Pre-detection history of #XDR #tuberculosis in #KwaZulu-Natal, South Africa (Proc Natl Acad Sci USA, abstract)

[Source: Proceedings of the National Academy of Sciences of the United States of America, full page: (LINK). Abstract, edited.]

Pre-detection history of extensively drug-resistant tuberculosis in KwaZulu-Natal, South Africa

Tyler S. Brown, Lavanya Challagundla, Evan H. Baugh, Shaheed Vally Omar, Arkady Mustaev, Sara C. Auld, N. Sarita Shah, Barry N. Kreiswirth, James C. M. Brust, Kristin N. Nelson, Apurva Narechania, Natalia Kurepina, Koleka Mlisana, Richard Bonneau, Vegard Eldholm, Nazir Ismail, Sergios-Orestis Kolokotronis, D. Ashley Robinson, Neel R. Gandhi, and Barun Mathema

PNAS first published October 28, 2019 / DOI:

Edited by Erwin Schurr, McGill University, Montreal, QC, Canada, and accepted by Editorial Board Member Carl F. Nathan October 3, 2019 (received for review April 17, 2019)



Epidemics of AMR pathogens are often only identified years or decades after they first evolved and distant from their place of origin. Consequently, evidence-based strategies for early containment of AMR epidemics are limited. This study employs whole-genome sequence data to reconstruct the “pre-detection” evolutionary and epidemiological history of an extensively drug-resistant Mycobacterium tuberculosis strain in KwaZulu-Natal, South Africa. We localize the geographic origin of this strain to an area hundreds of kilometers away from where the first clinical cases were reported and identify key host- and pathogen-specific factors that contributed to the rise of this important threat to global tuberculosis control. We propose that similar strategies can support the early identification and containment of AMR pathogens in the future.



Antimicrobial-resistant (AMR) infections pose a major threat to global public health. Similar to other AMR pathogens, both historical and ongoing drug-resistant tuberculosis (TB) epidemics are characterized by transmission of a limited number of predominant Mycobacterium tuberculosis (Mtb) strains. Understanding how these predominant strains achieve sustained transmission, particularly during the critical period before they are detected via clinical or public health surveillance, can inform strategies for prevention and containment. In this study, we employ whole-genome sequence (WGS) data from TB clinical isolates collected in KwaZulu-Natal, South Africa to examine the pre-detection history of a successful strain of extensively drug-resistant (XDR) TB known as LAM4/KZN, first identified in a widely reported cluster of cases in 2005. We identify marked expansion of this strain concurrent with the onset of the generalized HIV epidemic 12 y prior to 2005, localize its geographic origin to a location in northeastern KwaZulu-Natal ∼400 km away from the site of the 2005 outbreak, and use protein structural modeling to propose a mechanism for how strain-specific rpoB mutations offset fitness costs associated with rifampin resistance in LAM4/KZN. Our findings highlight the importance of HIV coinfection, high preexisting rates of drug-resistant TB, human migration, and pathoadaptive evolution in the emergence and dispersal of this critical public health threat. We propose that integrating whole-genome sequencing into routine public health surveillance can enable the early detection and local containment of AMR pathogens before they achieve widespread dispersal.

infectious disease – epidemics – tuberculosis – antimicrobial resistance – population genetics

Keywords: Antibiotics; Drugs Resistance; Rifampin; XDR-TB; Mycobacterium tuberculosis; TB; South Africa.


Non-lytic #antibiotic #treatment in community-acquired #pneumococcal #pneumonia does not attenuate inflammation: the #PRISTINE trial (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial

Geert H Groeneveld, Tanny J van der Reyden, Simone A Joosten, Hester J Bootsma, Christa M Cobbaert Jutte, J C de Vries, Ed J Kuijper, Jaap T van Dissel

Journal of Antimicrobial Chemotherapy, dkz207,

Published: 18 May 2019




The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.


We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.


In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).


Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.


The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Topic: antibiotics – rifampin – inflammation – immune response – community acquired  pneumonia – biological markers – cell wall – lactams – plasma – pneumococcal infections – pneumonia, pneumococcal – treatment outcome – inflammatory response – community – toll-like receptor 2 – attenuation


Keywords: Antibiotics; S. pneumoniae; Pneumonia; Beta-lactams; Rifampin.


#Assessment of the #potential for inducing #resistance in #MDR organisms from exposure to #minocycline, #rifampin and #chlorhexidine used to treat intravascular #devices (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Assessment of the potential for inducing resistance in multidrug resistant organisms from exposure to minocycline, rifampin and chlorhexidine used to treat intravascular devices.

Joel Rosenblatt, Nylev Vargas-Cruz, Ruth A. Reitzel, Issam I Raad

DOI: 10.1128/AAC.00040-19



To assess the potential for induction of antimicrobial resistance following repeated sub-inhibitory exposures to the combination Minocycline (M), Rifampin (R), and Chlorhexidine (CH), a total of 29 clinical microbial pathogenic isolates were repeatedly exposed to sub-inhibitory concentrations of M, R and CH for 20 passages. Minimum inhibitory concentrations (MICs) of the M, R and CH combination were assessed at each passage to evaluate the potential for resistance to have been induced. The combination of M, R and CH showed significant antimicrobial efficacy and synergy against organisms resistant to all 3 individual components (MIC ≥16 μg/mL for M, or MIC ≥4 μg/mL for R or CH). Among the organisms originally resistant to 2 or more individual components and the organisms originally susceptible to 2 or more individual components, there was no evidence that organisms became resistant following 20 repeated sub-inhibitory exposure cycles to the triple combination. The risk of resistance developing to the triple combination is extremely low because microbes are inhibited or killed before resistances can simultaneously emerge to all three agents. Surveillance studies monitoring development of resistance should be conducted in a clinical setting.

Copyright © 2019 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Minocycline; Rifampin; Chlorhexidine.


#Synergistic antimicrobial #activity of #colistin in combination with #rifampin and #azithromycin against #Escherichia coli producing #MCR-1 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Synergistic antimicrobial activity of colistin in combination with rifampin and azithromycin against Escherichia coli producing MCR-1

Yanqin Li, Xiaohuan Lin, Xuan Yao, Yan Huang, Wenguang Liu, Tao Ma, Binghu Fang

DOI: 10.1128/AAC.01631-18



The lack of available antibiotics is a global public health problem due to the emergence of antimicrobial resistance. Effective therapeutic regimens are urgently needed against Escherichia coli that produces colistin-resistance gene mcr-1 and to inhibit the emergence of resistance. In this study, we assessed the antimicrobial activity of a series of concentrations of colistin-based combinations with rifampin and/or azithromycin against three strains of Escherichia coli, including colistin-resistant isolate MZ1501R, HE1704R that produces MCR-1, and colistin-susceptible isolate MZ1509S. Experiments were conducted at a medium inoculum of ∼107 CFU/mL over 48 h. Subsequently, the in vivo therapeutic effect was investigated using a neutropenic thigh-infected mouse model. Almost all monotherapies showed unsatisfactory antibacterial activity against E. coli isolates producing MCR-1. By contrast, colistin in combination with rifampin or azithromycin resulted in an obvious decrease in bacterial burden, albeit with regrowth. More obviously, synergistic antimicrobial activity of colistin-based triple combination therapy with rifampin and azithromycin was observed, resulting in a rapid and exhaustive antibacterial effect. In vivo treatments confirmed these findings where a mean decrease of 0.38 to 0.90 log10 CFU and 1.27 to 1.78 log10 CFU was noted after 24 h and 48 h of treatment, respectively, against colistin-resistant E. coli strains when 5 mg/kg colistin was combined with rifampin and azithromycin. Colistin-based combinations with rifampin and azithromycin provide a more active therapeutic regimen than monotherapy or colistin-based double combinations against E. coli producing MCR-1.

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; E. Coli; MCR1; Azithromycin; Rifampin; Animal models.


Synergistic Activity of #Colistin-Containing #Combinations against Colistin-Resistant #Enterobacteriaceae (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae

Thea Brennan-Krohn a,b,d, Alejandro Pironti c and James E. Kirby a,d#

Author Affiliations: a Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; b Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA; c Broad Institute of MIT and Harvard, Cambridge, MA, USA; d Harvard Medical School, Boston, MA, USA



Resistance to colistin, a polypeptide drug used as an agent of last resort for treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria including carbapenem-resistant Enterobacteriaceae (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant Enterobacteriaceae isolates, 15 of which are also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the four most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.



#Corresponding Author: James E. Kirby, Beth Israel Deaconess Medical Center, 330 Brookline Avenue – YA309, Boston, MA 02215,, Phone: 617-667-3648, Fax: 617-667-4533

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; Linezolid; Rifampin; Azithromycin; Fusidic Acid.


#Neisseria meningitidis #antimicrobial #resistance in #Italy, 2006-2016 (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Neisseria meningitidis antimicrobial resistance in Italy, 2006-2016

Paola Vacca1, Cecilia Fazio1, Arianna Neri1, Luigina Ambrosio1, Annapina Palmieri1 and Paola Stefanelli1#

Author Affiliations: 1 Department Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy



The aim of the study was to evaluate the antimicrobial susceptibility of 866 Neisseria meningitidis invasive strains during 11-years of surveillance in Italy. Two and six strains were resistant to ciprofloxacin and rifampin, respectively. Forty-five percent were penicillin intermediate (PenI) associated with hypervirulent serogroup C clonal complex 11. All the strains were susceptible to cephalosporins.



#Corresponding author: Dr. Paola Stefanelli, Phone: +39 06 49902126, Fax: +39 06 49387112, Email:

Copyright © 2018 Vacca et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

Keywords: Antibiotics; Drugs Resistance; Neisseria meningitidis; Ciprofloxacin; Rifampin.