Primary Care Corner with Geoffrey Modest MD: Reduced Antibiotic Susceptibility of Meningococcus and Pseudomonas

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By Dr. Geoffrey Modest

Two recent articles highlight increasing antibiotic resistance.

  1. Neisseria Meningitides
  • Meningococcus is becoming increasingly resistant to third-generation cephalosporins (see or doi:10.1093/jac/dkw400). Details:
    • There are approx 500 cases annually of invasive culture-confirmed meningococcal disease in France, and about 76% of the samples go to theFrench National Reference Center for Meningococci for evaluation.
    • In 2012, of 357 invasive meningococcal isolates, 27% had a significant increase in their MICs (mean inhibitory concentrations) for penicillin G (increasing from 0.125 to 0.5 mg/L), though they still had low MICs for cefotaxime.
    • From 2012-15, 7% of these meningococcal isolates (25 of them) had higher penicillin G MICs (2% of all isolates), harboring a new allele (penA327), which was increasingly detected over this date range and not seen before 2012.
    • This allele additionally conferred a tenfold increase in the MIC for third-generation cephalosporins (C3Gs), and this seems to be specifically from this penA327 allele.
    • This penA327 allele is identical to one found in Neisseria gonorrheae, which is associated with reduced C3G for that species.
    • Several of these meningococcal isolates with the penA327 allele were from an outbreak of invasive meningococcal disease in MSM, from Germany and France.
    • Of note, similar isolates were also reported in patients with meningococcal urethritis, which raises the question of sexual transmission of meningococcus, acting like it was a gonococcus

Commentary:

  • There has been increasing meningococcal resistance to penicillin over the past several years. The French National Reference Center for Meningococci has detected reduced penicillin sensitivity in 26% of 1407 isolates from 2012-2015
  • This high-level N. meningitis resistance to penicillin has largely developed through b-lactamase production from the development of a Pen1 phenotype, leading to the recommendation that third-generation cephalosporins be used for treatment instead of penicillin for therapy. This Pen1 phenotype is mainly caused by alterations in the penA gene, and may well have been due to DNA changes in other Neisseria species. However, it appears that further alterations have led to a variant penA327 allele in a small but increasing number of samples, with attendant reduced susceptibility to C3Gs.
  • The fact that this allele was also reported in meningococcal urethritis, suggest both the possibility of sexual transmission as well as the possibility that there was transfer of resistance from Neisseria gonorrhoeae to Neisseria meningitides, perhaps through coincident infections
  • Although there is reduced susceptibility of N. Meningitidisto third-generation cephalosporins in these variants, the MICs are not high enough to change recommendations on using C3Gs for treatment.
  • The concern, of course, is the emergence of further resistance with clinically significant decreased sensitivity to cephalosporins. As we know, gonorrhea seems to be evolving into an increasingly untreatable disease (see https://stg-blogs.bmj.com/bmjebmspotlight/2016/07/27/primary-care-corner-with-geoffrey-modest-md-gonorrhea-resistance-increasing/ )

 

  1. Increasing Pseudomonas multidrug and carbapenem resistance (see DOI: 10.1093/jpids/piw064). Details:
  • This study looked at all pediatric patients (1 to 17 yo) between 1999 and 2012, reviewing the Surveillance Network Database-USA, which includes microbiology labs serving 300 hospitals across the nation. They defined multidrug resistant Pseudomonas as non-susceptibility to at least 3 of 5 antimicrobial classes (cephalosporins, b-lactam/b-lactamase inhibitor combinations, carbapenems, fluoroquinolones, and aminoglycosides.

Results:

  • 87,613 pediatric pseudomonas aeruginosa isolates were identified, of which 77,349 were tested against the 5 antibiotic classes.
  • 15,653 (20.2%) were multidrug resistant (MDR) and 8763 (11.3%) were carbapenem-resistant (CR). Of these resistant isolates, about 75% were from the respiratory tract, 45% occurred in children aged 13 to 17, and 44% were from the outpatient setting. Males and females were equally affected. The largest number, 24%, were from the West North Central region of the US but there were approximately 15% each from the South Atlantic, West South Central, and East North Central regions.
  • There’s been a linear increase in both CR and MDR over this time period, with MDR increasing from 15.4% to 26% and CR from 9.4% to 20%, both significant trends with p<0.001, representing a 4% annual increase

Commentary:

  • Pseudomonas resistance is mediated through several different mechanisms: enzymes that inactivate b-lactam antibiotics, including cephalosporinases and carbapenemases (leading to resistance to these medications), but also enzymatic and target site modifications (leading to resistance to aminoglycosides and fluoroquinolones), alterations in outer membrane permeability and multidrug efflux pumps (leading to multidrug resistance), the acquisition of mobile elements (plasmids and transposons), and production of protective biofilms. And, Pseudomonas has an unusual ability to survive in harsh environments.
  • The CDC estimates that 51,000 healthcare-associated pseudomonas aeruginosa infections occur in adults and children, of which greater than 6000 (13%) are MDR, and account for more than 400 deaths each year. The majority of cases in children are related to underlying cystic fibrosis. However, of significance, the above analysis excluded patients with CF, and therefore is more representative of the general population.
  • As per many prior blogs (see https://stg-blogs.bmj.com/bmjebmspotlight/category/antimicrobial-resistance/ which contains several blogs highlighting worldwide trends in antibiotic resistance/development of superbugs as well as guidelines from the World Health Organization), there is significant concern about increasing antimicrobial resistance. To me this is clearly a very scary and accelerating issue: when I look at any of the infectious disease journals, it seems now that most of the articles are about different microbes displaying increasing resistance. The reason i bring these above 2 articles up is mostly that we in primary care only see occasional articles that make it into the newspapers or general medical literature (e.g. the e. coli suberbug), and may not realize the true extent of the issue. And it is hard to invoke these big picture global public health concerns when treating the individual patient in the office requesting antibiotics.
  • There is some hope: several studies have suggested that aggressive antimicrobial stewardship programs, which restrict the use of broad-spectrum antibiotics, have been shown to be effective in decreasing CR pseudomonas in adult and pediatric populations. And a few studies have found decreasing inappropriate use of antibiotics e.g. see https://stg-blogs.bmj.com/bmjebmspotlight/2016/01/22/primary-care-corner-with-geoffrey-modest-md-antibiotic-overprescribing-and-acute-respiratory-infections/ ). But, as mentioned in several of the prior blogs, overall we need to have an increasingly aggressive program to decrease the development of resistance and, ultimately, to untreatable infections. This approach needs to be worldwide, including: using antibiotics only for clear indications, decreasing widespread antibiotic use in animals just to make them fatter/more profitable (this is 80% of antibiotic usage!!!), using the least broad-spectrum antibiotic that will work, as well as developing perhaps more consistent antibiotic stewardship programs as per the Pseudomonas issue. And we thereby protect our somewhat fragile and (it seems) frequently attacked microbiome….

 

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