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ID-microbial resistance

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

22 Nov, 16 | by EBM

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


  • 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 )


  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.


  • 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


  • 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 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 ). 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….


Primary Care Corner with Geoffrey Modest MD: Azithromycin Not Helpful In Acute Asthma

22 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Although antibiotics should not be routinely used in those with asthma exacerbations, per the British Thoracic Society and Global Initiative for Asthma guidelines, they are frequently prescribed at the pains of increased microbial resistance and microbiome changes, as well as potential adverse effects. A recent study found no efficacy for azithromycin for acute exacerbations of asthma (see doi:10.1001/jamainternmed.2016.5664), the AZALEA study.


  • 4582 patients from 31 centers in the UK, though only 199 patients qualified for the study (from their target of 380) and were randomized
  • Mean age 38; 70% female; 85% were on either:  regular preventer therapy, initial add-on therapy  or persistent poor control (i.e., few with either mild intermittent asthma or on continuous/frequent oral steroids); median FEV1=63% of predicted, FEV1/FVC=70%, peak expiratory flow (PEF) of 67% predicted
  • Inclusion criteria: 18-55 yo with any smoking history, 56-65 if less than 20 pack-year smoking, or >65 yo with <5 pack-year; documented asthma for >6 months; recruitment within 48 hours of asthma attack with acute deterioration of asthma control (increased wheeze/dyspnea/cough) necessitating systemic steroids per the attending MDs, and PEF or FEV1 <80% predicted
  • Randomized to azithro 500 daily for 3 days vs placebo, with posttherapy assessment at day 5 and 10, as well as serum sampling at 6 weeks
  • Primary outcome: diary card summary of symptom score (wheezing, dyspnea, cough assessed at 10 days after randomization). Secondary outcomes: acute Asthma Quality of Life Questionnaire, FEV1, FVC, FEV1/FVC, PEF, and time to 50% reduction of symptoms (and a few other measurements)


  • Primary outcome: asthma symptom score from 0-6, latter being severe symptoms — baseline 4.14 decreasing to 2.09 at day 10 with azithromycin, and 4.18 to 2.20 on placebo; i.e. no difference
  • Secondary outcomes: no difference in any (the graphs are basically overlaying for each of the first 10 days, including time to 50% reduction in symptoms)
  • Pathogens detected: 58% of patients provided sputum sample. 11% had bacteria or atypicals (e.g. mycoplasma/chlamydia); 18% had virus on nasal or throat swabs. and no difference by these results in azithro vs placebo groups [though numbers of patients were pretty small]
  • Adverse events: esp GI in the azithro group (35 vs 24 events). Also 4 vs 2 cardiac events. But respiratory/thoracic/mediastinal disorders were more in the placebo group (37 vs 27), none of these adverse effects were further defined


  • It is pretty striking that of the 4582 patients evaluated, 4383 were excluded (96% !!!), and, of these, 2044 (47% !!!!) were excluded because they were already on antibiotics. And this is at 30 secondary care hospitals and 1 primary care center. To me, this is what makes this study important: it is really common practice to give antibiotics to those with asthma exacerbations. Unfortunately the validity of this study was undermined by this recruitment dilemma: they took much longer to recruit patients than expected (took almost 3 years), loosened some of the recruitment exclusions (e.g., allowing people longer time until presentation to the ED), and still did not achieve their target number, getting only 67% of what they planned.
  • The expectation going into the study was, I think, that azithromycin would help because:
  • Respiratory URIs and atypical bacterial (mycoplasma and chlamydia, which can be as high as 40-60% by serology) are frequently associated with asthma exacerbations
  • Asthmatic patients have increased carriage of bacterial pathogens, susceptibility to bacterial infections, and impaired immunologic barriers (impaired interferon and type 1 T-helper cell responses)
  • Viral infections themselves impair innate antibacterial immune responses and increase bacterial adhesion to bronchial epithelium
  • So, clinically, acute bacterial infections are more common and more severe in asthmatic patients
  • Azithro has several appealing traits: it has broad anti-microbial activity (including against the atypicals), is anti-inflammatory (though all of these patients were on steroids), even has anti-viral properties, and augments the production of interferons (deficient in asthmatic patients)
  • And, as a marginally related issue, azithro can decrease recurrent COPD exacerbations (see Albert RK. N Engl J Med 2011; 365: 689)
  • There was a study showing that the antibiotic telithromycin works in decreasing asthma symptoms and leading to faster recovery (N Engl J Med 2006; 354: 1589), and telithromycin has less anti-viral activity than azithro. And has more hepatotoxicity to boot
  • There are some concerns about the AZALEA study: there may have been a real selection bias in who was recruited (i.e., most got antibiotics prior to the study. Were they sicker than the ones in this study, or did they have a disease that really was more amenable to the azithro?); and there were pretty low numbers of patients with atypical bacteria (chlamydia/mycoplasma) compared to many other studies (which also suggests a bias in the previously-treated excluded group). The telithromycin study had a  much higher percentage of atypicals, and most patients were not on steroids, which is a possibly major difference with the AZALEA study)
  • So, one question is whether there are ways to stratify patients who may or may not benefit. A recent blog (see ) reviewed community acquired pneumonias, noting for example that serum procalcitonin is quite specific for pneumonia (I.e. if <0.1 mg/L, one can either withhold or stop antibiotics). Or perhaps CRP levels are useful.
  • The bottom line: it would be great to have a more definitive study, with better recruitment than this one (i.e. early on and before antibiotics were prescribed), and which assessed potential biomarkers for more serious disease (e.g. procalcitonin, crp, ?others) to see if some group of patients might benefit from antibiotics. But at this point it seems that antibiotics are given to patients with acute asthma attacks probably much more often than necessary. My guess is that the patients who did qualify for this study probably should be on a short course of oral steroids and not antibiotics, and that we should be following them closely. Perhaps a phone call the next day or so, with re-evaluation if they are not improving.

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