Faculty Opinions recommendation of Effect of high-dose amoxicillin on the prevalence of penicillin-resistant Streptococcus pneumoniae in rural Alaska.

ABSTRACT High-dose oral amoxicillin (3 g/day) is the recommended empirical outpatient treatment of community-acquired pneumonia (CAP) in many European guidelines. To investigate the clinical efficacy of this treatment in CAP caused by Streptococcus pneumoniae strains with MICs of amoxicillin ≥2 μg/ml, we used a lethal bacteremic pneumonia model in leukopenic female Swiss mice with induced renal failure to replicate amoxicillin kinetics in humans given 1 g/8 h orally. Amoxicillin (15 mg/kg of body weight/8 h subcutaneously) was given for 3 days. We used four S. pneumoniae strains with differing amoxicillin susceptibility and tolerance profiles. Rapid bacterial killing occurred with an amoxicillin-susceptible nontolerant strain: after 4 h, blood cultures were negative and lung homogenate counts under the 2 log10 CFU/ml detection threshold (6.5 log10 CFU/ml in controls, P < 0.01). With an amoxicillin-intermediate nontolerant strain, significant pulmonary bacterial clearance was observed after 24 h (4.3 versus 7.9 log10 CFU/ml, P < 0.01), and counts were undetectable 12 h after treatment completion. With an amoxicillin-intermediate tolerant strain, 24-h bacterial clearance was similar (5.4 versus 8.3 log10 CFU/ml, P < 0.05), but 12 h after treatment completion, lung homogenates contained 3.3 log10 CFU/ml. Similar results were obtained with an amoxicillin-resistant and -tolerant strain. Day 10 survival rates were usually similar across strains. Amoxicillin with pharmacokinetics simulating 1 g/8 h orally in humans is bactericidal in mice with pneumonia due to S. pneumoniae for which MICs were 2 to 4 μg/ml. The killing rate depends not only on resistance but also on tolerance of the S. pneumoniae strains.

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Activity of ceftaroline versus ceftobiprole against staphylococci and pneumococci in the UK and Ireland: analysis of BSAC surveillance data

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkaa306 ◽

2020 ◽

Vol 75 (11) ◽

pp. 3239-3243

Author(s):

Carolyne Horner ◽

Shazad Mushtaq ◽

David M Livermore ◽

M Allen ◽

D F J Brown ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Streptococcus Pneumoniae ◽

Time Trend ◽

High Dose ◽

Good Activity ◽

Surveillance Programme ◽

Gram Negative ◽

Methicillin Resistant ◽

Agar Dilution ◽

The Uk

Abstract Background Ceftaroline and ceftobiprole inhibit most MRSA and MDR pneumococci. Few direct comparisons of their activity have been published, but in several years (2008, 2013, 2017 and 2018) both were tested in parallel in the BSAC Resistance Surveillance Programme, giving paired results. These are reviewed. Methods Isolates included were bloodstream Staphylococcus aureus [n = 1884 (MRSA, n = 234)], bloodstream CoNS (n = 813; 574 methicillin resistant), and bloodstream (n = 852) and respiratory (n = 670) Streptococcus pneumoniae. MICs were determined by BSAC agar dilution and reviewed against EUCAST breakpoints; S. aureus breakpoints were assumed for CoNS. Results Ceftaroline MICs were mostly 2-fold lower than those of ceftobiprole, but, for all groups, MICs of both agents were strongly inter-related. Methicillin-susceptible staphylococci were universally susceptible to both agents; all MRSA were susceptible to ceftobiprole, whereas 10/234 had intermediate/high-dose susceptibility to ceftaroline. Among methicillin-resistant CoNS, 88% were susceptible to both agents, but reduced ceftaroline susceptibility and ceftobiprole resistance were frequent (65%) among methicillin-resistant Staphylococcus haemolyticus. One S. pneumoniae was resistant to both ceftaroline (MIC 0.5 mg/L) and ceftobiprole (MIC 1 mg/L) and seven others were only resistant to ceftobiprole (MIC 1 mg/L); seven of these eight pneumococci belonged to serotype 19A or 19F. No time trend in susceptibility was seen for either cephalosporin. Conclusions Ceftaroline and ceftobiprole have similarly good activity against staphylococci and pneumococci. Therapeutic choices between these agents should be predicated on other differentiating factors, including licensed indications, clinical experience and need for Gram-negative coverage.

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Mutations in PneumococcalcpsEGenerated viaIn VitroSerial Passaging Reveal a Potential Mechanism of Reduced Encapsulation Utilized by a Conjunctival Isolate

Journal of Bacteriology ◽

10.1128/jb.02602-14 ◽

2015 ◽

Vol 197 (10) ◽

pp. 1781-1791 ◽

Cited By ~ 12

Author(s):

Mara G. Shainheit ◽

Michael D. Valentino ◽

Michael S. Gilmore ◽

Andrew Camilli

Keyword(s):

Streptococcus Pneumoniae ◽

Invasive Disease ◽

Adaptive Mutation ◽

Specific Gene ◽

High Dose ◽

Wild Type ◽

Single Nucleotide ◽

Content Type ◽

Sepsis Model

ABSTRACTThe polysaccharide capsule ofStreptococcus pneumoniaeis required for nasopharyngeal colonization and for invasive disease in the lungs, blood, and meninges. In contrast, the vast majority of conjunctival isolates are acapsular. The first serotype-specific gene in the capsule operon,cpsE, encodes the initiating glycosyltransferase and is one of the few serotype-specific genes that can tolerate null mutations. This report characterizes a spontaneously arising TIGR4 mutant exhibiting a reduced capsule, caused by a 6-nucleotide duplication incpsEwhich results in duplication of Ala and Ile at positions 45 and 46. This strain (AI45dup) possessed more exposed phosphorylcholine and was hypersusceptible to C3 complement deposition compared to the wild type. Accordingly, the mutant was significantly better at forming abiotic biofilms and binding epithelial cellsin vitrobut was avirulent in a sepsis model.In vitroserial passaging of the wild-type strain failed to reproduce the AI45dup mutation but instead led to a variety of mutants with reduced capsule harboring single nucleotide polymorphisms (SNPs) incpsE. A single passage in the sepsis model after high-dose inoculation readily yielded revertants of AI45dup with restored wild-type capsule level, but the majority of SNP alleles ofcpsEcould not revert, suppress, or bypass. Analysis ofcpsEin conjunctival isolates revealed a strain with a single missense mutation at amino acid position 377, which was responsible for reduced encapsulation. This study supports the hypothesis that spontaneous, nonreverting mutations incpsEserve as a form of adaptive mutation by providing a selective advantage toS. pneumoniaein niches where expression of capsule is detrimental.IMPORTANCEWhile the capsule ofStreptococcus pneumoniaeis required for colonization and invasive disease, most conjunctival isolates are acapsular by virtue of deletion of the entire capsular operon. We show that spontaneous acapsular mutants isolatedin vitroharbor mostly nonrevertible single nucleotide polymorphism (SNP) null mutations incpsE, encoding the initiating glycosyltransferase. From a small collection of acapsular conjunctival isolates, we identified one strain with a complete capsular operon but containing a SNP incpsEthat we show is responsible for the acapsular phenotype. We propose that acapsular conjunctival isolates may arise initially from such nonreverting SNP null mutations incpsE, which can be followed later by deletion of portions or all of thecpsoperon.

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Effect of high dose oral zinc in mice with severe infection with Streptococcus pneumoniae

Scandinavian Journal of Infectious Diseases ◽

10.1080/00365540701716833 ◽

2008 ◽

Vol 40 (5) ◽

pp. 363-367

Author(s):

Berit S. H. Hembre ◽

David E. Briles ◽

Harleen M. S. Grewal ◽

Tor A. Strand

Keyword(s):

Streptococcus Pneumoniae ◽

Severe Infection ◽

High Dose ◽

Dose Oral

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Homology analysis of 51 penicillin-intermediate Streptococcus pneumoniae isolates from Wenzhou City, China

Journal of International Medical Research ◽

10.1177/0300060520919061 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006052091906

Author(s):

Jin Zhang ◽

Da-Kang Hu ◽

Chun-Yan Gao ◽

Wei-Wei Shen ◽

Xin-Hua Luo ◽

...

Keyword(s):

Cluster Analysis ◽

Drug Resistance ◽

Streptococcus Pneumoniae ◽

Hierarchical Cluster Analysis ◽

Gel Electrophoresis ◽

Hierarchical Cluster ◽

Multi Drug Resistance ◽

High Dose ◽

Effective Prevention ◽

Contact Isolation

Objective To investigate drug resistance features and homology among penicillin-intermediate Streptococcus pneumoniae isolates from Wenzhou City, China. Methods Fifty-one penicillin-intermediate S. pneumoniae isolates were obtained from respiratory samples of infants and children hospitalized with lung infections. An antimicrobial susceptibility test was used to assess drug resistance. Polymerase chain reaction and agarose gel electrophoresis were used to identify S. pneumoniae isolates and pulsed-field gel electrophoresis (PFGE) was used to analyze molecular subtypes. Hierarchical cluster analysis of PFGE fingerprints was used to compare genetic diversity and relatedness of S. pneumoniae isolates. The Quellung test was used for serotyping. Results Fifty-one penicillin-intermediate S. pneumoniae isolates showed evidence of multi-drug resistance and polyclonal origins. The isolates were classified into 25 subtypes through hierarchical cluster analysis of PFGE fingerprints. Three of these subtypes formed a supertype (15/51, 16/51 and 8/51 isolates), while the remaining subtypes occurred sporadically (12/51 isolates). Conclusions Transmission of penicillin-intermediate S. pneumoniae is mostly vertical and to a lesser extent horizontal. Effective prevention strategies, including respiratory tract management and contact isolation, are essential to control nosocomial S. pneumoniae infection. Once susceptibility is confirmed, vancomycin, high-dose penicillin or third-generation cephalosporins (cefotaxime and ceftriaxone) may be used to treat penicillin-intermediate S. pneumoniae.

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Evaluation of a volunteer sample in nasopharyngeal colonization surveys for Streptococcus pneumoniae in rural Alaska

International Journal of Circumpolar Health ◽

10.3402/ijch.v64i1.17950 ◽

2005 ◽

Vol 64 (1) ◽

pp. 16-25 ◽

Cited By ~ 3

Author(s):

Dana L. Bruden ◽

Thomas W. Hennessy ◽

Jay C. Butler ◽

Debra A. Hurlburt ◽

Debra J. Parks ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Nasopharyngeal Colonization ◽

Rural Alaska

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Importance of Bacterial Replication and Alveolar Macrophage-Independent Clearance Mechanisms during Early Lung Infection with Streptococcus pneumoniae

Infection and Immunity ◽

10.1128/iai.02788-14 ◽

2015 ◽

Vol 83 (3) ◽

pp. 1181-1189 ◽

Cited By ~ 21

Author(s):

Emilie Camberlein ◽

Jonathan M. Cohen ◽

Ricardo José ◽

Catherine J. Hyams ◽

Robin Callard ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Alveolar Macrophage ◽

Half Life ◽

Doubling Time ◽

Lung Infection ◽

Inoculum Size ◽

High Dose ◽

Content Type ◽

Bacterial Replication ◽

Doubling Times

Although the importance of alveolar macrophages for host immunity during earlyStreptococcus pneumoniaelung infection is well established, the contribution and relative importance of other innate immunity mechanisms and of bacterial factors are less clear. We have used a murine model ofS. pneumoniaeearly lung infection with wild-type, unencapsulated, andpara-amino benzoic acid auxotroph mutant TIGR4 strains to assess the effects of inoculum size, bacterial replication, capsule, and alveolar macrophage-dependent and -independent clearance mechanisms on bacterial persistence within the lungs. Alveolar macrophage-dependent and -independent (calculated indirectly) clearance half-lives and bacterial replication doubling times were estimated using a mathematical model. In this model, after infection with a high-dose inoculum of encapsulatedS. pneumoniae, alveolar macrophage-independent clearance mechanisms were dominant, with a clearance half-life of 24 min compared to 135 min for alveolar macrophage-dependent clearance. In addition, after a high-dose inoculum, successful lung infection required rapid bacterial replication, with an estimatedS. pneumoniaedoubling time of 16 min. The capsule had wide effects on early lung clearance mechanisms, with reduced half-lives of 14 min for alveolar macrophage-independent and 31 min for alveolar macrophage-dependent clearance of unencapsulated bacteria. In contrast, with a lower-dose inoculum, the bacterial doubling time increased to 56 min and theS. pneumoniaealveolar macrophage-dependent clearance half-life improved to 42 min and was largely unaffected by the capsule. These data demonstrate the large effects of bacterial factors (inoculum size, the capsule, and rapid replication) and alveolar macrophage-independent clearance mechanisms during early lung infection withS. pneumoniae.

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Disruption of the cpsE and endA Genes Attenuates Streptococcus pneumoniae Virulence: Towards the Development of a Live Attenuated Vaccine Candidate

Vaccines ◽

10.3390/vaccines8020187 ◽

2020 ◽

Vol 8 (2) ◽

pp. 187 ◽

Cited By ~ 2

Author(s):

Malik Amonov ◽

Nordin Simbak ◽

Wan Mohd. Razin Wan Hassan ◽

Salwani Ismail ◽

Nor Iza A. Rahman ◽

...

Keyword(s):

Developing Countries ◽

Streptococcus Pneumoniae ◽

Mutant Strain ◽

Double Mutant ◽

Gene Knockout ◽

High Serum ◽

High Dose ◽

Wild Type ◽

Knockout Mutant ◽

Double Mutant Strain

The majority of deaths due to Streptococcus pneumoniae infections are in developing countries. Although polysaccharide-based pneumococcal vaccines are available, newer types of vaccines are needed to increase vaccine affordability, particularly in developing countries, and to provide broader protection across all pneumococcal serotypes. To attenuate pneumococcal virulence with the aim of engineering candidate live attenuated vaccines (LAVs), we constructed knockouts in S. pneumoniae D39 of one of the capsular biosynthetic genes, cpsE that encodes glycosyltransferase, and the endonuclease gene, endA, that had been implicated in the uptake of DNA from the environment as well as bacterial escape from neutrophil-mediated killing. The cpsE gene knockout significantly lowered peak bacterial density, BALB/c mice nasopharyngeal (NP) colonisation but increased biofilm formation when compared to the wild-type D39 strain as well as the endA gene knockout mutant. All constructed mutant strains were able to induce significantly high serum and mucosal antibody response in BALB/c mice. However, the cpsE-endA double mutant strain, designated SPEC, was able to protect mice from high dose mucosal challenge of the D39 wild-type. Furthermore, SPEC showed 23-fold attenuation of virulence compared to the wild-type. Thus, the cpsE-endA double-mutant strain could be a promising candidate for further development of a LAV for S. pneumoniae.

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Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection

Vaccines ◽

10.3390/vaccines7040146 ◽

2019 ◽

Vol 7 (4) ◽

pp. 146

Author(s):

Sean Roberts ◽

Clare M. Williams ◽

Sharon L. Salmon ◽

Jesse L. Bonin ◽

Dennis W. Metzger ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Influenza A Virus ◽

Influenza A ◽

Influenza Infection ◽

Protein A ◽

Surface Protein ◽

Vaccine Antigen ◽

High Dose ◽

Pneumococcal Surface Protein A ◽

Relevant Dose

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

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