum colistin release kinetics (following dextrin degradation by physiological concentrations of amylase (100 IU/L)) were observed in conjugates containing low molecular weight (∼7500 g/mol) dextrin with ∼1 mol % succinoylation (∼80% drug release within 48 h, compared to ∼33% from sodium colistin methanesulfonate (CMS, Colomycin)). These conjugates exhibited comparable antimicrobial activity to CMS in conventional MIC assays against a range of Gram-negative pathogens, but with significantly reduced in vitro toxicity toward kidney (IC₅₀ = CMS, 15.4 μg/mL; dextrin-colistin, 63.9 μg/mL) and macrophage (IC₅₀ = CMS, 111.3 μg/mL; dextrin-colistin, 303.9 μg/mL) cells. In vivo dose-escalation studies in rats demonstrated improved pharmacokinetics of the conjugates, with prolonged plasma levels of colistin (t₁/₂ 135-1271 min vs 53 min) and decreased toxicity, compared to colistin sulfate. These studies highlight the potential utility of "nanoantibiotic" polymer therapeutics to aid the safe, effective, and targeted delivery of colistin in the management of MDR infections.

Establishing the role of tigecycline in an era of antimicrobial resistance

Tigecycline is a glycylcycline antibacterial agent derived from minocycline with a broad spectrum of activity. Like tetracycline agents, it inhibits bacterial protein synthesis but is able to bind to target sites with higher affinity and overcome tetracycline-resistance mechanisms due to structural modifications. The safety and efficacy of tigecycline has been demonstrated in clinical trials for complicated intra-abdominal and complicated skin and skin-structure infections. It has received approval for these indications in several countries, including the USA in 2005, and European Union in 2006. Aside from approved indications and in vitro data, growing clinical experience suggests a potential role for tigecycline in the management of multi-drug resistant infections due to drug-resistant pathogens. Further study is necessary to determine the ultimate role of tigecycline in treating these types of infections.

Poor Central Nervous System Penetration of Tigecycline in a Patient with Sepsis and Ventriculitis Caused by Multidrug-Resistant Klebsiella Pneumoniae

Objective: To report the use of tigecycline in a case of ventriculitis and concurrent bacteremia. Case Summary: A 57-year-old African American male with a ruptured brain aneurysm was admitted to the intensive care unit after surgical intervention and external ventricular drainage placement. His hospital course was complicated by myocardial infarction, ventilator-associated pneumonia, ventriculitis, and sepsis, with multidrug-resistant (MDR) Klebsiella pneumoniae isolated from multiple sites, including blood and cerebral spinal fluid (CSF). The patient was treated with high doses of intravenous tigecycline and gentamicin along with intrathecal gentamicin. This combination eradicated infections outside the central nervous system (CNS) within 48 hours, but it took approximately 8 days for the CSF culture to become negative. Timed serum and CSF fluid samples were collected to determine CSF penetration of tigecycline on day 12 of therapy. CSF concentrations obtained 30 minutes after the dose and at the end of the dosing interval remained below the detectable limit of 0.05 μg/mL. Discussion: Although CSF tigecycline concentrations may not represent actual CNS tissue concentrations at the site of infection, the low CSF concentrations observed in our case may be responsible for the slow CSF clearance of infection. It was not clear whether gentamicin therapy alone, administered both intravenously and intrathecally, would have achieved the same outcome and cleared the infection from the CNS in this patient. Conclusions: Until additional clinical data are available, tigecycline should not be used for the management of MDR infections associated with the CNS.