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Jakubu V, Vrbova I, Bitar I, Cechova M, Malisova L, Zemlickova H. Evolution of mutations in the ftsI gene leading to amino acid substitutions in PBP3 in Haemophilus influenzae strains under the selective pressure of ampicillin and cefuroxime. Int J Med Microbiol 2024; 316:151626. [PMID: 38954914 DOI: 10.1016/j.ijmm.2024.151626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2023] [Revised: 04/25/2024] [Accepted: 06/16/2024] [Indexed: 07/04/2024] Open
Abstract
BACKGROUND Aminopenicillins are recommended agents for non-invasive Haemophilus influenzae infections. One of the mechanisms of resistance to β-lactams is the alteration of the transpeptidase region of penicillin binding protein 3 (PBP3) which is caused by mutations in the ftsI gene. It was shown that exposure to beta-lactams has a stimulating effect on increase of prevalence of H. influenzae strains with the non-enzymatic mechanism of resistance. OBJECTIVES The aim of our study was to compare the mutational potential of ampicillin and cefuroxime in H. influenzae strains, determination of minimum inhibitory concentration and the evolution of mutations over time, focusing on amino acid substitutions in PBP3. METHODS 30 days of serial passaging of strains in liquid broth containing increasing concentrations of ampicillin or cefuroxime was followed by whole-genome sequencing. RESULTS On average, cefuroxime increased the minimum inhibitory concentration more than ampicillin. The minimum inhibitory concentration was increased by a maximum of 32 fold. Substitutions in the PBP3 started to appear after 15 days of passaging. In PBP3, cefuroxime caused different substitutions than ampicillin. CONCLUSIONS Our experiment observed differences in mutation selection by ampicillin and cefuroxime. Selection pressure of antibiotics in vitro generated substitutions that do not occur in clinical strains in the Czech Republic.
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Affiliation(s)
- Vladislav Jakubu
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, Srobarova 49/48, 100 00 Prague 10, Prague, Czech Republic; Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, Ruska 87, 100 00 Prague 10, Prague, Czech Republic
| | - Iveta Vrbova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, Srobarova 49/48, 100 00 Prague 10, Prague, Czech Republic
| | - Ibrahim Bitar
- Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Alej Svobody 1237/65, 301 00, Plzen, Czech Republic
| | - Marketa Cechova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, Srobarova 49/48, 100 00 Prague 10, Prague, Czech Republic
| | - Lucia Malisova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, Srobarova 49/48, 100 00 Prague 10, Prague, Czech Republic; Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, Ruska 87, 100 00 Prague 10, Prague, Czech Republic
| | - Helena Zemlickova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, Srobarova 49/48, 100 00 Prague 10, Prague, Czech Republic; Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, Ruska 87, 100 00 Prague 10, Prague, Czech Republic.
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Baciu AP, Baciu C, Baciu G, Gurau G. The burden of antibiotic resistance of the main microorganisms causing infections in humans - review of the literature. J Med Life 2024; 17:246-260. [PMID: 39044924 PMCID: PMC11262613 DOI: 10.25122/jml-2023-0404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Accepted: 02/21/2024] [Indexed: 07/25/2024] Open
Abstract
One of the biggest threats to human well-being and public health is antibiotic resistance. If allowed to spread unchecked, it might become a major health risk and trigger another pandemic. This proves the need to develop antibiotic resistance-related global health solutions that take into consideration microdata from various global locations. Establishing positive social norms, guiding individual and group behavioral habits that support global human health, and ultimately raising public awareness of the need for such action could all have a positive impact. Antibiotic resistance is not just a growing clinical concern but also complicates therapy, making adherence to current guidelines for managing antibiotic resistance extremely difficult. Numerous genetic components have been connected to the development of resistance; some of these components have intricate paths of transfer between microorganisms. Beyond this, the subject of antibiotic resistance is becoming increasingly significant in medical microbiology as new mechanisms underpinning its development are identified. In addition to genetic factors, behaviors such as misdiagnosis, exposure to broad-spectrum antibiotics, and delayed diagnosis contribute to the development of resistance. However, advancements in bioinformatics and DNA sequencing technology have completely transformed the diagnostic sector, enabling real-time identification of the components and causes of antibiotic resistance. This information is crucial for developing effective control and prevention strategies to counter the threat.
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Key Words
- AOM, acute otitis media
- CDC, Centers for Disease Control and Prevention
- CRE, carbapenem-resistant Enterobacterales
- ESBL, extended-spectrum beta-lactamase
- Hib, Haemophilus influenzae type b
- LVRE, linezolid/vancomycin -resistant enterococci
- MBC, minimum bactericidal concentration
- MBL, metallo-beta-lactamases
- MDR, multidrug-resistant
- MIC, minimum inhibitor concentration
- MRSA, methicillin-resistant Staphylococcus aureus
- PBP, penicillin-binding protein
- SCCmec staphylococcal chromosomal cassette mec
- VRE, vancomycin-resistant enterococci
- XDR, extensively drug-resistant
- antibiotic resistance
- antibiotics
- beta-lactamase
- cIAI, complicated intra-abdominal infection
- cUTI, complicated urinary tract infection
- carbapenems
- methicillin-resistant Staphylococcus aureus
- vancomycin
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Affiliation(s)
| | - Carmen Baciu
- MedLife Hyperclinic Nicolae Balcescu, Galati, Romania
| | - Ginel Baciu
- Sf. Ioan Emergency Clinical Hospital for Children, Galati, Romania
- Faculty of Medicine and Pharmacy, Dunarea de Jos University, Galati, Romania
| | - Gabriela Gurau
- Sf. Ioan Emergency Clinical Hospital for Children, Galati, Romania
- Faculty of Medicine and Pharmacy, Dunarea de Jos University, Galati, Romania
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Jakubu V, Malisova L, Musilek M, Pomorska K, Zemlickova H. Characterization of Haemophilus influenzae Strains with Non-Enzymatic Resistance to β-Lactam Antibiotics Caused by Mutations in the PBP3 Gene in the Czech Republic in 2010-2018. Life (Basel) 2021; 11:life11111260. [PMID: 34833138 PMCID: PMC8624647 DOI: 10.3390/life11111260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 11/11/2021] [Accepted: 11/16/2021] [Indexed: 01/20/2023] Open
Abstract
The surveillance data on antibiotic resistance of Haemophilus influenzae have shown that strains with non-enzymatic resistance to β-lactam antibiotics have been on the rise in the Czech Republic over the last decade. This type of resistance is more difficult to detect than β-lactamase production. Analysis of 228 H. influenzae strains revealed that isolates with non-enzymatic resistance to β-lactams due to mutations in the ftsI gene could be reliably demonstrated by single run testing of susceptibility to amoxicillin/clavulanic acid (sensitivity of detection is 84.6%), cefuroxime (92.6%), ampicillin and penicillin (both 95.7%). Thirty-seven different amino acid substitution combinations were detected in the PBP3 protein at 23 positions (V329I, D350N, S357N, A368T, M377I, S385T, A388V, L389F, P393L, A437S, I449V, G490E, I491V, R501L, A502S, A502T, A502V, V511A, R517H, I519L, N526K, A530S, and T532S). The most common combination (35%) of amino acid substitutions was the combination D350N, M377I, A502V, N526K. Epidemiological typing does not indicate a clonal spread of a particular MLST type. Altogether there has been detected 74 STs. The most prevalent ST 1034 was associated mainly with a combination D350N, M377I, A502V, N526K. Clonal analysis revealed six clonal complexes (CCs) with the founder found, eight CCs without founder and 33 singletons.
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Affiliation(s)
- Vladislav Jakubu
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, 10000 Prague, Czech Republic; (V.J.); (L.M.); (K.P.)
- Department of Clinical Microbiology, Faculty of Medicine and University Hospital, Charles University, 53002 Hradec Kralove, Czech Republic
- Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, 10000 Prague, Czech Republic
| | - Lucia Malisova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, 10000 Prague, Czech Republic; (V.J.); (L.M.); (K.P.)
- Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, 10000 Prague, Czech Republic
| | - Martin Musilek
- National Reference Laboratory for Meningococcal Infections, Centre for Epidemiology and Microbiology, National Institute of Public Health, 10000 Prague, Czech Republic;
| | - Katarina Pomorska
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, 10000 Prague, Czech Republic; (V.J.); (L.M.); (K.P.)
| | - Helena Zemlickova
- National Reference Laboratory for Antibiotics, Centre for Epidemiology and Microbiology, National Institute of Public Health, 10000 Prague, Czech Republic; (V.J.); (L.M.); (K.P.)
- Department of Clinical Microbiology, Faculty of Medicine and University Hospital, Charles University, 53002 Hradec Kralove, Czech Republic
- Department of Microbiology, 3rd Faculty of Medicine, Kralovske Vinohrady University Hospital and National Institute of Public Health, Charles University, 10000 Prague, Czech Republic
- Correspondence: ; Tel.: +420-267-082-202
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da Silva PB, Araújo VHS, Fonseca-Santos B, Solcia MC, Ribeiro CM, da Silva IC, Alves RC, Pironi AM, Silva ACL, Victorelli FD, Fernandes MA, Ferreira PS, da Silva GH, Pavan FR, Chorilli M. Highlights Regarding the Use of Metallic Nanoparticles against Pathogens Considered a Priority by the World Health Organization. Curr Med Chem 2021; 28:1906-1956. [PMID: 32400324 DOI: 10.2174/0929867327666200513080719] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 02/11/2020] [Accepted: 03/20/2020] [Indexed: 11/22/2022]
Abstract
The indiscriminate use of antibiotics has facilitated the growing resistance of bacteria, and this has become a serious public health problem worldwide. Several microorganisms are still resistant to multiple antibiotics and are particularly dangerous in the hospital and nursing home environment, and to patients whose care requires devices, such as ventilators and intravenous catheters. A list of twelve pathogenic genera, which especially included bacteria that were not affected by different antibiotics, was released by the World Health Organization (WHO) in 2017, and the research and development of new antibiotics against these genera has been considered a priority. The nanotechnology is a tool that offers an effective platform for altering the physicalchemical properties of different materials, thereby enabling the development of several biomedical applications. Owing to their large surface area and high reactivity, metallic particles on the nanometric scale have remarkable physical, chemical, and biological properties. Nanoparticles with sizes between 1 and 100 nm have several applications, mainly as new antimicrobial agents for the control of microorganisms. In the present review, more than 200 reports of various metallic nanoparticles, especially those containing copper, gold, platinum, silver, titanium, and zinc were analyzed with regard to their anti-bacterial activity. However, of these 200 studies, only 42 reported about trials conducted against the resistant bacteria considered a priority by the WHO. All studies are in the initial stage, and none are in the clinical phase of research.
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Affiliation(s)
- Patricia Bento da Silva
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | | | - Bruno Fonseca-Santos
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Mariana Cristina Solcia
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | | | | | - Renata Carolina Alves
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Andressa Maria Pironi
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | | | | | - Mariza Aires Fernandes
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Paula Scanavez Ferreira
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Gilmar Hanck da Silva
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Fernando Rogério Pavan
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
| | - Marlus Chorilli
- Sao Paulo State University (UNESP), School of Pharmaceutical Sciences, Araraquara-SP, Brazil
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Ferjani S, Sassi I, Saidani M, Mhiri E, Ghariani A, Boutiba Ben Boubaker I, Slim L, Amine S. Polymorphism of ftsI gene in Haemophilus influenzae and emergence of cefotaxime resistance in two Tunisian hospitals. New Microbes New Infect 2020; 36:100690. [PMID: 32489667 PMCID: PMC7262452 DOI: 10.1016/j.nmni.2020.100690] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 03/19/2020] [Accepted: 04/27/2020] [Indexed: 11/23/2022] Open
Abstract
The decreased affinity to β-lactams in Haemophilus influenzae is usually caused by specific alterations in penicillin-binding protein 3 due to varieties of substitutions in ftsI gene. This study aimed to characterize the polymorphism of ftsI gene in 19 H. influenzae strains, isolated between 2014 and 2016 (different resistance phenotypes to β-lactams (n = 9) and susceptible strains (n = 10) used for comparative purposes). All strains were characterized for capsular type by PCR and agglutination tests and for β-lactam resistance by amplification and sequencing of ftsI. Biotyping and clonality were performed by API-NH and pulsed-field gel electrophoresis, respectively. Four strains were β-lactamase-negative ampicillin-resistant and five were β-lactamase-positive clavulanic-acid-resistant. One strain from each group was resistant to cefotaxime. Our isolates belonged mainly to biotype IV and I and were non-typeable and genetically unrelated. According to mutation profiles of their ftsI, strains were classified as group I (n = 3), group II (n = 4), group–III–like (n = 1) and group III (n = 1). All group II strains were further classified as subgroup IIb, except for one strain, which harboured a new mutation (N422I). Ampicillin MICs of β-lactamase-negative ampicillin-resistant strains were 6 to 12 times the MICs of susceptible strains. Only blaTEM-1 was detected in β-lactamase-positive clavulanic-acid-resistant strains, and was responsible for high MICs for ampicillin (>256 mg/L), whatever the ftsI mutational resistance group. The emergence of cefotaxime-resistant isolates in our country is a matter of concern and requires strict surveillance and rationalization of antibiotic use to preserve these molecules.
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Affiliation(s)
- S Ferjani
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia
| | - I Sassi
- Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia
| | - M Saidani
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.,Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia
| | - E Mhiri
- Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia
| | - A Ghariani
- Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia
| | - I Boutiba Ben Boubaker
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.,Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia
| | - L Slim
- Abderrahmen Mami Hospital, Laboratory of Microbiology, Ariana, Tunisia
| | - S Amine
- University of Tunis El Manar, Faculty of Medicine of Tunis, LR99ES09 Laboratory of Research 'Resistance to Antimicrobial Agents, Tunis, Tunisia.,Charles Nicolle Hospital, Laboratory of Microbiology, Tunis, Tunisia
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Baumgartner M, Bayer F, Pfrunder-Cardozo KR, Buckling A, Hall AR. Resident microbial communities inhibit growth and antibiotic-resistance evolution of Escherichia coli in human gut microbiome samples. PLoS Biol 2020; 18:e3000465. [PMID: 32310938 PMCID: PMC7192512 DOI: 10.1371/journal.pbio.3000465] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 04/30/2020] [Accepted: 04/02/2020] [Indexed: 01/05/2023] Open
Abstract
Countering the rise of antibiotic-resistant pathogens requires improved understanding of how resistance emerges and spreads in individual species, which are often embedded in complex microbial communities such as the human gut microbiome. Interactions with other microorganisms in such communities might suppress growth and resistance evolution of individual species (e.g., via resource competition) but could also potentially accelerate resistance evolution via horizontal transfer of resistance genes. It remains unclear how these different effects balance out, partly because it is difficult to observe them directly. Here, we used a gut microcosm approach to quantify the effect of three human gut microbiome communities on growth and resistance evolution of a focal strain of Escherichia coli. We found the resident microbial communities not only suppressed growth and colonisation by focal E. coli but also prevented it from evolving antibiotic resistance upon exposure to a beta-lactam antibiotic. With samples from all three human donors, our focal E. coli strain only evolved antibiotic resistance in the absence of the resident microbial community, even though we found resistance genes, including a highly effective resistance plasmid, in resident microbial communities. We identified physical constraints on plasmid transfer that can explain why our focal strain failed to acquire some of these beneficial resistance genes, and we found some chromosomal resistance mutations were only beneficial in the absence of the resident microbiota. This suggests, depending on in situ gene transfer dynamics, interactions with resident microbiota can inhibit antibiotic-resistance evolution of individual species.
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Affiliation(s)
- Michael Baumgartner
- Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland
| | - Florian Bayer
- Biosciences, University of Exeter, Penryn, Cornwall, United Kingdom
| | - Katia R. Pfrunder-Cardozo
- Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland
| | - Angus Buckling
- Biosciences, University of Exeter, Penryn, Cornwall, United Kingdom
| | - Alex R. Hall
- Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland
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Wang XL, Xie J, Guo YB, Zhu BQ, Shao ZJ, Guo HM, Yang LL, Liu HW, Wang ZH, Hu J, Huang LF. Lower respiratory tract isolates of non-typeable Haemophilus influenzae in Western Sichuan, China: Antimicrobial susceptibility, mechanisms of β-lactam resistance and decade changes. J Glob Antimicrob Resist 2019; 21:324-330. [PMID: 31704169 DOI: 10.1016/j.jgar.2019.10.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/08/2019] [Accepted: 10/28/2019] [Indexed: 10/25/2022] Open
Abstract
OBJECTIVES The aims of this study were to analyse the serotypes of epidemic Haemophilus influenzae and changes in mechanisms of β-lactam resistance over the past decade. RESULTS Haemophilus influenzae isolates in Western Sichuan from 2013-2014 were non-typeable H. influenzae (NTHi). β-Lactam MICs for NTHi isolated during 2013-2014 were significantly higher than those from 2003-2004 (P < 0.05). Of 274 NTHi, 141 (51.5%) were β-lactamase-positive (TEM-1 type). There were 35 amino acid (AA) substitutions in ftsI among NTHi isolated from 2013-2014. However, NTHi isolates from 2003-2004 had only nine AA substitutions. Ordered multiple classification logistic regression analysis showed that different AA substitution patterns in ftsI had different effects on β-lactam MICs. The main factors affecting the ampicillin MIC were the mutations R517H (OR = 6.999), L389F (OR = 7.128), N526K (OR = 4.660) and D350N (OR = 0.450). The main factor influencing the amoxicillin/clavulanic acid MIC was an N526K mutation (OR = 9.349). The main factors affecting the cefuroxime MIC were the mutations S357N (OR = 37.453) and N526K (OR = 14.816). Compared with 2003-2004, gBLNAR and gBLPAR isolated from 2013-2014 increased significantly from 13.0% (7/54) and 9.3% (5/54) to 38.2% (84/220) and 45.5% (100/220), respectively (P < 0.001). In the 'others' group of ftsI gene mutations, 13 NTHi had the same ftsI gene mutation pattern and 24 AA substitutions. CONCLUSION These results confirm that β-lactam-resistant NTHi isolates increased rapidly. AA substitutions in ftsI were more complex and diversified in 2013-2014.
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Affiliation(s)
- Xiao Lei Wang
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China.
| | - Jiang Xie
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Yuan Biao Guo
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Bing Qing Zhu
- Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Zhu Jun Shao
- Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
| | - Hui Min Guo
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Li Li Yang
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Hua Wei Liu
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Zhan Hao Wang
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Jun Hu
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
| | - Lu Fei Huang
- Affiliated Hospital of South West Jiao Tong University & The Third People's Hospital of Chengdu, Chengdu 610031, China
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Novel and Improved Crystal Structures of H. influenzae, E. coli and P. aeruginosa Penicillin-Binding Protein 3 (PBP3) and N. gonorrhoeae PBP2: Toward a Better Understanding of β-Lactam Target-Mediated Resistance. J Mol Biol 2019; 431:3501-3519. [PMID: 31301409 DOI: 10.1016/j.jmb.2019.07.010] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Revised: 07/02/2019] [Accepted: 07/02/2019] [Indexed: 01/26/2023]
Abstract
Even with the emergence of antibiotic resistance, penicillin and the wider family of β-lactams have remained the single most important family of antibiotics. The periplasmic/extra-cytoplasmic targets of penicillin are a family of enzymes with a highly conserved catalytic activity involved in the final stage of bacterial cell wall (peptidoglycan) biosynthesis. Named after their ability to bind penicillin, rather than their catalytic activity, these key targets are called penicillin-binding proteins (PBPs). Resistance is predominantly mediated by reducing the target drug concentration via β-lactamases; however, naturally transformable bacteria have also acquired target-mediated resistance by inter-species recombination. Here we focus on structural based interpretations of amino acid alterations associated with the emergence of resistance within clinical isolates and include new PBP3 structures along with new, and improved, PBP-β-lactam co-structures.
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Ubukata K, Morozumi M, Sakuma M, Adachi Y, Mokuno E, Tajima T, Iwata S. Genetic characteristics and antibiotic resistance of Haemophilus influenzae isolates from pediatric patients with acute otitis media after introduction of 13-valent pneumococcal conjugate vaccine in Japan. J Infect Chemother 2019; 25:720-726. [PMID: 30987951 DOI: 10.1016/j.jiac.2019.03.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 01/29/2019] [Accepted: 03/25/2019] [Indexed: 01/30/2023]
Abstract
Acute otitis media (AOM) occurs commonly in pediatric populations. We examined resistance genotype, antibiotic susceptibility, quinolone (QL) resistance, and multilocus sequence type (MLST) among Haemophilus influenzae isolates causing AOM following introduction of pneumococcal conjugate vaccines in Japan. The AOM surveillance group included 69 participating otolaryngologists. Causative pathogens isolated from middle ear fluid (MEF) samples collected from 582 children with AOM were identified using both bacterial culture and real-time PCR. H. influenzae isolates among these pathogens were characterized by capsular type, resistance genotype, antibiotic susceptibility, QL resistance, and MLST. In 2016, H. influenzae was identified in 319 samples (54.8%), among which 72.4% (n = 231) tested positive by both culture and PCR; remaining H. influenzae cases were only PCR-positive. This proportion of H. influenzae positivity has increased significantly from 41.2% in 2006 (p < 0.001). Among culture-positive strains, genotypic β-lactamase-nonproducing ampicillin (AMP)-resistant (gBLNAR) strains were frequent (63.2%), with β-lactamase-nonproducing AMP-susceptible (gBLNAS) strains accounting for only 24.2%. Susceptibilities of gBLNAR to oral antimicrobials were best for tosufloxacin, followed by cefditoren and tebipenem; MIC90s were 0.031 μg/mL, 0.5 μg/mL, and 1 μg/mL, respectively. In 7 gBLNAR isolates (3.0%), QL susceptibility was low, owing to amino acid substitutions in GyrA and/or ParC. Sequence types identified numbered 107, including 28 that were new. Prevention of further increases in resistance to antimicrobial agents will require antibiotic selection based on characterization of causative pathogens in clinical practice.
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Affiliation(s)
- Kimiko Ubukata
- Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan.
| | - Miyuki Morozumi
- Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan
| | - Megumi Sakuma
- Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan
| | - Yoko Adachi
- Department of Infectious Diseases, Keio University, School of Medicine, Tokyo, Japan
| | - Eriko Mokuno
- Department of Otorhinolaryngology, Hakujikai Memorial Hospital, Tokyo, Japan
| | - Takeshi Tajima
- Department of Pediatrics, Hakujikai Memorial Hospital, Tokyo, Japan
| | - Satoshi Iwata
- Department of Infectious Diseases, National Cancer Center Hospital, Tokyo, Japan
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Karash S, Kwon YM. Iron-dependent essential genes in Salmonella Typhimurium. BMC Genomics 2018; 19:610. [PMID: 30107784 PMCID: PMC6092869 DOI: 10.1186/s12864-018-4986-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 07/31/2018] [Indexed: 12/17/2022] Open
Abstract
Background The molecular mechanisms underlying bacterial cell death due to stresses or bactericidal antibiotics are complex and remain puzzling. Due to the current crisis of antibiotic resistance, development of effective antibiotics is urgently required. Previously, it has been shown that iron is required for effective killing of bacterial cells by numerous bactericidal antibiotics. Results We investigated the death or growth inhibition of S. Typhimurium under iron-restricted conditions, following disruption of essential genes, by transposon mutagenesis using transposon sequencing (Tn-seq). Our high-resolution Tn-seq analysis revealed that transposon mutants of S. Typhimurium with insertions in essential genes escaped immediate killing or growth inhibition under iron-restricted conditions for approximately one-third of all previously known essential genes. Based on this result, we classified all essential genes into two categories, iron-dependent essential genes, for which the insertion mutants can grow slowly if iron is restricted, and iron-independent essential genes, for which the mutants become nonviable regardless of iron concentration. The iron-dependency of the iron-dependent essential genes was further validated by the fact that the relative abundance of these essential gene mutants increased further with more severe iron restrictions. Our unexpected observation can be explained well by the common killing mechanisms of bactericidal antibiotics via production of reactive oxygen species (ROS). In this model, iron restriction would inhibit production of ROS, leading to reduced killing activity following blocking of essential gene functions. Interestingly, the targets of most antibiotics currently in use clinically are iron-dependent essential genes. Conclusions Our result suggests that targeting iron-independent essential genes may be a better strategy for future antibiotic development, because blocking their essential gene functions would lead to immediate cell death regardless of the iron concentration. This work expands our knowledge on the role of iron to a broad range of essential functions and pathways, providing novel insights for development of more effective antibiotics. Electronic supplementary material The online version of this article (10.1186/s12864-018-4986-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Sardar Karash
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA.,Department of Biology, College of Education, Salahaddin University, Erbil, Kurdistan, Iraq
| | - Young Min Kwon
- Cell and Molecular Biology Program, University of Arkansas, Fayetteville, AR, USA. .,Department of Poultry Science, University of Arkansas, Fayetteville, AR, 72701, USA.
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11
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Carbapenem-Nonsusceptible Haemophilus influenzae with Penicillin-Binding Protein 3 Containing an Amino Acid Insertion. Antimicrob Agents Chemother 2018; 62:AAC.00671-18. [PMID: 29784853 DOI: 10.1128/aac.00671-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Accepted: 05/16/2018] [Indexed: 01/29/2023] Open
Abstract
The prevalence of β-lactamase-negative ampicillin-resistant (BLNAR) Haemophilus influenzae has become a clinical concern. In BLNAR isolates, amino acid substitutions in penicillin-binding protein 3 (PBP3) are relevant to the β-lactam resistance. Carbapenem-nonsusceptible H. influenzae isolates have been rarely reported. Through antimicrobial susceptibility testing, nucleotide sequence analysis of ftsI, encoding PBP3, and the utilization of a collection of H. influenzae clinical isolates in our laboratory, we obtained a carbapenem-nonsusceptible clinical isolate (NUBL1772) that possesses an altered PBP3 containing V525_N526insM. The aim of this study was to reveal the effect of altered PBP3 containing V525_N526insM on reduced carbapenem susceptibility. After generating recombinant strains with altered ftsI, we performed antimicrobial susceptibility testing and competitive binding assays with fluorescent penicillin (Bocillin FL) and carbapenems. Elevated carbapenem MICs were found for the recombinant strain harboring the entire ftsI gene of NUBL1772. The recombinant PBP3 of NUBL1772 also exhibited reduced binding to carbapenems. These results demonstrate that altered PBP3 containing V525_N526insM influences the reduced carbapenem susceptibility. The revertant mutant lacking the V525_N526insM exhibited lower MICs for carbapenems than NUBL1772, suggesting that this insertion affects reduced carbapenem susceptibility. The MICs of β-lactams for NUBL1772 were higher than those for the recombinant possessing ftsI of NUBL1772. NUBL1772 harbored AcrR with early termination, resulting in low-level transcription of acrB and high efflux pump activity. These findings suggest that the disruption of AcrR also contributes to the reduced carbapenem susceptibility found in NUBL1772. Our results provide the first evidence that the altered PBP3 containing V525_N526insM is responsible for the reduced susceptibility to carbapenems in H. influenzae.
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Butler DF, Myers AL. Changing Epidemiology of Haemophilus influenzae in Children. Infect Dis Clin North Am 2017; 32:119-128. [PMID: 29233576 DOI: 10.1016/j.idc.2017.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Haemophilus influenzae remains a common cause of illness in children throughout the world. Before the introduction of vaccination, H influenzae type b (Hib) disease was the leading cause of bacterial meningitis in young children and a frequent cause of pneumonia, epiglottitis, and septic arthritis. Clinicians should remain diligent in counseling parents on the dangers of Hib and provide vaccination starting at 2 months of age. The epidemiology of invasive H influenzae disease is shifting. It is imperative that clinicians recognize the changing epidemiology and antibiotic resistance patterns for H influenzae to optimize care in hospital and ambulatory settings.
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Affiliation(s)
- David F Butler
- Division of Pediatric Critical Care Medicine, Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, FA.2.112, 4800 Sand Point Way NE, Seattle, WA 98105, USA
| | - Angela L Myers
- Division of Pediatric Infectious Diseases, Children's Mercy, Kansas City, University of Missouri-Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA.
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Wienholtz NH, Barut A, Nørskov-Lauritsen N. Substitutions in PBP3 confer resistance to both ampicillin and extended-spectrum cephalosporins in Haemophilus parainfluenzae as revealed by site-directed mutagenesis and gene recombinants. J Antimicrob Chemother 2017; 72:2544-2547. [DOI: 10.1093/jac/dkx157] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2016] [Accepted: 04/27/2017] [Indexed: 11/14/2022] Open
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Tsang RSW, Shuel M, Whyte K, Hoang L, Tyrrell G, Horsman G, Wylie J, Jamieson F, Lefebvre B, Haldane D, Gad RR, German GJ, Needle R. Antibiotic susceptibility and molecular analysis of invasive Haemophilus influenzae in Canada, 2007 to 2014. J Antimicrob Chemother 2017; 72:1314-1319. [PMID: 28137937 PMCID: PMC5890693 DOI: 10.1093/jac/dkw565] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2016] [Revised: 10/19/2016] [Accepted: 12/08/2016] [Indexed: 11/13/2022] Open
Abstract
Background Previously we studied the antibiotic susceptibility of invasive Haemophilus influenzae collected in Canada from 1990 to 2006 and characterized isolates by serotype, MLST and ftsI gene sequencing for significant PBP3 mutations. Objectives To provide an update based on isolates collected from 2007 to 2014. Methods A total of 882 case isolates were characterized by serotype using slide agglutination and PCR. MLST was carried out to determine ST. Isolates were tested for β-lactamase production, presence of significant PBP3 mutations and antibiotic susceptibility by disc diffusion against 14 antibiotics. MIC values of three antibiotics were determined for 316 isolates using microbroth dilution. Results Non-typeable H. influenzae accounted for 54.6% of the isolates and 45.4% were serotypeable, predominantly type a (23.1%), type b (8.3%) and type f (10.8%). The overall rate of ampicillin resistance due to β-lactamase production was 16.4% and increased from 13.5% in 2007-10 to 19% in 2011-14. Significant PBP3 mutations were identified in 129 isolates (14.6%) with 23 (2.6%) also producing β-lactamase. MLST identified related STs (ST-136, ST-14 and ST-367) associated exclusively with genetically β-lactamase-negative, ampicillin-resistant isolates and confirmed previously reported associations between significant PBP3 mutations and ST. Conclusions A significant increase in β-lactamase-producing isolates was observed from 2007 to 2014; the rate of significant PBP3 mutations has increased since previously reported and 52.5% of non-typeable H. influenzae now show resistance markers. Resistance to trimethoprim/sulfamethoxazole was common and no resistance to fluoroquinolones or third-generation cephalosporins was found.
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Affiliation(s)
- Raymond S. W. Tsang
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Michelle Shuel
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Kathleen Whyte
- National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canada
| | - Linda Hoang
- BC Public Health Microbiology and Reference Laboratory, Vancouver, British Columbia, Canada
| | - Gregory Tyrrell
- Provincial Laboratory for Public Health, Edmonton, Alberta, Canada
| | - Greg Horsman
- Saskatchewan Disease Control Laboratory, Regina, Saskatchewan, Canada
| | - John Wylie
- Cadham Provincial Laboratory, Winnipeg, Manitoba, Canada
| | - Frances Jamieson
- Public Health Ontario, Toronto, Ontario, Canada
- Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Brigitte Lefebvre
- Laboratoire de santé publique du Québec, Institut National de santé publique du Québec, Sainte-Anne-de-Bellevue, Québec, Canada
| | - David Haldane
- Nova Scotia Health Authority, Halifax, Nova Scotia, Canada
- Dalhousie University, Halifax, Nova Scotia, Canada
| | - Rita R. Gad
- Communicable Disease Control Unit, Department of Health, Government of New Brunswick, Fredericton, New Brunswick, Canada
| | - Gregory J. German
- Department of Health, Government of Prince Edward Island, Charlottetown, Prince Edward Island, Canada
| | - Robert Needle
- Public Health Laboratory and Microbiology, Eastern Health, St John’s, Newfoundland and Labrador, Canada
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15
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Rise in Haemophilus influenzae With Reduced Quinolone Susceptibility and Development of a Simple Screening Method. Pediatr Infect Dis J 2017; 36:263-266. [PMID: 27870809 DOI: 10.1097/inf.0000000000001415] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND β-Lactamase-nonproducing ampicillin-resistant Haemophilus influenzae are prevalent in Japan. Resistance has increased as a consequence of the expanded use of antimicrobial agents, raising concerns about the rise of multidrug (macrolide and fluoroquinolone)-resistant H. influenzae. METHODS In this study, we investigated susceptibility to fluoroquinolones in H. influenzae clinical isolates from 2013 to 2014 and identified the amino acid substitutions in quinolone resistance-determining regions of gyrA and parC. RESULTS All isolates (n = 145) were susceptible to fluoroquinolones; however, some showed reduced susceptibility. The minimum inhibitory concentration of levofloxacin for these strains was 0.063-0.5 µg/mL, and the strains harbored the amino acid substitution S84L in GyrA. Such strains have seen a significant increase. Importantly, all mutants from 2014 were isolated from pediatric patients. In addition, we developed a simple polymerase chain reaction-based screening method for detecting isolates with reduced fluoroquinolone susceptibility. CONCLUSIONS The mutation in GyrA is important as a first step in the development of fluoroquinolone resistance. Hence, detection of reduced susceptible strains may influence the choice of antimicrobial treatment.
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Molecular Epidemiology of Ampicillin-resistant Haemophilus influenzae Causing Acute Otitis Media in Japanese Infants and Young Children. Pediatr Infect Dis J 2016; 35:501-6. [PMID: 26808724 DOI: 10.1097/inf.0000000000001066] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND Nontypeable Haemophilus influenzae is a particularly important cause of acute otitis media (AOM). There is a high prevalence of β-lactamase-nonproducing ampicillin-resistant (BLNAR) strains in Japanese children, which is associated with recurrent AOM and prolonged treatment. The aim of this study was to investigate the antimicrobial susceptibility profile, mechanisms of ampicillin resistance and molecular epidemiology of ampicillin resistance in H. influenzae strains causing AOM in Japanese children. METHODS One hundred fifty-seven strains of H. influenzae isolated from the middle ear fluid of pediatric patients (aged 0-3 years) with AOM from various areas of Japan were studied. The antimicrobial susceptibility profile, genes encoding β-lactamase and alterations of penicillin-binding protein 3 were investigated. Genetic relatedness among ampicillin-resistant isolates was examined by multilocus sequence typing and pulsed-field gel electrophoresis. RESULTS Of 157 isolates, 108 (68.8%) demonstrated reduced susceptibility to ampicillin, including 95 (60.5%) of β-lactamase-nonproducing isolates and 13 (8.3%) of β-lactamase-producing isolates. All BLNAR (minimum inhibitory concentration of ampicillin ≥ 4 mg/L) isolates had amino acid substitutions related to ampicillin resistance. Multilocus sequence typing and pulsed-field gel electrophoresis demonstrated genetic diversity although there were 2 clusters of highly resistant isolates with identical STs (sequence types; ST161 and 549). CONCLUSIONS Alterations of penicillin-binding protein 3 represented the most prevalent mechanism of ampicillin resistance among H. influenzae isolates causing AOM in Japanese children. BLNAR isolates from children with AOM demonstrated genetic diversity. This study identified for the first time ST clones associated with BLNAR H. influenzae causing AOM in Japanese children.
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17
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Prevalence of macrolide-non-susceptible isolates among β-lactamase-negative ampicillin-resistant Haemophilus influenzae in a tertiary care hospital in Japan. J Glob Antimicrob Resist 2016; 6:22-26. [PMID: 27530834 DOI: 10.1016/j.jgar.2016.01.014] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2015] [Revised: 01/26/2016] [Accepted: 01/30/2016] [Indexed: 11/21/2022] Open
Abstract
β-Lactamase-negative ampicillin-resistant (BLNAR) Haemophilus influenzae account for a large portion of H. influenzae clinical isolates in Japan. The aim of this study was to clarify the antimicrobial susceptibility of BLNAR H. influenzae clinical isolates as well as the annual changes in susceptibility. BLNAR H. influenzae isolates were collected from a tertiary care hospital from 2007 to 2012. Antimicrobial susceptibility testing was performed and resistance mechanisms were analysed. All of the isolates (n=304) had amino acid substitutions in penicillin-binding protein 3 (PBP3) and isolates were classified by these amino acid substitutions: R517H or N526K (class I); S385T and R517H (class II); and S385T and N526K (class III). Classes I, II and III represented 8.2% (n=25), 9.5% (n=29) and 81.6% (n=248) of the isolates, respectively; 2 isolates could not be classified because they had a PBP3 with a substantially mutated FtsI transpeptidase domain. All of the isolates were highly susceptible to fluoroquinolones and carbapenems. The number of clarithromycin (CAM)-non-susceptible [minimum inhibitory concentration (MIC) ≥16μg/mL] H. influenzae isolates increased significantly between 2010 and 2012. Moreover, CAM-non-susceptible H. influenzae isolates were prevalent among class II and class III BLNAR H. influenzae. Multilocus sequence typing (MLST) of the CAM-resistant (MIC ≥32μg/mL) H. influenzae isolates showed that they were not specific sequence types, suggesting that CAM resistance may occur in any isolates. These results raise concern regarding the occurrence of multidrug-resistant BLNAR H. influenzae.
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18
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Cherkaoui A, Diene SM, Emonet S, Renzi G, Francois P, Schrenzel J. Ampicillin-resistant Haemophilus influenzae isolates in Geneva: serotype, antimicrobial susceptibility, and β-lactam resistance mechanisms. Eur J Clin Microbiol Infect Dis 2015; 34:1937-45. [PMID: 26187432 DOI: 10.1007/s10096-015-2435-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 06/22/2015] [Indexed: 01/21/2023]
Abstract
The purpose of this study was to analyze the molecular mechanisms of ampicillin-resistant Haemophilus influenzae isolated in Geneva, Switzerland. We investigated the association between specific patterns of amino acid substitutions in penicillin-binding protein 3 (with or without β-lactamase production) and β-lactam susceptibility. Another main focus for this study was to compare the accuracy of disk diffusion and Etest methods to detect resistance to ampicillin and amoxicillin/clavulanic acid. The antibiotic susceptibility to β-lactam antibiotics of 124 H. influenzae isolates was determined by disk diffusion and Etest methods, and interpreted by European Committee on Antimicrobial Susceptibility Testing (EUCAST) and Clinical and Laboratory Standards Institute (CLSI) breakpoints. Alterations in PBP3 were investigated by sequencing the ftsI gene. Of the 124 clinical isolates analyzed, ampicillin resistance was found in 36% (45 out of 124). The rate of resistance to amoxicillin/clavulanic acid was 9% and 0.8%, using EUCAST and CLSI breakpoints respectively. For the 78 β-lactamase negative ampicillin-susceptible (BLNAS) isolates for which the Etest method indicated a high degree of susceptibility (MIC ≤ 1 mg/L), the disk diffusion method revealed resistance to ampicillin and amoxicillin/clavulanic acid in 33 cases (42%). Most common amino acid substitutions were Asn526Lys and Val547Ile, followed by Asp569Ser, Ala502Val, Asp350Asn, Met377Ile, Ile449Val, and Arg517His. The patterns observed were classified into six groups (IIa, IIb, IIc, IId, III-like, and miscellaneous). Continued characterization of both invasive and respiratory H. influenzae isolates is necessary in order to observe changes in the microbiology and epidemiology of this pathogen that could lead to clinical failure when treated by empirical antibiotic therapy.
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Affiliation(s)
- A Cherkaoui
- Bacteriology Laboratory, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland.
| | - S M Diene
- Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland
| | - S Emonet
- Bacteriology Laboratory, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland
| | - G Renzi
- Bacteriology Laboratory, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland
| | - P Francois
- Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland
| | - J Schrenzel
- Bacteriology Laboratory, Division of Laboratory Medicine, Department of Genetics and Laboratory Medicine, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland.,Genomic Research Laboratory, Service of Infectious Diseases, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland
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Cardines R, Daprai L, Giufrè M, Torresani E, Garlaschi ML, Cerquetti M. Genital carriage of the genus Haemophilus in pregnancy: species distribution and antibiotic susceptibility. J Med Microbiol 2015; 64:724-730. [PMID: 25976004 DOI: 10.1099/jmm.0.000083] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Recent reports have hypothesized that colonization of the maternal genital tract with non-capsulated Haemophilus influenzae could result in neonatal invasive disease. In this study, genital carriage of the genus Haemophilus was investigated in 510 pregnant women attending an Italian hospital for routine controls. Overall, vaginal carriage of the genus Haemophilus was 9.0 % (46/510). A high colonization rate with Haemophilus parainfluenzae (37/510, 7.3 %) was found; other species, such as Haemophilus pittmaniae (7/510, 1.4 %) and Haemophilus haemolyticus (2/510, 0.4 %), were detected for the first time in the genital flora by 16S rRNA gene sequencing. Notably, no H. influenzae was identified, in agreement with previous investigations indicating that this species is rarely isolated from the genito-urinary tract of pregnant women. No antibiotic resistance was detected in H. pittmaniae and H. haemolyticus, but quite a high degree of ampicillin (10/37, 27 %) and ciprofloxacin (3/37, 8.1 %) resistance was observed in H. parainfluenzae. Five ampicillin-resistant isolates were β-lactamase producers, whereas five isolates exhibited a β-lactamase-negative ampicillin-resistant (BLNAR) phenotype. Sequencing of penicillin-binding protein 3 revealed that Val511Ala, Asn526Ser, Ala530Ser and Thr574Ala changes were associated with BLNAR phenotypes. Two ciprofloxacin-resistant isolates carried substitutions in both GyrA (Ser84Phe and Asp88Tyr) and ParC (Ser84Tyr and Met198Leu); the other ciprofloxacin-resistant isolate had substitutions in ParC, only (Ser138Thr and Met198Leu). In conclusion, ∼10 % of pregnant women carried a species of Haemophilus in their genital tract. The emergence of non-β-lactamase-mediated resistance in genital H. parainfluenzae is a matter of concern because of the risk of mother-to-baby transmission.
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Affiliation(s)
- Rita Cardines
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Laura Daprai
- Unit of Microbiology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Giufrè
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
| | - Erminio Torresani
- Unit of Microbiology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Maria Laura Garlaschi
- Unit of Microbiology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Marina Cerquetti
- Department of Infectious, Parasitic and Immune-Mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
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Interspecies transfer of the penicillin-binding protein 3-encoding gene ftsI between Haemophilus influenzae and Haemophilus haemolyticus can confer reduced susceptibility to β-lactam antimicrobial agents. Antimicrob Agents Chemother 2015; 59:4339-42. [PMID: 25918135 DOI: 10.1128/aac.04854-14] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2014] [Accepted: 04/19/2015] [Indexed: 11/20/2022] Open
Abstract
Mutations in ftsI, encoding penicillin-binding protein 3, can cause decreased β-lactam susceptibility in Haemophilus influenzae. Sequencing of ftsI from clinical strains has indicated interspecies recombination of ftsI between H. influenzae and Haemophilus haemolyticus. This study documented apparently unrestricted homologous recombination of ftsI between H. influenzae and H. haemolyticus in vitro. Transfer of ftsI from resistant isolates conferred similar but not identical increases in the MICs of susceptible strains of H. influenzae and H. haemolyticus.
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Van Eldere J, Slack MPE, Ladhani S, Cripps AW. Non-typeable Haemophilus influenzae, an under-recognised pathogen. THE LANCET. INFECTIOUS DISEASES 2014; 14:1281-92. [PMID: 25012226 DOI: 10.1016/s1473-3099(14)70734-0] [Citation(s) in RCA: 236] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Non-typeable Haemophilus influenzae (NTHi) is a major cause of mucosal infections such as otitis media, sinusitis, conjunctivitis, and exacerbations of chronic obstructive pulmonary disease. In some regions, a strong causal relation links this pathogen with infections of the lower respiratory tract. In the past 20 years, a steady but constant increase has occurred in invasive NTHi worldwide, with perinatal infants, young children, and elderly people most at risk. Individuals with underlying comorbidities are most susceptible and infection is associated with high mortality. β-lactamase production is the predominant mechanism of resistance. However, the emergence and spread of β-lactamase-negative ampicillin-resistant strains in many regions of the world is of substantial concern, potentially necessitating changes to antibiotic treatment guidelines for community-acquired infections of the upper and lower respiratory tract and potentially increasing morbidity associated with invasive NTHi infections. Standardised surveillance protocols and typing methodologies to monitor this emerging pathogen should be implemented. International scientific organisations need to raise the profile of NTHi and to document the pathobiology of this microbe.
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Affiliation(s)
- Johan Van Eldere
- Department of Microbiology and Immunology, Catholic University Leuven, Belgium; Clinical Department of Laboratory Medicine, University Hospital Leuven, Belgium.
| | - Mary P E Slack
- WHO Collaborating Centre for Haemophilus influenzae, Respiratory and Vaccine Preventable Bacteria Reference Unit, Microbiology Services, Public Health England, Colindale, London, UK
| | - Shamez Ladhani
- Immunisation, Hepatitis and Blood Safety Department, Health Protection Services, Public Health England, Colindale, London, UK
| | - Allan W Cripps
- School of Medicine, Griffith Health Institute, Griffith University, Gold Coast, QLD, Australia
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Witherden EA, Bajanca-Lavado MP, Tristram SG, Nunes A. Role of inter-species recombination of the ftsI gene in the dissemination of altered penicillin-binding-protein-3-mediated resistance in Haemophilus influenzae and Haemophilus haemolyticus. J Antimicrob Chemother 2014; 69:1501-9. [PMID: 24562614 DOI: 10.1093/jac/dku022] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVES To screen the ftsI gene sequences obtained from clinical isolates of non-typeable Haemophilus influenzae (NTHi) and Haemophilus haemolyticus for the presence of mosaic ftsI gene structures, and to evaluate the role of inter-species recombination of the ftsI gene in the formation and distribution of resistant ftsI genes. METHODS The ftsI genes of 100 Haemophilus isolates comprising genetically defined β-lactamase-negative ampicillin-susceptible (gBLNAS), β-lactamase-positive ampicillin-resistant (gBLPAR), β-lactamase-negative ampicillin-resistant (gBLNAR) and β-lactamase-positive amoxicillin/clavulanate-resistant (gBLPACR) isolates of NTHi (n = 50) and H. haemolyticus (n = 50) were analysed in this study. Both the flanking regions and the full-length ftsI gene sequences of all study isolates were screened for mosaic structures using H. influenzae Rd and H. haemolyticus ATCC 33390 as reference parental sequences, and bioinformatics methods were used for recombination analysis using SimPlot. RESULTS Of the 100 clinical isolates analysed 34% (34/100) harboured mosaic ftsI gene structures containing distinct ftsI gene fragments similar to both reference parental sequences. The inter-species recombination events were exclusively encountered in the ftsI gene of gBLNAR/gBLPACR isolates of both NTHi and H. haemolyticus, and were always associated with the formation of a mosaic fragment at the 3' end of the ftsI gene. There was no evidence supporting horizontal gene transfer (HGT) involving the entire ftsI gene among the clinical isolates in vivo. CONCLUSIONS We provide evidence for the HGT and inter-species recombination of the ftsI gene among gBLNAR/gBLPACR isolates of NTHi and H. haemolyticus in a clinical setting, highlighting the importance of recombination of the ftsI gene in the emergence of altered penicillin-binding protein 3 and BLNAR-mediated resistance.
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Affiliation(s)
- Elizabeth A Witherden
- School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, Australia
| | - Maria Paula Bajanca-Lavado
- Department of Infectious Disease, National Institute of Health, Av. Padre Cruz, 1649-016 Lisbon, Portugal
| | - Stephen G Tristram
- School of Human Life Sciences, University of Tasmania, Launceston, Tasmania, Australia
| | - Alexandra Nunes
- Department of Infectious Disease, National Institute of Health, Av. Padre Cruz, 1649-016 Lisbon, Portugal
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García-Cobos S, Arroyo M, Campos J, Pérez-Vázquez M, Aracil B, Cercenado E, Orden B, Lara N, Oteo J. Novel mechanisms of resistance to β-lactam antibiotics in Haemophilus parainfluenzae: β-lactamase-negative ampicillin resistance and inhibitor-resistant TEM β-lactamases. J Antimicrob Chemother 2013; 68:1054-9. [DOI: 10.1093/jac/dks525] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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24
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Park C, Kim KH, Shin NY, Byun JH, Kwon EY, Lee JW, Kwon HJ, Choi EY, Lee DG, Sohn WY, Kang JH. Genetic diversity of the ftsI gene in β-lactamase-nonproducing ampicillin-resistant and β-lactamase-producing amoxicillin-/clavulanic acid-resistant nasopharyngeal Haemophilus influenzae strains isolated from children in South Korea. Microb Drug Resist 2013; 19:224-30. [PMID: 23308379 DOI: 10.1089/mdr.2012.0116] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Haemophilus influenzae frequently colonizes the nasopharynx of children and adults, which can lead to a variety of infections. We investigated H. influenzae carriage in the nasopharynx of 360 children, in terms of (1) the prevalence of strains with decreased susceptibility, and (2) the presence of amino acid substitutions in PBP3. One hundred twenty-three strains were isolated (34.2%, 123/360), 122 of which were classified as nontypable H. influenzae (NTHi). Of these, β-lactamase-nonproducing ampicillin-susceptible strains accounted for 26.2%, β-lactamase-producing-ampicillin-resistant strains for 9.0%, β-lactamase-nonproducing ampicillin-resistant (BLNAR) strains for 40.2%, and β-lactamase-producing amoxicillin-/clavulanic acid-resistant (BLPACR) for 24.6%, respectively. Pulsed field gel electrophoresis (PFGE) patterns were so diverse that they were clustered into 41 groups. The amino acid substitutions in the transpeptidase domain (292 amino acids) of ftsI in BLNAR isolates showed that group IIb accounted for 30.6%, IIc for 8.2%, IId for 16.3%, III for 32.7%, and the others for 12.2%. Moreover, groups IIb (56.7%; 17/30) and III (23.3%; 7/30) were prevalent among BLPACR strains. They were subclassified into more diverse sequence subtypes by analysis of the entire PBP3 (610 amino acids). Groups IIb, IIc, IId, and III exhibited 13, four, six, and four sequence subtypes, respectively. Such a genetic diversity is likely indicative of significant potential for decreased antimicrobial susceptibility in nasopharyngeal-colonizing NTHi strains.
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Affiliation(s)
- Chulmin Park
- Vaccine Bio Research Institute, The Catholic University of Korea, Seoul, Republic of Korea
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25
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Morozumi M, Chiba N, Ubukata K, Okada T, Sakata H, Matsubara K, Iwata S. Antibiotic susceptibility in relation to genotype of Streptococcus pneumoniae, Haemophilus influenzae, and Mycoplasma pneumoniae responsible for community-acquired pneumonia in children. J Infect Chemother 2013; 19:432-40. [DOI: 10.1007/s10156-012-0500-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 10/02/2012] [Indexed: 01/29/2023]
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26
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Hagiwara E, Baba T, Shinohara T, Nishihira R, Komatsu S, Ogura T. Antimicrobial resistance genotype trend and its association with host clinical characteristics in respiratory isolates of Haemophilus influenzae. Chemotherapy 2012. [PMID: 23183338 DOI: 10.1159/000343973] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND β-Lactam resistance genotype trends in clinical isolates of Haemophilus influenzae and their correlation with the clinical background were analyzed. METHODS Five hundred and ten respiratory isolates of H. influenzae collected during the period 2002-2009 were classified by PCR into gBLNAS (genotype for β-lactamase-negative ampicillin-susceptible), gBLNAR (genotype for β-lactamase-negative ampicillin-resistant) and 3 other genotypes. The associations with host clinical data and antimicrobial susceptibility were analyzed in all 144 isolates between 2008 and 2009. RESULTS The 8-year trend analysis detected an increase in gBLNAR with a decrease in gBLNAS. The probability of being a causative pathogen did not differ between genotypes. Host clinical characteristics such as age and gender did not differ with gBLNAR or gBLNAS, but the underlying respiratory diseases did differ. gBLNAR was found at the highest rate in 83% of isolates from patients with nontuberculous mycobacteriosis. In contrast, gBLNAR accounted for as little as 33% of isolates from chronic obstructive pulmonary disease. CONCLUSIONS There were no differences in the pathogenicity of gBLNAR and gBLNAS. The underlying respiratory diseases may be related to the resistance genotype.
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Affiliation(s)
- Eri Hagiwara
- Department of Respiratory Medicine, Kanagawa Cardiovascular and Respiratory Center, Yokohama, Japan.
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27
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Soriano F, Giménez MJ, Aguilar L. Pharmacodynamics for predicting therapeutic outcome and countering resistance spread: The cefditoren case. World J Clin Infect Dis 2012; 2:28-38. [DOI: 10.5495/wjcid.v2.i3.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The relationship between pharmacokinetics and pharmacodynamics is a key instrument to improve antimicrobial stewardship and should be aimed to identification of the drug exposure measure that is closely associated not only with the ability to kill organisms but also to suppress the emergence of resistant subpopulations. This article reviews published studies for efficacy prediction with cefditoren and those aimed to explore its potential for countering resistance spread, focusing on the three most prevalent community-acquired isolates from respiratory infections: Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) and Streptococcus pyogenes (S. pyogenes). Studies for efficacy prediction include in vitro pharmacodynamic simulations (using physiological concentrations of human albumin) and mice models (taking advantage of the same protein binding rate in mice and humans) to determine the value of the pharmacodynamic indices predicting efficacy, and Monte Carlo simulations to explore population pharmacodynamic coverage, as weapons for establishing breakpoints. Studies exploring the potential of cefditoren (free concentrations obtained with 400 mg cefditoren bid administration) for countering spread of resistance showed its capability for countering (1) intra-strain spread of resistance linked to ftsI gene mutations in H. influenzae; (2) the spread of H. influenzae resistant strains (with ftsI gene mutations) in multi-strain H. influenzae niches or of S. pneumoniae strains with multiple resistance traits in multi-strain S. pneumoniae niches; and (3) for overcoming indirect pathogenicity linked to β-lactamase production by H. influenzae that protects S. pyogenes in multibacterial niches. This revision evidences the ecological potential for cefditoren (countering resistance spread among human-adapted commensals) and its adequate pharmacodynamic coverage of respiratory pathogens (including those resistant to previous oral compounds) producing community-acquired infections.
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Barberán J, Aguilar L, Giménez MJ. Update on the clinical utility and optimal use of cefditoren. Int J Gen Med 2012; 5:455-64. [PMID: 22675264 PMCID: PMC3367410 DOI: 10.2147/ijgm.s25989] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This article reviews and updates published data on cefditoren. The in vitro activity of cefditoren and its potential pharmacokinetic/pharmacodynamic adequacy to cover emerging resistance phenotypes in the present decade is reviewed. Cefditoren’s in vitro activity against most prevalent bacterial respiratory pathogens in the community and its pharmacokinetic/pharmacodynamic profile suggests a significant role for cefditoren in the treatment of respiratory tract infections. Clinical trials (in acute exacerbations of chronic bronchitis, community-acquired pneumonia, pharyngotonsillitis, and sinusitis) performed during clinical development outside Japan, mainly in adults, are reviewed, together with new clinical studies in the treatment of pharyngotonsillitis, sinusitis, and otitis media in children, mainly in Japan, for efficacy and safety assessment. The results of these studies support the adequacy of cefditoren for the treatment of community-acquired respiratory tract infections with a safety profile similar to previous oral antibiotics. From the data reviewed, it is concluded that cefditoren is an adequate option for the treatment of mild-to-moderate community-acquired respiratory infections, especially in geographical areas with a reported prevalence of phenotypes exhibiting nonsusceptibility to common oral antibiotics.
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Affiliation(s)
- José Barberán
- Infectious Diseases Department, Hospital Central de la Defensa Gomez Ulla, Madrid, Spain
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29
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Barbosa AR, Giufrè M, Cerquetti M, Bajanca-Lavado MP. Polymorphism in ftsI gene and {beta}-lactam susceptibility in Portuguese Haemophilus influenzae strains: clonal dissemination of beta-lactamase-positive isolates with decreased susceptibility to amoxicillin/clavulanic acid. J Antimicrob Chemother 2011; 66:788-96. [PMID: 21393206 DOI: 10.1093/jac/dkq533] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES The aim of this study was to characterize ampicillin resistance mechanisms in clinical isolates of Haemophilus influenzae from Portugal. Association between specific patterns of amino acid substitutions in penicillin-binding protein 3 (PBP3) (with or without β-lactamase production) and β-lactam susceptibility as well as genetic relatedness among isolates were investigated. METHODS Two-hundred and forty non-consecutive H. influenzae isolates chosen according to their different ampicillin MICs [101 β-lactamase-non-producing ampicillin-resistant (BLNAR) isolates, 80 β-lactamase-producing ampicillin-resistant (BLPAR) isolates and 59 β-lactamase-non-producing ampicillin-susceptible (BLNAS) isolates] were analysed. The β-lactamase-encoding bla(TEM-1) gene was detected by PCR. The ftsI gene encoding PBP3 was sequenced. Genetic relatedness among isolates was examined by PFGE. RESULTS Of the 240 H. influenzae isolates, 141 had mutations in the transpeptidase domain of the ftsI gene, including most BLNAR strains (94/101, 93.1%) and a high percentage of BLPAR strains (47/80, 58.8%). As previously reported, the latter have been described as β-lactamase-positive amoxicillin/clavulanic acid resistant (BLPACR). The most common amino acid substitutions were identified near the KTG motif: N526K (136/141, 96.5%), V547I (124/141, 87.9%) and N569S (121/141, 85.8%). The 141 strains were divided into 31 ftsI mutation patterns and included six groups (I, IIa, IIb, IIc, IId and III-like). BLNAR strains were genetically diverse but close genetic relationships were demonstrated among BLPACR strains. CONCLUSIONS This study shows that the non-enzymatic mechanism of resistance to β-lactams is widespread among H. influenzae isolates in Portugal. Clonal dissemination of BLPACR strains showing high resistance to ampicillin and reduced susceptibility to amoxicillin/clavulanic acid was documented.
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Affiliation(s)
- Ana Raquel Barbosa
- National Reference Laboratory for Bacterial Respiratory Infections, Department of Infectious Disease, National Institute of Health Dr. Ricardo Jorge, Av. Padre Cruz, 1649-016 Lisbon, Portugal
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Direct detection by real-time PCR of ftsI gene mutations affecting MICs of β-lactam agents for Haemophilus influenzae isolates from meningitis. J Infect Chemother 2011; 17:671-7. [DOI: 10.1007/s10156-011-0256-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2010] [Accepted: 03/23/2011] [Indexed: 10/18/2022]
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SUNAKAWA K, TAKEUCHI Y, IWATA S. Nontypeable Haemophilus influenzae （NTHi） Epidemiology. ACTA ACUST UNITED AC 2011; 85:227-37. [DOI: 10.11150/kansenshogakuzasshi.85.227] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
| | | | - Satoshi IWATA
- Center for Infectious Diseases and Infection Control, Keio University School of Medicine
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Llarrull LI, Testero SA, Fisher JF, Mobashery S. The future of the β-lactams. Curr Opin Microbiol 2010; 13:551-7. [PMID: 20888287 DOI: 10.1016/j.mib.2010.09.008] [Citation(s) in RCA: 129] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2010] [Revised: 09/08/2010] [Accepted: 09/09/2010] [Indexed: 11/15/2022]
Abstract
In the 80 years since their discovery the β-lactam antibiotics have progressed through structural generations, each in response to the progressive evolution of bacterial resistance mechanisms. The generational progression was driven by the ingenious, but largely empirical, manipulation of structure by medicinal chemists. Nonetheless, the true creative force in these efforts was Nature, and as the discovery of new β-lactams from Nature has atrophied while at the same time multi-resistant and opportunistic bacterial pathogens have burgeoned, the time for empirical drug discovery has passed. We concisely summarize recent developments with respect to bacterial resistance, the identity of the new β-lactams, and the emerging non-empirical strategies that will ensure that this incredible class of antibiotics has a future.
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Affiliation(s)
- Leticia I Llarrull
- Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA
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Okada T, Morozumi M, Matsubara K, Komiyama O, Ubukata K, Takahashi T, Iwata S. Characteristic findings of pediatric inpatients with pandemic (H1N1) 2009 virus infection among severe and nonsevere illnesses. J Infect Chemother 2010; 17:238-45. [PMID: 20827563 DOI: 10.1007/s10156-010-0115-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Accepted: 07/29/2010] [Indexed: 10/19/2022]
Abstract
We analyzed the clinical features of inpatients at a Japanese pediatric department who were infected with pandemic (H1N1) 2009 virus. Study participants included 46 children hospitalized from July 2009 to January 2010. Infection with the virus was confirmed using real-time reverse transcriptase polymerase chain reaction (RT-PCR). The epidemic month was October 2009; 34 patients were boys, and median age was 7 years. Pandemic influenza-associated respiratory diseases included pneumonia (n = 42), bronchitis (n = 3), and pharyngitis (n = 1). The median time from onset to admission was 3 days. Children were divided into those with severe (n = 32) versus nonsevere illnesses (n = 14) according to Japanese guidelines. Significant features in the severe group were younger age, previous asthmatic attack, exacerbation of asthma, decreased oxygen saturation, elevated white blood cell/neutrophil counts and serum lactate dehydrogenase, and longer times from admission to being afebrile and discharged. Both groups showed lymphopenia at admission. Additional infection with Streptococcus pneumoniae was frequent in the severe group. Whereas 44 patients received antiviral therapy (median times from onset to initiation 2 days), 32 received antibiotics (median duration 7 days). All children recovered, with a median hospital stay of 8 days. Our observations suggest that history of asthma and preschool age might be risk factors for severe illness. Prompt initiation of antiviral and antibiotic treatments should be considered to prevent development of severe illness.
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Affiliation(s)
- Takafumi Okada
- Department of Pediatrics, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka, Meguro-ku, Tokyo, 152-8902, Japan
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