Pan-resistant, Currently Untreatable Gram-Negative Infections Come Closer to Home

The global emergence of antimicrobial resistance among gram-negative (GN) species is a major public health concern. This year the US Centers for Disease Control and Prevention reported multiple cases of pan drug-resistant (PDR) Pseudomonas aeruginosa originating from a bariatric surgery clinic in Tijuana, Mexico, prompting the agency to issue travel warnings. Organisms were isolated from 10 patients across 2 states, and effective therapeutic options were very limited. As pan-resistant infections have become a reality, clinicians face an increasing dilemma with how to treat multidrug-resistant strains.

The first US case of pan-resistant bacteria was reported by McGann et al, which identified an Escherichia coli strain isolated from a urine culture in which both mcr-1 and bla_CTX-M were present on a novel IncF plasmid, resulting in resistance to both colistin and β-lactamase.

A 2016 case of pan-resistant Klebsiella pneumoniae was documented in the US in a woman who had recently arrived from India and was admitted to a Nevada hospital with SIRS. A K pneumoniae strain isolated from her hip abscess was shown to be resistant to all 26 antimicrobials tested, including B-lactams, colistin, and aminoglycosides (Table). Tigecycline demonstrated intermediate activity against this strain, but the patient died from septic shock within 1 month.³ Whole genome sequencing of the isolate revealed a 5.4Mb chromosome and 3 plasmids belonging to multi-locus sequence strain (ST)15, and 4 β-lactamase genes: 2 chromosomal extended-spectrum β-lactamase (ESBL) (bla _CTX-M-15 and bla _SVH-28) and 2 plasmid borne elements (the carbapenemase bla _NDM-1 and class C B-lactamase bla _CMY-6.). Genetically conferring resistance to all tested β-lactams and β-lactamase inhibitors.

K pneumoniae ST15, associated with transferable mcr-1 colistin resistance, has spread globally and resulted in the high prevalence of _CTX-M-15 observed in Asia and Europe. Although this strain was colistin-resistant, it lacked the mcr genes. These plasmids also contained elements similar to GN bacteria isolated from China, Nepal, India, the United States, and Kenya. However, not all recently approved or developmental agents were tested.

At the recent ASM Microbe conference in San Francisco, Lonsway et al characterized a P aeruginosa isolated from a urine culture of a US patient recently treated in India. Genetic characterization showed a combination of bla _NDM-1, bla _IMP-1, and bla _PME-1 (Pseudomonas ESBL). The bla _PME-1 ESBL gene was previously found in a Middle East isolate. None of these resistance mechanisms was plasmid borne; all were found on a 7.1mB Mb chromosome pair. Interestingly, colistin resistance was not due to mcr-1 or mcr-2; the mechanism is currently unknown. A range of approved and developmental agents were tested, however the only antibiotic with a minimum inhibitory concentrations (MIC) not considered resistant was cefiderocol, MIC 8 ug/ml (intermediate based on tentative CLSI breakpoints). The Table shows the MIC for these 2 strains.

As pan-resistant bacteria emerge globally, in order to prevent inappropriate therapy being instituted, susceptibility testing methods need to be current and able to detect these strains. Additionally, rapid genomic analysis is needed to identify resistance mechanisms, with reporting and surveillance of these strains imperative to monitoring resistance patterns.

Nicolette graduated from the University of Liverpool with an MPH in International Public Health. Currently a research consultant at GST Micro, she is interested in antimicrobial resistance, particularly how it affects patient quality of life, as well as health care policy, and women's health.

Glenn has worked in infectious disease with a special interest in antibiotic resistance for over 30 years. Formerly of Bayer, Oscient and ,most recently, Cempra he has recently been consulting with several companies on developing new antibiotics. He is also a member of the Contagion® Editorial Advisory Board.