Therapies for multidrug resistant and extensively drug-resistant non-fermenting gram-negative bacteria causing nosocomial infections: a perilous journey toward ‘molecularly targeted’ therapy

Background Multidrug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to detect and phenotypically characterize carbapenem no- susceptible gram-negative bacilli at the Ethiopian Public Health Institute. Materials and methods A prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated for each sample in accordance with standard protocol. Antimicrobial susceptibility testing was conducted using Kirby-Bauer disk diffusion method. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant isolates were classified using a standardized definition established by the European Centre for Disease Prevention and Control and the United States Centers for Disease Prevention and Control. Gram-negative organisms with reduced susceptibility to carbapenem antibiotics were considered candidate carbapenemase producers and subjected to modified carbapenem inactivation and simplified carbapenem inactivation methods. Meropenem with EDTA was used to differentiate metallo-β-lactamase (MBL) from serine carbapenemase. Meropenem (MRP)/meropenem + phenylboronic acid (MBO) were used to differentiate Klebsiella pneumoniae carbapenemase (KPC) from other serine carbapenemase producing gram-negative organisms. Results A total of 1,337 clinical specimens were analyzed, of which 429 gram-negative bacterial isolates were recovered. Out of 429 isolates, 319, 74, and 36 were Enterobacterales, Acinetobacter species, and Pseudomonas aeruginosa respectively. In our study, the prevalence of multidrug-resistant, extensively drug-resistant, carbapenemase-producing, and carbapenem nonsusceptible gram-negative bacilli were 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 429 isolates, 66 demonstrated reduced susceptibility to the antibiotics meropenem and imipenem. These isolates were tested for carbapenemase production of which 34.8% (23/66) were carbapenemase producers. Out of 23 carbapenemase positive gram-negative bacteria, ten (10) and thirteen (13) were metallo-beta-lactamase and serine carbapenemase respectively. Three of 13 serine carbapenemase positive organisms were Klebsiella pneumoniae carbapenemase. Conclusion This study revealed an alarming level of antimicrobial resistance (AMR), with a high prevalence of multidrug-resistant (MDR) and extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among intensive care unit patients at the health facility level. These findings point to a scenario in which clinical management of infected patients becomes increasingly difficult and necessitates the use of “last-resort” antimicrobials likely exacerbating the magnitude of the global AMR crisis. This mandates robust AMR monitoring and an infection prevention and control program.

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Multidrug resistant, extensively drug resistant and pan drug resistant gram negative bacteria at a tertiary care centre in Bhubaneswar

International Journal of Community Medicine and Public Health ◽

10.18203/2394-6040.ijcmph20190170 ◽

2019 ◽

Vol 6 (2) ◽

pp. 567 ◽

Cited By ~ 4

Author(s):

Dipti Pattnaik ◽

Subhra Snigdha Panda ◽

Nipa Singh ◽

Smrutilata Sahoo ◽

Ipsa Mohapatra ◽

...

Keyword(s):

Tertiary Care ◽

Multidrug Resistant ◽

Diffusion Method ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Extensively Drug Resistant ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Esbl Producers

Background: Multidrug resistance has emerged as a challenge in health care settings. Again increasing prevalence of multidrug resistant (MDR), extensively drug resistant (XDR) and pan drug resistant (PDR) gram negative bacteria is making the condition more critical because of limited options of antibiotics, increasing morbidity, mortality and hospital stay of the patients. The present study is carried out with an aim to estimate the prevalence of MDR, XDR, PDR gram negative bacteria in a tertiary care hospital.Methods: Total of 912 gram negative bacterial isolates obtained from various samples of indoor patients in a tertiary care hospital, were studied over a period of six months. The bacteria were identified by conventional methods. Antibiotic sensitivity testing was done by Kirby Bauer disc diffusion method. Minimum inhibitory concentration (MIC) of antibiotics for the resistant isolates were detected by Vitek-2 automated method. MDR, XDR and PDR were determined according to the definitions suggested by European Centre for Disease Prevention and Control (ECDC), and Centers for Disease Control and Prevention (CDC). Prevalence of extended spectrum beta lactamase (ESBL) producers was estimated.Results: Out of 912 isolates, prevalence of MDR, XDR and PDR were 66.12%, 34.32% and 0.98% respectively. Prevalence of MDR and XDR were higher in ICUs than clinical wards (p<0.0001). Prevalence of ESBL producers was 48.4%.Conclusions: The study highlights increased prevalence of multidrug resistant and extensively drug resistant strains in our hospital. Stringent surveillance, proper implementation of hospital infection control practices and antimicrobial stewardship will help in limiting the emergence and spread of drug resistant strains.

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Detection and phenotypic characterization of carbapenem non susceptible gram-negative bacilli isolated from clinical specimens

10.1101/2021.08.17.456671 ◽

2021 ◽

Author(s):

Abera Abdeta ◽

Adane Bitew ◽

Surafel Fentaw ◽

Estifanos Tsige ◽

Dawit Assefa ◽

...

Keyword(s):

Public Health ◽

Prevention And Control ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Clinical Specimens ◽

Extensively Drug Resistant ◽

And Control ◽

Public Health Institute

Background Multi-drug resistant, extremely drug-resistant, pan-drug resistant, carbapenem-resistant, and carbapenemase-producing gram-negative bacteria are becoming more common in health care settings and are posing a growing threat to public health. Objective The study was aimed to determine the magnitude of multi-drug resistant, extremely drug-resistant, carbapenem non-susceptible, and carbapenemase-producing gram-negative bacilli at Ethiopian Public Health Institute. Materials and methods Prospective cross-sectional study was conducted from June 30, 2019, to May 30, 2020, at the national reference laboratory of the Ethiopian Public Health Institute. Clinical samples were collected, inoculated, and incubated in accordance to standard protocol for each sample. Antimicrobial susceptibility testing was done using Kirby Bauer disk diffusion. Identification was done using the traditional biochemical method. Multidrug-resistant and extensively drug-resistant were classified using a standardized definition established by European Centers for Disease prevention and control and the United States Centers for Disease prevention and control experts. Carbapenemase production was confirmed by modified carbapenem inactivation and a simplified carbapenem inactivation method. Meropenem with EDTA was used to differentiate serine carbapenemase and Metallo β-lactamase. Results A total of 1337 clinical specimens were analyzed, of which 429-gram negative bacilli isolates were recovered. Out of 429 isolates 319, 74, and 36 were Enterobacterales, Acinetobacter species, and P. aeruginosa respectively. In our study, the prevalence of Multidrug-resistant, extensively drug-resistant, Carbapenemase-producing, and carbapenem non-susceptible Gram-negative bacilli were, 45.2%, 7.7%, 5.4%, and 15.4% respectively. Out of 66 isolates screened for Carbapenemase, 34.8% (23/66) were Carbapenemase enzyme producers. Ten out of twenty-three Carbapenemase-positive organisms were Metallo-beta-lactamase producers. Thirteen out of twenty-three isolates were serine carbapenemase producers. Three out of 13 serine Carbapenemase positive organisms were Klebsiella pneumoniae Carbapenemase. Conclusion The finding from this study revealed a high prevalence of Multidrug-resistant, extremely drug-resistant, carbapenemase-producing gram-negative bacteria, particularly among Intensive care unit patients at the health facility level, this necessitates a robust laboratory-based antimicrobial resistance monitoring and infection prevention and control program.

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Intrathecal or intraventricular antimicrobial therapy for post-neurosurgical intracranial infection due to multidrug-resistant and extensively drug-resistant Gram-negative bacteria: A systematic review and meta-analysis

International Journal of Antimicrobial Agents ◽

10.1016/j.ijantimicag.2019.08.002 ◽

2019 ◽

Vol 54 (5) ◽

pp. 556-561 ◽

Cited By ~ 2

Author(s):

Yangmin Hu ◽

Wei He ◽

Difei Yao ◽

Haibin Dai

Keyword(s):

Systematic Review ◽

Antimicrobial Therapy ◽

Meta Analysis ◽

Multidrug Resistant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Intracranial Infection ◽

Extensively Drug Resistant

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Extensively drug-resistant and pandrug-resistant Gram-negative bacteria in a tertiary-care hospital in Eastern India: A 4-year retrospective study

Journal of Global Antimicrobial Resistance ◽

10.1016/j.jgar.2018.08.010 ◽

2018 ◽

Vol 15 ◽

pp. 246-249 ◽

Cited By ~ 6

Author(s):

Debi Prasad Mohapatra ◽

Nagen Kumar Debata ◽

Santosh Kumar Singh

Keyword(s):

Retrospective Study ◽

Tertiary Care Hospital ◽

Tertiary Care ◽

Gram Negative Bacteria ◽

Care Hospital ◽

Drug Resistant ◽

Eastern India ◽

Gram Negative ◽

Extensively Drug Resistant

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Intravenous fosfomycin in patients with liver disease for extensively drug-resistant Gram-negative bacteria

Journal of Infection ◽

10.1016/j.jinf.2018.07.013 ◽

2018 ◽

Vol 77 (5) ◽

pp. 448-454 ◽

Cited By ~ 3

Author(s):

Athina Pyrpasopoulou ◽

Georgia Pitsava ◽

Elias Iosifidis ◽

George Imvrios ◽

Eleni Massa ◽

...

Keyword(s):

Liver Disease ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Gram Negative ◽

Extensively Drug Resistant

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Carbapenemases: Transforming Acinetobacter baumannii into a Yet More Dangerous Menace

Biomolecules ◽

10.3390/biom10050720 ◽

2020 ◽

Vol 10 (5) ◽

pp. 720 ◽

Cited By ~ 10

Author(s):

Maria Soledad Ramirez ◽

Robert A. Bonomo ◽

Marcelo E. Tolmasky

Keyword(s):

Acinetobacter Baumannii ◽

Nosocomial Infections ◽

Acquired Resistance ◽

Clinical Manifestations ◽

High Capacity ◽

Bloodstream Infections ◽

Multidrug Resistant ◽

Drug Resistant ◽

Wound Infections ◽

Extensively Drug Resistant

Acinetobacter baumannii is a common cause of serious nosocomial infections. Although community-acquired infections are observed, the vast majority occur in people with preexisting comorbidities. A. baumannii emerged as a problematic pathogen in the 1980s when an increase in virulence, difficulty in treatment due to drug resistance, and opportunities for infection turned it into one of the most important threats to human health. Some of the clinical manifestations of A. baumannii nosocomial infection are pneumonia; bloodstream infections; lower respiratory tract, urinary tract, and wound infections; burn infections; skin and soft tissue infections (including necrotizing fasciitis); meningitis; osteomyelitis; and endocarditis. A. baumannii has an extraordinary genetic plasticity that results in a high capacity to acquire antimicrobial resistance traits. In particular, acquisition of resistance to carbapenems, which are among the antimicrobials of last resort for treatment of multidrug infections, is increasing among A. baumannii strains compounding the problem of nosocomial infections caused by this pathogen. It is not uncommon to find multidrug-resistant (MDR, resistance to at least three classes of antimicrobials), extensively drug-resistant (XDR, MDR plus resistance to carbapenems), and pan-drug-resistant (PDR, XDR plus resistance to polymyxins) nosocomial isolates that are hard to treat with the currently available drugs. In this article we review the acquired resistance to carbapenems by A. baumannii. We describe the enzymes within the OXA, NDM, VIM, IMP, and KPC groups of carbapenemases and the coding genes found in A. baumannii clinical isolates.

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Colonization and Infection With Extensively Drug Resistant Gram-Negative Bacteria in Liver Transplant Recipients

Transplantation Proceedings ◽

10.1016/j.transproceed.2019.01.076 ◽

2019 ◽

Vol 51 (2) ◽

pp. 454-456 ◽

Cited By ~ 3

Author(s):

E. Massa ◽

E. Michailidou ◽

D. Agapakis ◽

S. Papadopoulos ◽

T. Tholioti ◽

...

Keyword(s):

Liver Transplant ◽

Gram Negative Bacteria ◽

Drug Resistant ◽

Transplant Recipients ◽

Gram Negative ◽

Extensively Drug Resistant ◽

Liver Transplant Recipients

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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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