Treatment Of Invasive Infections Research Articles

Antibiotic Resistance and Presence of Persister Cells in the Biofilm-like Environments in Streptococcus agalactiae.

Objectives: This study investigated antibiotic resistance and presence of persister cells in Streptococcus agalactiae strains belonging to capsular types Ia/ST-103, III/ST-17, and V/ST-26 in biofilm-like environments. Results: S. agalactiae strains were susceptible to penicillin, clindamycin, and erythromycin. Resistance genes were associated with tetM (80%), tetO (20%), ermB (80%), and linB (40%). Persister cells were detected in bacterial strains exposed to high concentrations of penicillin, clindamycin, and erythromycin. S. agalactiae capsular type III/ST-17 exhibited the highest percentage of persister cells in response to penicillin and clindamycin, while type Ia/ST-103 presented the lowest percentages of persister cells for all antimicrobials tested. Additionally, persister cells were also detected at lower levels for erythromycin, regardless of capsular type or sequence type. Further, all S. agalactiae isolates presented efflux pump activity in ethidium bromide-refractory cell assays. LIVE/DEAD fluorescence microscopy confirmed the presence of >85% viable persister cells after antibiotic treatment. Conclusions: These findings suggest that persister cells play a key role in the persistence of S. agalactiae during antibiotic therapy, interfering with the treatment of invasive infections. Monitoring persister formation is crucial for developing strategies to combat recurrent infections caused by this pathogen.

Identification of antibiotic induced persister cells in Streptococcus agalactiae.

Antibiotic persistence is a phenomenon, where a small fraction of a bacterial population expresses a phenotypic variation that allows them to survive antibiotic treatment, which is lethal to the rest of the population. These cells are called persisters cells, and their occurrence has been associated with recurrent disease. Streptococcus agalactiae is a human pathobiont, able to cause invasive infections, and recurrent infections have been reported to occur in both newborns and adults. In this study, we demonstrated that S. agalactiae NEM316 can form persister cells when exposed to antibiotics from different classes. The frequency of persister cell formation was dependent on bacterial growth phase and the class of antibiotics. The ability to form persister cells in response to penicillin was shown to be a general trait among different clinical S. agalactiae isolates, independent of sero- and sequence-type. Taken together, this study shows the existence of antibiotic tolerant S. agalactiae persister cells, which may explain why this bacterial species frequently persists after treatment of invasive infection and can be associated with recurrent disease.

An Overview on Candida auris in Healthcare Settings.

Candida auris has become a major concern in critical care medicine due to the increasing number of immunocompromised patients and candidiasis is the most frequent cause of fungal infections. C. auris and other fungal pathogens are responsible for at least 13 million infections and 1.5 million deaths globally per year. In immunocompromised patients, infections can quickly become severe, causing wound infections, otitis and candidemia, resulting in high morbidity and mortality. The clinical presentation of C. auris is often non-specific and similar to other types of systemic infections; in addition, it is harder to identify from cultures than other, more common types of Candida spp. Some infections are particularly difficult to treat due to multi-resistance to several antifungal agents, including fluconazole (and other azoles), amphotericin B and echinocandins. This entails treatment with more drugs and at higher doses. Even after treatment for invasive infections, patients generally remain colonized for long periods, so all infection control measures must be followed during and after treatment of the C. auris infection. Screening patients for C. auris colonization enables facilities to identify individuals with C. auris colonization and to implement infection prevention and control measures. This pathogenic fungus shows an innate resilience, enabling survival and persistence in healthcare environment and the ability to rapidly colonize the patient's skin and be easily transmitted within the healthcare setting, thus leading to a serious and prolonged outbreak.

Species Distribution and Antifungal Susceptibilities of Aspergillus Section Terrei Isolates in Clinical Samples from the United States and Description of Aspergillus pseudoalabamensis sp. nov.

Aspergillus section Terrei consists of numerous cryptic species in addition to A. terreus sensu stricto. The treatment of invasive infections caused by these fungi may pose a unique challenge prior to diagnosis and species identification, in that they are often clinically resistant to amphotericin B, with poor outcomes and low survival rates in patients treated with this polyene. Data on the species distributions and susceptibility profiles of isolates within section Terrei from the United States (U.S.) are limited. Here, we report the species distributions and susceptibility profiles for amphotericin B, isavuconazole, itraconazole, posaconazole, voriconazole, and micafungin against 278 clinical isolates of this section from institutions across the U.S. collected over a 52-month period. Species identification was performed by DNA sequence analysis and phenotypic characterization. Susceptibility testing was performed using the CLSI broth microdilution method. The majority of isolates were identified as Aspergillus terreus sensu stricto (69.8%), although several other cryptic species were also identified. Most were cultured from specimens collected from the respiratory tract. Posaconazole demonstrated the most potent activity of the azoles (MIC range ≤ 0.03-1 mg/L), followed by itraconazole (≤0.03-2 mg/L), voriconazole, and isavuconazole (0.125-8 mg/L for each). Amphotericin B demonstrated reduced in vitro susceptibility against this section (MIC range 0.25-8 mg/L), although this appeared to be species-dependent. A new species within this section, A. pseudoalabamensis, is also described. Our results, which are specific to the U.S., are similar to previous surveillance studies of the Aspergillus section Terrei.

Prevalence and Genetic Analysis of Resistance Mechanisms of Linezolid-Nonsusceptible Enterococci in a Tertiary Care Hospital Examined via Whole-Genome Sequencing.

(1) Background: Linezolid plays an important role in the treatment of invasive infections caused by vancomycin-resistant enterococci after its introduction to clinical practice. However, a detailed examination of linezolid-nonsusceptible enterococci (LNSE) is required. In this study, we attempted to analyze the mechanisms of LNSE strains isolated from a tertiary care hospital. (2) Methods: From 2019 to 2020, 18 Enterococcus faecalis, 14 E. faecium, and 2 E. gallinarum clinical isolates were collected at Severance Hospital. Agar dilution was performed to evaluate precise linezolid minimum inhibitory concentrations (MICs). Short-read whole-genome sequencing (WGS) was used to analyze resistance determinants. (3) Results: The presence of the optrA gene was likely the primary resistance mechanism in these three species, typically demonstrating a MIC value of 8 μg/mL. The co-existence of the cfr(D) and poxtA2 gene was the second major mechanism, primarily predicting a phenotype showing intermediate susceptibility to linezolid. G2576U mutation on 23S rRNA was only found in E. faecium; it mediated the most significant increase in linezolid MIC. (4) Conclusion: This is the first report examining poxtA2-cfr(D) co-harboring clinical enterococcal isolates in Korea and demonstrating the poxtA EF9F6-harboring clinical E. gallinarum strain worldwide. The comparison with resistance-gene-containing fragments in the isolates obtained from different countries and different sources demonstrated the spread of linezolid-resistance genes and suggested the possibility of foodborne transmission.

New Perspectives on Antimicrobial Agents: Long-Acting Lipoglycopeptides.

The long-acting lipoglycopeptides (LGPs) dalbavancin and oritavancin are semisynthetic antimicrobials with broad and potent activity against Gram-positive bacterial pathogens. While they are approved by the Food and Drug Administration for acute bacterial skin and soft tissue infections, their pharmacological properties suggest a potential role of these agents for the treatment of deep-seated and severe infections, such as bloodstream and bone and joint infections. The use of these antimicrobials is particularly appealing when prolonged therapy, early discharge, and avoidance of long-term intravascular catheter access are desirable or when multidrug-resistant bacteria are suspected. This review describes the current evidence for the use of oritavancin and dalbavancin in the treatment of invasive infections, as well as the hurdles that are preventing their optimal use. Moreover, this review discusses the current knowledge gaps that need to be filled to understand the potential role of LGPs in highly needed clinical scenarios and the ongoing clinical studies that aim to address these voids in the upcoming years.

687. Use of Dalbavancin in Gram-positive Infective Endocarditis: Review of Current Literature

BackgroundDalbavancin is a long acting, semisynthetic derivative of teicoplanin that is currently approved for treatment of acute bacterial skin and skin structure infections. Its efficacy and role of in the treatment of invasive infections, in particular infective endocarditis, is not well known.MethodsWe reviewed the English-language literature for the use of Dalbavancin in the treatment of endocarditis due to Gram-positive organisms, using Pubmed.Results15 publications were reviewed. All the publications were retrospective in nature, with relatively small numbers of patients, including a few case reports.A total of 159 patients received Dalbavancin for endocarditis. The mean age was 47 years. The main reasons for using Dalbavancin were non-feasibility of a standard outpatient regimen (mainly due to drug use) or the need for a simpler regimen. 75 patients had infection of a native valve, 44 of a prosthetic valve and 19 of a cardiac device. The type of infection for the rest of the patients was not specified. The tricuspid valve was the most frequently reported. The etiologic organisms causing endocarditis were Staphylococcus species, followed by Streptococcus species and Enterococcus species, with Staphylococcus aureus being the most common. All, but one, patients received Dalbavancin as sequential therapy, after receiving other intravenous antibiotics initially. The duration of antibiotics received prior to initiation of Dalbavancin was variable, with the median being 3 weeks. The median duration of Dalbavancin use was 2.7 weeks. The dosage regimens varied, with the more common ones using a loading dose of either 1500 mg or 1000 mg, followed by one or more weekly doses of 500 mg. The overall clinical efficacy was around 89%. Adverse events were mild, including nausea, vomiting, rash, headache and reversible acute kidney injury. None of the patients had to discontinue the drug because of adverse events. Two publications evaluated the cost effectiveness of Dalbavancin and found it to save about &9000 per patient, the saving being mainly due to reduced length of hospital stay.ConclusionDalbavancin appears to be an efficacious, safe and cost-effective option for sequential treatment of endocarditis caused by Staph aureus and other Gram-positive organisms.Disclosures All Authors: No reported disclosures

Терапевтичний потенціал бактеріофагів та ендолізинів при лікуванні гострих респіраторних інфекцій, викликаних бактеріальними патогенами

Бактеріофаги являють собою віруси, які за рахунок рецептор/ліганд-взаємодії здатні специфічно зв’язуватися з бактеріальною стінкою і відновлюватися всередині певних мікроорганізмів. Літичні ферменти бактеріофагів ефективно руйнують клітинну стінку бактерій, але на відміну від антибіотиків не впливають на життєдіяльність симбіотичної флори. На сьогодні існує велика кількість наукових матеріалів, що стосуються ефективності антистрептококових, антистафілококових, антиклебсієльозних, антисинегнійних бактеріофагів і ендолізинiв, які здатні викликати загибель антибіотикорезистентних бактерій, у зв’язку з чим їх використовують як бактерицидні лікарські засоби, що є потенційно ефективним терапевтичним методом протимікробної терапії. Високий рівень ефективності бактерицидної дії ендолізинів дозволяє висловити припущення, що майбутні лікарські засоби, створені на молекулярній основі ендолізинів, можуть стати ключовими протимікробними препаратами при лікуванні інфекційних захворювань.

In Vitro Interaction and Killing-Kinetics of Amphotericin B Combined with Anidulafungin or Caspofungin against Candida auris

Treatment of invasive infections caused by Candida auris is challenging due to the limited therapeutic options. The combination of antifungal drugs may be an interesting and feasible approach to be investigated. The aim of this study was to examine the in vitro activity of amphotericin B in combination with anidulafungin or caspofungin against C. auris. In vitro static time–kill curve experiments were conducted for 48 h with different combinations of amphotericin B with anidulafungin or caspofungin against six blood isolates of C. auris. The antifungal activity of 0.5 mg/L of amphotericin B was limited against the six isolates of C. auris. Similarly, echinocandins alone had a negligible effect, even at the highest tested concentrations. By contrast, 1 mg/L of amphotericin B showed fungistatic activity. Synergy was rapidly achieved (8 h) with 0.5 mg/L of amphotericin B plus 2 mg/L of anidulafungin or caspofungin. These combinations lead to a sustained fungistatic effect, and the fungicidal endpoint was reached against some C. auris isolates. Additionally, ≥0.5 mg/L of either of the two echinocandins with 1 mg/L of amphotericin B resulted in fungicidal effect against all C. auris isolates. In conclusion, combinations of amphotericin B with anidulafungin or caspofungin provided greater killing with a lower dose requirement for amphotericin B compared to monotherapy, with synergistic and/or fungicidal outcomes.

FORMULATION EVALUATION AND OPTIMIZATION OF CHITOSAN COATED CEFTRIAXONE LOADED MICROPARTICLES

Ceftriaxone, a third generation cephalosporin antibiotic is an important antibiotic used in the treatment of invasive infections caused by the certain bacteria such as the penicillin-resistant microorganisms like Staphyloccocus aureus, strains of S. pneumonia, S. aureus and Enterobacteriaceae , particularly among E. coli. There is increasing antimicrobial resistance of Ceftriaxone in particular against these strains of bacteria. This study has been conducted to formulate, evaluate and optimize chitosan coated ceftriaxone loaded microparticles with better efficacy and also observes the MIC against strains of bacteria. Emulsion crosslinking method was used for the formulation of microparticles of ceftriaxone by using chitosan as a polymer and glutraldehyde as a cross linking agent which is optimized by using Box-Behnken Design. Three independent variables were taken; effect of drug and the polymer ratio, effect of the stirring speed and effect of crosslinking agent and dependent variables were microparticles entrapment efficiency and the In vitro drug release. Following optimization of the formulations, physical characterization as well as entrapment efficiency and ultimately in-vitro evaluation was performed. Physical characterization include optical microscopy, SEM and DLS to check there physical properties. The method used for the formulation of microparticle had the optimum entrapment efficiency of 61.7% which was increase with the increase in the addition of the more amount of chitosan and glutraldehyde and method also achieved the good in vitro release. MIC studies of microparticles were done against Klebsiella pneumonia, Staphylococcus aureus, Streptococcus mutans, Escherichia coli and it was found that the formulations showed decrease in MIC.

Carbapenem-Resistant Klebsiella pneumoniae Strains: Susceptibility to Novel Antibiotics and Molecular Detection of the Resistance Mechanisms - A Study from Two Greek Tertiary Teaching Hospitals

Objectives: We evaluated the carbapenem resistance mechanisms of Klebsiella pneumoniae strains isolated in two Greek tertiary teaching hospitals and their susceptibility to currently used and novel antimicrobial agents. Materials and methods: Forty-seven carbapenem resistant K. pneumoniae strains were collected in G. Papanikolaou and Ippokrateio hospital of Thessaloniki from 1/11/2016 to 5/1/2018 and 26/1/2017 to 19/4/2017 respectively. Strain identification and antimicrobial susceptibility was conducted by Vitek 2 system (Biomerieux France). Susceptibility against new antimicrobial agents was examined by disk diffusion method. Polymerase chain reaction (PCR) was used for the detection of blaKPC, blaVIM, blaNDM and blaOXA-48 genes. Results: The EDTA-boronic acid disk synergy test performed on the 24 K. pneumoniae strains from G. Papanikolaou hospital demonstrated that 8 (33.3%) yielded positive for metallo-b-lactamases (MBL) and 16 (66.6%) for K. pneumoniae carbapenemases (KPC) production. Gentamycin demonstrated the highest in vitro activity (82.6%) among the 23 K. pneumoniae strains from Ippokrateio hospital followed by colistin (73.9%) and tigecycline (69.5%). All strains from G. Papanikolaou hospital were sensitive to colistin whereas the 70.8% of them displayed susceptibility to gentamycin. Ceftazidime/ avibactam showed the highest sensitivity (76.6%) in all strains followed by eravacyclin (66.6%). The blaKPC gene was present in 30 strains (63.8%), the blaNDM in 11 (23.4%) and the blaVIM in 6 (12.8%). The blaOXA-48 gene was not detected. Conclusions: Well established antimicrobial agents such as colistin, gentamycin and tigecycline and novel antibiotics like ceftazidime/avibactam and eravacycline may be reliable options for the treatment of invasive infections caused by KPC-producing pathogens.

Evaluation of the expanding spectrum of sertraline against uncommon fungal pathogens

The emergence of non-Aspergillus mold pathogens has increased notoriously in the last decades with serious health consequences. The options of treatment for these microorganisms often resistant to a wide variety of antifungals is limited. Sertraline is an antidepressant with invitro and invivo antifungal properties which has been recently studied as an adjuvant in the treatment of invasive infections. In this study, we evaluated the invitro interaction of sertraline with voriconazole and amphotericin B against Lomentospora prolificans, Scedosporium spp., Fusarium spp., Paecilomyces spp., Alternaria spp. and Curvularia spp. The minimum inhibitory concentration and minimum fungicidal concentration for sertraline were in the range of 8-32μg/mL. Sertraline showed antifungal capacity against all fungi tested and synergism in combination with amphotericin B against some strains of Lomentospora prolificans, Scedosporium apiospermum and Alternaria alternata, antagonism with voriconazole against Purpureocillium lilacinum and indifference in both combinations for most of the other strains tested. These results suggest a potential role of sertraline as an adjuvant in the treatment of some of these serious mycoses.

Rapid Emergence of Daptomycin Resistance in Nonstriatum Corynebacterium Species: A Multicenter Study

Abstract Members of the genus Corynebacterium are increasingly recognized as causes of opportunistic infection; some species can be multidrug resistant, posing a treatment challenge. Daptomycin is frequently used as therapy of last resort in this setting, but previous work from our group demonstrated the ability of C striatum clinical isolates to rapidly develop high-level resistance to daptomycin, both in vivo and in vitro. Here, our objective was to expand this investigation into a multicenter study evaluating multiple Corynebacterium species. Corynebacterium strains from three tertiary-care academic medical centers (total, n = 76; site 1, n = 44; site 2, n = 15; site 3, n = 17) were evaluated, representing 16 species. Isolates were identified during routine clinical testing and reported to species level in accordance with each laboratory’s standard operating procedures. Identification of each species was confirmed using both VITEK MS and Bruker BioTyper MALDI-TOF MS. MICs to daptomycin (Etest), vancomycin (Etest), and telavancin (Liofilchem) at baseline were determined using gradient diffusion methods on Mueller-Hinton agar with blood (Hardy Diagnostics). Each isolate was then inoculated in duplicate to 5 mL Tryptic Soy Broth. A daptomycin Etest was submerged in one tube from each pair, and growth was observed after 24-hour incubation. If turbidity was observed in the tube with daptomycin, MICs for each of the 3 antimicrobials were reassessed. High-level daptomycin resistance emerged in 24 strains: C aurimucosum (1/1 isolate tested), C bovis (1/2), C jeikeium (2/11), C macginleyi (3/3), C resistens (1/1), C simulans (1/1), C striatum (14/14 isolates), and C ulcerans (1/1). The majority of these isolates had MIC values >256 µg/mL following exposure to daptomycin. Forty-eight other isolates remained susceptible to daptomycin: C afermentans (1/1), C amycolatum (19/20), C diphtheriae (1/1), C jeikeium (7/11), C kroppenstedtii (2/2), C propinquum (3/3), C pseudodiphtheriticum (6/6), C tuberculostearicum (0/6), and C urealyticum (0/3). Many of these isolates did not undergo MIC testing postdaptomycin exposure in broth due to complete lack of growth. Among those that did (n = 19), the median daptomycin MIC was 0.38 µg/mL (mean 0.42 µg/mL; range 0.023-1.0 µg/mL). One isolate of C bovis and two isolates of C jeikeium yielded variable susceptibility to daptomycin; a subset of resistant colonies grew adjacent to the gradient diffusion strip. Upon isolation and further MIC testing, these colonies maintained high-level resistance. In addition, one isolate of C amycolatum exhibited high-level daptomycin resistance (MIC >256 µg/mL) prior to in vitro exposure. All isolates in the cohort were susceptible to vancomycin and telavancin, both before and after daptomycin exposure. Our findings suggest that multiple Corynebacterium species can rapidly develop high-level daptomycin resistance after a short period of exposure to this antimicrobial. This finding has important clinical implications, especially in the treatment of invasive infections or infections of indwelling medical devices.

Phenotypic Detection of Efflux Mechanism in Panaminoglycoside Resistant Acinetobacter baumannii from Egyptian Clinical Isolates

Background: Over the last several years, Acinetobacter has emerged as a leading cause of hospital-acquired infections. Aminoglycosides are frequently used in the treatment of invasive infections. Factors associated with the resistance to aminoglycosides include the reduction of drug uptake, modification of aminoglycosides, and aminoglycoside efflux. Objectives: The aim of our study was to phenotypically detect the presence of efflux mechanism using carbonyl cyanide 3-chlorophenylhydrazone (CCCP) in aminoglycoside resistant Acinetobacter baumannii strains isolated from different hospital wards. Methods: In total, 57 A. baumannii isolates were collected from two Egyptian hospitals. The antimicrobial susceptibility pattern was determined. The activity of the efflux system was evaluated using CCCP. Results: Among 57 A. baumannii isolates, most resistance was observed against tobramycin, amikacin, kanamycin, neomycin, and gentamicin. The minimum inhibitory concentrations (MIC) range of A. baumannii was between 2 and 1024 µg/mL based on the tested antibiotics. The phenotypic detection of efflux pumps displaying a reduction of at least two folds in the MICs of antibiotics after addition of the efflux pump inhibitor showed that 19.4% of the isolates became less resistant to kanamycin, 44% to tobramycin, and 46% to amikacin but lower rates were recorded against gentamicin (12.2%) and neomycin (9.4 %). Conclusions: Our study suggests that the efflux mechanism is getting widespread in clinical settings to play an important role in aminoglycoside resistance. Acinetobacter baumannii has the ability to gain resistance to different antibiotic classes through these active efflux pumps. Hence, the application of strict infection control measures together with novel approaches to eradicate those efflux transporters should be applied in hospital settings.

PEGylated Self-Assembled Nano-Bacitracin A: Probing the Antibacterial Mechanism and Real-Time Tracing of Target Delivery in Vivo.

Although nano-self-assemblies of hydrophobic-modified bacitracin A with poly(d,l-lactic- co-glycolic acid) (PLGA) (nano-BAPLGA) have demonstrated promising antibacterial activities, the application of nano-BAPLGA was severely compromised by low water solubility. In this study, a series of PEGylated PLGA copolymers were selected to conjugate with the N-terminus of bacitracin A to construct PEGylated self-assembled nano-BAs and to further develop nano-self-assemblies of bacitracin A with strong antibacterial potency and high solubility. Compared with nano-BAPLGA, all PEGylated nano-BAs, except nano-BA5k, exhibited strong antibacterial efficiency against both Gram-positive and Gram-negative bacteria by inducing loss of cytoplasmic membrane potential, membrane permeabilization, and leakage of calcein from artificial cell membranes. Studies elucidating the underlying mechanism of PEGylated nano-BAs against Gram-negative bacteria indicated that the strong hydrophobic and van der Waals interactions between PLGA and lipopolysaccharide (LPS) could bind, neutralize, and disassociate LPS, facilitating cellular uptake of the nanoparticles, which could destabilize the membrane, resulting in cell death. Moreover, PEGylated nano-BAs (nano-BA12k) with a longer PLGA block were expected to occupy a higher local density of BA mass on the surface and result in stronger hydrophobic and van der Waals interactions with LPS, which were responsible for the enhanced antibacterial activity against Gram-positive and emerging antibacterial activity against Gram-negative bacteria, respectively. In vivo imaging verified that PEGylated nano-BAs exhibited higher inflammatory tissue distribution and longer circulation time than nano-BAPLGA. Therefore, although PEGylation did not affect antibacterial activity, it is necessary for target delivery and resistance to clearance of the observed PEGylated nano-BAs. In vivo, nano-BA12k also showed the highest therapeutic index against infection burden in a mouse thigh infection model among the tested formulations, which showed good correlation with the in vitro results. In conclusion, nano-BA12k showed high efficacy in the treatment of invasive infections. This new approach of constructing nanoantibiotics by modification of commercially available antibiotics with PEGylated copolymers is safe, cost-effective, and environmentally friendly.

Combination therapy for carbapenem-resistant Gram-negative bacteria.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) represent an increasing hazard in healthcare settings. A central question concerning the treatment of invasive infections caused by CR-GNB involves the use of combination therapy. Potential advantages of combination therapy include improved efficacy due to synergy, while the disadvantages include adverse events and increased antibiotic use with a potential drive towards resistance. Several observational studies have examined whether combination therapy offers an advantage over colistin/polymyxin monotherapy. We highlight the inherent limitations of these studies related to their observational design and sample size to show why they do not at present provide an answer to the question of combination versus monotherapy. This distinction is important to guide clinical practice until solid evidence has been obtained and to enable the recruitment of patients into randomized controlled trials. A few randomized controlled trials examining specific combinations have recently been completed or are ongoing. Currently, however, there is no evidence-based support for most combination therapies against CR-GNB, including colistin/carbapenem combination therapy.

Is there really no benefit to combination therapy with colistin?

Evaluation of: Colistin and Rifampicin compared with colistin alone for the treatment of serious infections due to extensively drug-resistant Acinetobacter baumannii: a multicenter, randomized, clinical trial. Clin. Infect. Dis. 57(3), 349–358 (2013).Despite many theoretical and in vitro advantages, clinical data comparing combination therapy with colistin + rifampicin to colistin alone for infection due to extremely-drug resistant (XDR) Acinetobacter baumanni are scarce and limited by small numbers and/or low quality evidence. This article represents the first large, randomized, controlled, prospective study comparing colistin monotherapy and combination therapy. The reviewed article found no difference in all cause or infection related mortality, though there was an improved rate of microbiological clearance in the combination therapy arm. This study adds important new data to the literature and sets the stage for future studies that can be designed to overcome the limitations of this study, which are discussed in detail below. Based on this study, we cannot say definitively that combination therapy is not warranted for treatment of invasive infection due to A. baumannii, but the results do suggest that rifampicin is not an ideal agent to be combined with colistin.

Clinical management of infections caused by multidrug-resistant Enterobacteriaceae.

Enterobacteriaceae showing resistance to cephalosporins due to extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC enzymes, and those producing carbapenemases have spread worldwide during the last decades. Many of these isolates are also resistant to other first-line agents such as fluoroquinolones or aminoglycosides, leaving few available options for therapy. Thus, older drugs such as colistin and fosfomycin are being increasingly used. Infections caused by these bacteria are associated with increased morbidity and mortality compared with those caused by their susceptible counterparts. Most of the evidence supporting the present recommendations is from invitro data, animal studies, and observational studies. While carbapenems are considered the drugs of choice for ESBL and AmpC producers, recent data suggest that certain alternatives may be suitable for some types of infections. Combined therapy seems superior to monotherapy in the treatment of invasive infections caused by carbapenemase-producing Enterobacteriaceae. Optimization of dosage according to pharmacokinetics/pharmacodynamics data is important for the treatment of infections caused by isolates with borderline minimum inhibitory concentration due to low-level resistance mechanisms. The increasing frequency and the rapid spread of multidrug resistance among the Enterobacteriaceae is a true and complex public health problem.

Revisiting “Older” Antimicrobials in the Era of Multidrug Resistance

Infections due to multidrug-resistant (MDR) organisms continue to increase, and the antimicrobial pipeline remains unacceptably lean. Given this challenge, it is has become necessary to use older antimicrobials for treatment of MDR pathogens despite concerns regarding toxicity and the lack of clinical efficacy data. In some cases, older antimicrobials offer potential advantages compared with new agents, including lower cost and better in vitro activity. In this review, we focus on the pharmacology, in vitro activity, and clinical experience of older agents, including colistin, minocycline, trimethoprim-sulfamethoxazole, and fosfomycin. We also discuss some new antimicrobial agents that are used to treat MDR pathogens. As MDR pathogens continue to outpace the development of new antimicrobials, it will become imperative to develop strategies regarding the optimal use of older agents in terms of monotherapy versus combination therapy, dosing regimens, and treatment of invasive infections caused by these pathogens.

F-18 FDG PET in Infectious Diseases in Children

The aim is to report our observations regarding the role of F-18 FDG PET in children's infectious processes. A presentation is made of 3 neonatal infections unresponsive to treatment, 2 invasive infections in immunocompromised children, and 1 discitis in an immunocompetent child. PET or PET/CT was performed to address a specific question pertaining to the management of the diseases. Results were correlated with the clinical outcome. The impact on patient management is discussed. In 1 neonate, PET localized the infection in a bone which allowed surgical curettage. In another one, it localized the infection in recently renewed exogenous material and led to subsequent removal. It was negative in the third one, whose evolution was rapidly favorable. In the immunocompromised children, treatment of invasive infection was adapted according to the metabolic inflammatory activity of the disease. In a limping child with slight abnormalities on bone scintigraphy but major misleading involvement on MRI, PET/CT demonstrated hypermetabolism limited to a disc, thus avoiding further invasive procedures. Although not meant as a first choice examination, F-18 FDG PET should be considered in difficult cases of neonatal infection or in challenging diagnoses like discitis in the young child. It provides more accurate staging and treatment monitoring of the inflammatory process in invasive infections of immunocompromised children.