Bacteria causing ventriculoperitoneal shunt infections in a Kenyan population

OBJECT Ventriculoperitoneal shunt (VPS) infections are a major cause of morbidity and mortality in patients with hydrocephalus. Most data about these infections come from the Western literature. Few data about infecting organisms in Africa are available, yet knowledge of these organisms is important for the prevention and treatment of infectious complications. The purpose of this study was to determine the organisms cultured from infected shunts in a rural Kenyan hospital. METHODS The authors conducted a retrospective study of patients with VPS infections recorded in the neurosurgical database of BethanyKids at Kijabe Hospital between September 2010 and July 2012. RESULTS Among 53 VPS infections confirmed by culture, 68% occurred in patients who were younger than 6 months. Seventy-nine percent of the infections occurred within 2 months after shunt insertion. Only 51% of infections were caused by Staphylococcus species (Staphylococcus aureus 25%, other Staphylococcus species 26%), whereas 40% were caused by gram-negative bacteria. All S. aureus infections and 79% of other Staphylococcus infections were sensitive to cefazolin, but only 1 of 21 gram-negative bacteria was sensitive to it. The majority of gram-negative bacterial infections were multidrug resistant, but 17 of the 20 gram-negative bacteria were sensitive to meropenem. Gram-negative bacterial infections were associated with worse outcomes. CONCLUSIONS The high proportion of gram-negative infections differs from data in the Western literature, in which Staphylococcus epidermidis is by far the most common organism. Once a patient is diagnosed with a VPS infection in Kenya, immediate treatment is recommended to cover both gram-positive and gram-negative bacterial infections. Data from other Sub-Saharan countries are needed to determine if those countries have the same increased frequency of gram-negative infections.

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Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC

mBio ◽

10.1128/mbio.00674-17 ◽

2017 ◽

Vol 8 (4) ◽

Cited By ~ 13

Author(s):

Nadine Lemaître ◽

Xiaofei Liang ◽

Javaria Najeeb ◽

Chul-Jin Lee ◽

Marie Titecat ◽

...

Keyword(s):

Bacterial Infections ◽

Biosynthetic Pathway ◽

Lipid A ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Bubonic Plague ◽

Gram Negative ◽

New Class

ABSTRACT The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram-negative bacterial infections. However, experimental proof of this concept is lacking. Here, we describe our discovery and characterization of a biphenylacetylene-based inhibitor of LpxC, an essential enzyme in the biosynthesis of the lipid A component of the outer membrane of Gram-negative bacteria. The compound LPC-069 has no known adverse effects in mice and is effective in vitro against a broad panel of Gram-negative clinical isolates, including several multiresistant and extremely drug-resistant strains involved in nosocomial infections. Furthermore, LPC-069 is curative in a murine model of one of the most severe human diseases, bubonic plague, which is caused by the Gram-negative bacterium Yersinia pestis. Our results demonstrate the safety and efficacy of LpxC inhibitors as a new class of antibiotic against fatal infections caused by extremely virulent pathogens. The present findings also highlight the potential of LpxC inhibitors for clinical development as therapeutics for infections caused by multidrug-resistant bacteria. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains. IMPORTANCE The rapid spread of antimicrobial resistance among Gram-negative bacilli highlights the urgent need for new antibiotics. Here, we describe a new class of antibiotics lacking cross-resistance with conventional antibiotics. The compounds inhibit LpxC, a key enzyme in the lipid A biosynthetic pathway in Gram-negative bacteria, and are active in vitro against a broad panel of clinical isolates of Gram-negative bacilli involved in nosocomial and community infections. The present study also constitutes the first demonstration of the curative treatment of bubonic plague by a novel, broad-spectrum antibiotic targeting LpxC. Hence, the data highlight the therapeutic potential of LpxC inhibitors against a wide variety of Gram-negative bacterial infections, including the most severe ones caused by Y. pestis and by multidrug-resistant and extensively drug-resistant carbapenemase-producing strains.

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Bacteriocins, Antimicrobial Peptides from Bacterial Origin: Overview of Their Biology and Their Impact against Multidrug-Resistant Bacteria

Microorganisms ◽

10.3390/microorganisms8050639 ◽

2020 ◽

Vol 8 (5) ◽

pp. 639 ◽

Cited By ~ 13

Author(s):

Alexis Simons ◽

Kamel Alhanout ◽

Raphaël E. Duval

Keyword(s):

Antimicrobial Resistance ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Multidrug Resistant ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Multidrug Resistant Bacteria ◽

Gram Negative ◽

Gram Positive Bacteria ◽

Further Development

Currently, the emergence and ongoing dissemination of antimicrobial resistance among bacteria are critical health and economic issue, leading to increased rates of morbidity and mortality related to bacterial infections. Research and development for new antimicrobial agents is currently needed to overcome this problem. Among the different approaches studied, bacteriocins seem to be a promising possibility. These molecules are peptides naturally synthesized by ribosomes, produced by both Gram-positive bacteria (GPB) and Gram-negative bacteria (GNB), which will allow these bacteriocin producers to survive in highly competitive polymicrobial environment. Bacteriocins exhibit antimicrobial activity with variable spectrum depending on the peptide, which may target several bacteria. Already used in some areas such as agro-food, bacteriocins may be considered as interesting candidates for further development as antimicrobial agents used in health contexts, particularly considering the issue of antimicrobial resistance. The aim of this review is to present an updated global report on the biology of bacteriocins produced by GPB and GNB, as well as their antibacterial activity against relevant bacterial pathogens, and especially against multidrug-resistant bacteria.

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Correlated Transcriptional Responses Provide Insights into the Synergy Mechanisms of the Furazolidone, Vancomycin, and Sodium Deoxycholate Triple Combination in Escherichia coli

mSphere ◽

10.1128/msphere.00627-21 ◽

2021 ◽

Author(s):

Catrina Olivera ◽

Murray P. Cox ◽

Gareth J. Rowlands ◽

Jasna Rakonjac

Keyword(s):

Escherichia Coli ◽

Bacterial Infections ◽

Sodium Deoxycholate ◽

Multidrug Resistant ◽

Alternative Strategy ◽

Gram Negative Bacteria ◽

Triple Combination ◽

Transcriptional Responses ◽

Promising Alternative ◽

Gram Negative

Synergistic antibiotic combinations are a promising alternative strategy for developing effective therapies for multidrug-resistant bacterial infections. The synergistic combination of the existing antibiotics nitrofurans and vancomycin with sodium deoxycholate shows promise in inhibiting and killing multidrug-resistant Gram-negative bacteria.

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Diversity and Proliferation of Metallo-β-Lactamases: a Clarion Call for Clinically Effective Metallo-β-Lactamase Inhibitors

Applied and Environmental Microbiology ◽

10.1128/aem.00698-18 ◽

2018 ◽

Vol 84 (18) ◽

Cited By ~ 30

Author(s):

Anou M. Somboro ◽

John Osei Sekyere ◽

Daniel G. Amoako ◽

Sabiha Y. Essack ◽

Linda A. Bester

Keyword(s):

Bacterial Infections ◽

Bacterial Resistance ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Structural Variations ◽

Gram Negative ◽

Clinical Phase ◽

Class B ◽

Life Threatening ◽

Made In

ABSTRACTThe worldwide proliferation of life-threatening metallo-β-lactamase (MBL)-producing Gram-negative bacteria is a serious concern to public health. MBLs are compromising the therapeutic efficacies of β-lactams, particularly carbapenems, which are last-resort antibiotics indicated for various multidrug-resistant bacterial infections. Inhibition of enzymes mediating antibiotic resistance in bacteria is one of the major promising means for overcoming bacterial resistance. Compounds having potential MBL-inhibitory activity have been reported, but none are currently under clinical trials. The need for developing safe and efficient MBL inhibitors (MBLIs) is obvious, particularly with the continuous spread of MBLs worldwide. In this review, the emergence and escalation of MBLs in Gram-negative bacteria are discussed. The relationships between different class B β-lactamases identified up to 2017 are represented by a phylogenetic tree and summarized. In addition, approved and/or clinical-phase serine β-lactamase inhibitors are recapitulated to reflect the successful advances made in developing class A β-lactamase inhibitors. Reported MBLIs, their inhibitory properties, and their purported modes of inhibition are delineated. Insights into structural variations of MBLs and the challenges involved in developing potent MBLIs are also elucidated and discussed. Currently, natural products and MBL-resistant β-lactam analogues are the most promising agents that can become clinically efficient MBLIs. A deeper comprehension of the mechanisms of action and activity spectra of the various MBLs and their inhibitors will serve as a bedrock for further investigations that can result in clinically useful MBLIs to curb this global menace.

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New β-Lactamase Inhibitors: a Therapeutic Renaissance in an MDR World

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00826-13 ◽

2013 ◽

Vol 58 (4) ◽

pp. 1835-1846 ◽

Cited By ~ 178

Author(s):

Sarah M. Drawz ◽

Krisztina M. Papp-Wallace ◽

Robert A. Bonomo

Keyword(s):

Bacterial Infections ◽

Clinical Problem ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Therapeutic Approaches ◽

Preclinical Development ◽

Gram Negative ◽

The Past ◽

Wide Range ◽

Dosing Regimens

ABSTRACTAs the incidence of Gram-negative bacterial infections for which few effective treatments remain increases, so does the contribution of drug-hydrolyzing β-lactamase enzymes to this serious clinical problem. This review highlights recent advances in β-lactamase inhibitors and focuses on agents with novel mechanisms of action against a wide range of enzymes. To this end, we review the β-lactamase inhibitors currently in clinical trials, select agents still in preclinical development, and older therapeutic approaches that are being revisited. Particular emphasis is placed on the activity of compounds at the forefront of the developmental pipeline, including the diazabicyclooctane inhibitors (avibactam and MK-7655) and the boronate RPX7009. With its novel reversible mechanism, avibactam stands to be the first new β-lactamase inhibitor brought into clinical use in the past 2 decades. Our discussion includes the importance of selecting the appropriate partner β-lactam and dosing regimens for these promising agents. This “renaissance” of β-lactamase inhibitors offers new hope in a world plagued by multidrug-resistant (MDR) Gram-negative bacteria.

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Ceftazidime/Avibactam and Ceftolozane/Tazobactam for Multidrug-Resistant Gram Negatives in Patients with Hematological Malignancies: Current Experiences

Antibiotics ◽

10.3390/antibiotics9020058 ◽

2020 ◽

Vol 9 (2) ◽

pp. 58 ◽

Cited By ~ 2

Author(s):

Marianna Criscuolo ◽

Enrico Maria Trecarichi

Keyword(s):

Hematological Malignancies ◽

Real Life ◽

Bloodstream Infections ◽

Multidrug Resistant ◽

Infectious Complications ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Life Threatening ◽

Severe Infections ◽

Tract Infections

Patients suffering from hematological malignancies are at high risk for severe infections, including in particular bloodstream infections, which represent one of the most frequent life-threatening complications for these patients, with reported mortality rates reaching 40%. Furthermore, a worrisome increase in antimicrobial resistance of Gram-negative bacteria (e.g., cephalosporin- and/or carbapenem-resistant Enterobacteriaceae and multidrug-resistant (MDR) Pseudomonas aeruginosa) involved in severe infectious complications among patients with hematological malignancies has been reported during the last years. The two novel combination of cephalosporins and β-lactamase inhibitors, ceftolozane/tazobactam and ceftazidime/avibactam, were recently approved for treatment of complicated intra-abdominal and urinary tract infections and nosocomial pneumonia and display activity against several MDR Gram-negative strains. Although not specifically approved for neutropenic and/or cancer patients, these drugs are used in this setting due to increasing rates of infections caused by MDR Gram-negative bacteria. The aim of this review is to describe the actual evidence from scientific literature about the “real-life” use of these two novel drugs in patients with hematological malignancies and infections caused by MDR Gram-negative bacteria.

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Vaccines for multidrug resistant Gram negative bacteria: lessons from the past for guiding future success

FEMS Microbiology Reviews ◽

10.1093/femsre/fuaa054 ◽

2020 ◽

Author(s):

Mireia López-Siles ◽

Andrés Corral-Lugo ◽

Michael J McConnell

Keyword(s):

Bacterial Infections ◽

Vaccine Development ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Global Public Health ◽

Future Directions ◽

Gram Negative ◽

The Past ◽

Successful Vaccine ◽

Future Success

Abstract Antimicrobial resistance is a major threat to global public health. Vaccination is an effective approach for preventing bacterial infections, however it has not been successfully applied to infections caused by some of the most problematic multidrug resistant pathogens. In this review, the potential for vaccines to contribute to reducing the burden of disease of infections caused by multidrug resistant Gram negative bacteria is presented. Technical, logistical and societal hurdles that have limited successful vaccine development for these infections in the past are identified, and recent advances that can contribute to overcoming these challenges are assessed. A synthesis of vaccine technologies that have been employed in the development of vaccines for key multidrug resistant Gram negative bacteria is included, and emerging technologies that may contribute to future successes are discussed. Finally, a comprehensive review of vaccine development efforts over the last 40 years for three of the most worrisome multidrug resistant Gram negative pathogens, Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa is presented, with a focus on recent and ongoing studies. Finally, future directions for the vaccine development field are highlighted.

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Increased Azithromycin Susceptibility of Multidrug-Resistant Gram-Negative Bacteria on RPMI-1640 Agar Assessed by Disk Diffusion Testing

Antibiotics ◽

10.3390/antibiotics9050218 ◽

2020 ◽

Vol 9 (5) ◽

pp. 218 ◽

Cited By ~ 2

Author(s):

Milton Meerwein ◽

Andrea Tarnutzer ◽

Michelle Böni ◽

Françoise Van Bambeke ◽

Michael Hombach ◽

...

Keyword(s):

Bacterial Infections ◽

Low Complexity ◽

Multidrug Resistant ◽

Disk Diffusion ◽

Gram Negative Bacteria ◽

Broth Microdilution ◽

Gram Negative ◽

Minimal Inhibitory Concentrations ◽

Mueller Hinton

Increasing antibiotic resistances and a lack of new antibiotics render the treatment of Gram-negative bacterial infections increasingly difficult. Therefore, additional approaches are being investigated. Macrolides are not routinely used against Gram-negative bacteria due to lack of evidence of in vitro effectiveness. However, it has been shown that Pseudomonas spp. are susceptible to macrolides in liquid RPMI-1640 and clinical data suggest improvement in patients’ outcomes. So far, these findings have been hardly applicable to the clinical setting due to lack of routine low-complexity antimicrobial susceptibility testing (AST) for macrolides. We therefore optimized and compared broth microdilution and disk diffusion AST. Multidrug-resistant Gram-negative bacteria (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa) were tested for azithromycin susceptibility by disk diffusion and broth microdilution in Mueller–Hinton and RPMI-1640 media. Azithromycin susceptibility of Enterobacteriaceae and a subgroup of P. aeruginosa increased significantly on RPMI-1640 agar compared to Mueller–Hinton agar. Further, a significant correlation (Kendall, τ, p) of zone diameters and minimal inhibitory concentrations (MICs) was found on RPMI-1640 agar for E. coli (−0.4279, 0.0051), E. cloacae (−0.3783, 0.0237) and P. aeruginosa (−0.6477, <0.0001). Performing routine disk diffusion AST on RPMI-1640 agar may lead to the identification of additional therapeutic possibilities for multidrug-resistant bacterial infections in the routine clinical diagnostic setting.

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Current Status of Endolysin-Based Treatments against Gram-Negative Bacteria

Antibiotics ◽

10.3390/antibiotics10101143 ◽

2021 ◽

Vol 10 (10) ◽

pp. 1143

Author(s):

Marco Túlio Pardini Gontijo ◽

Genesy Perez Jorge ◽

Marcelo Brocchi

Keyword(s):

Outer Membrane ◽

Bacterial Infections ◽

Recombinant Protein Expression ◽

Multidrug Resistant ◽

Health Concern ◽

Current Status ◽

Resistant Bacteria ◽

Gram Negative Bacteria ◽

Membrane Permeation ◽

Gram Negative

The prevalence of multidrug-resistant Gram-negative bacteria is a public health concern. Bacteriophages and bacteriophage-derived lytic enzymes have been studied in response to the emergence of multidrug-resistant bacteria. The availability of tRNAs and endolysin toxicity during recombinant protein expression is circumvented by codon optimization and lower expression levels using inducible pET-type plasmids and controlled cultivation conditions, respectively. The use of polyhistidine tags facilitates endolysin purification and alters antimicrobial activity. Outer membrane permeabilizers, such as organic acids, act synergistically with endolysins, but some endolysins permeate the outer membrane of Gram-negative bacteria per se. However, the outer membrane permeation mechanisms of endolysins remain unclear. Other strategies, such as the co-administration of endolysins with polymyxins, silver nanoparticles, and liposomes confer additional outer membrane permeation. Engineered endolysins comprising domains for outer membrane permeation is also a strategy used to overcome the current challenges on the control of multidrug-resistant Gram-negative bacteria. Metagenomics is a new strategy for screening endolysins with interesting antimicrobial properties from uncultured phage genomes. Here, we review the current state of the art on the heterologous expression of endolysin, showing the potential of bacteriophage endolysins in controlling bacterial infections.

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POLYMIXIN IN ONCOLOGY CLINICAL PRACTICE

Siberian Journal of Oncology ◽

10.21294/1814-4861-2018-17-3-88-93 ◽

2018 ◽

Vol 17 (3) ◽

pp. 88-93 ◽

Cited By ~ 1

Author(s):

N. V. Dmitrieva ◽

I. N. Petukhova ◽

Z. V. Grigorievskaya ◽

N. S. Bagirova ◽

I. V. Тereshchenko ◽

...

Keyword(s):

Polymyxin B ◽

Multidrug Resistant ◽

Infectious Complications ◽

Cochrane Library ◽

Clinical Response Rate ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Hospital Acquired Pneumonia ◽

Hospital Acquired

The purpose of the study was to present data on polymixin-based antibiotics with activity against infections caused by multidrug- resistant Gram-negative bacteria, such as Acinetobacter baumannii, Klebsiella pneumoniae, and Pseudomonas aeruginosa.Material and methods. The review includes data from clinical as well as in vitro studies for the period 1998–2017. The search for relevant sources was carried out in the Medline, Cochrane Library, Elibrary and other databases.Results. The analysis of the data showed the presence of synergism and additive activity of polymyxin in combination with carbapenems, rifampicin and azithromycin. However, experimental data showed no direct positive correlation between combination of polymyxim and azithromycin/ rifampicin. In clinical studies, in hospital-acquired pneumonia, including ventilator-associated pneumonia, the clinical response rate of polymyxin B combined with other antibiotics ranged from 38 % to 88 %. High nephro-and neurotoxicity of polymyxin observed in previous studies can be explained by a lack of understanding of its toxicodynamics or the use of an incorrect dose.Conclusion. Polymyxin B in combination with other antibiotics is a promising treatment against infectious complications caused by multidrug resistant Gram-negative bacteria.

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