KPC-Oxa 48? Yep. Good morning all and Welcome to Grand Rounds here at Blogmocracy General Hospital. The Doc’s downstairs in the Infectious Disease Lab wanted you to get out ahead of these dangerous bacteria. What makes this bacteria so dangerous is that it is immune to any and all antibiotics that we have in the arsenal.
Class D OXA β-lactamases are characterized as penicillinases that can hydrolyze oxacillin and cloxacillin and are poorly inhibited by clavulanic acid and EDTA. OXA-48 is one of the few members of this family to possess notable carbapenem-hydrolyzing activity (1). First described in 2004 in Turkey, OXA-48 has recently started to spread in Europe and the Middle East (2). We report the recent emergence of the plasmid-encoded blaOXA-48 gene in multidrug-resistant Enterobacteriaceae recovered from patients in Dakar, Senegal, in hospitals and in the community.
From November 2008 through October 2009, 11 Enterobacteriaceae isolates (8 Klebsiella pneumoniae, 1 Escherichia coli, 1 Enterobacter cloacae, and 1 Enterobacter sakazakii) with reduced susceptibility to imipenem were identified at the Institut Pasteur (Dakar, Senegal). Antibacterial drug susceptibility was determined by the disk diffusion method and interpreted according to the European Committee on Antimicrobial Susceptibility Testing guidelines (www.eucast.org
). Nine isolates were resistant to expanded-spectrum cephalosporins and also to other antibacterial drug classes.
What is happening here is that the bacteria has found a way to either render the antibiotic molecule useless or to absorb the ring that the antibiotic uses to disrupt the RNA/DNA of the bacteria reproductive cycle.
Antibiotic resistance can be a result of horizontal gene transfer,[73] and also of unlinked point mutations in the pathogen genome at a rate of about 1 in 108 per chromosomal replication. The antibiotic action against the pathogen can be seen as an environmental pressure. Those bacteria with a mutation that allows them to survive live to reproduce. They then pass this trait to their offspring, which leads to the evolution of a fully resistant colony.
The four main mechanisms by which microorganisms exhibit resistance to antimicrobials are:
- Drug inactivation or modification: for example, enzymatic deactivation of penicillin G in some penicillin-resistant bacteria through the production of β-lactamases
- Alteration of target site: for example, alteration of PBP—the binding target site of penicillins—in MRSA and other penicillin-resistant bacteria
- Alteration of metabolic pathway: for example, some sulfonamide-resistant bacteria do not require para-aminobenzoic acid (PABA), an important precursor for the synthesis of folic acid and nucleic acids in bacteria inhibited by sulfonamides, instead, like mammalian cells, they turn to using preformed folic acid.
- Reduced drug accumulation: by decreasing drug permeability and/or increasing active efflux (pumping out) of the drugs across the cell surface[74]
There are three known mechanisms of fluoroquinolone resistance. Some types of efflux pumps can act to decrease intracellular quinolone concentration.[75] In Gram-negative bacteria, plasmid-mediated resistance genes produce proteins that can bind to DNA gyrase, protecting it from the action of quinolones. Finally, mutations at key sites in DNA gyrase or topoisomerase IV can decrease their binding affinity to quinolones, decreasing the drug’s effectiveness.[76] Research has shown the bacterial protein LexA may play a key role in the acquisition of bacterial mutations giving resistance to quinolones and rifampicin.[77]
Antibiotic resistance can also be introduced artificially into a microorganism through laboratory protocols, sometimes used as a selectable marker to examine the mechanisms of gene transfer or to identify individuals that absorbed a piece of DNA that included the resistance gene and another gene of interest. A recent study demonstrated that the extent of horizontal gene transfer among Staphylococcus is much greater than previously expected—and encompasses genes with functions beyond antibiotic resistance and virulence, and beyond genes residing within the mobile genetic elements.[78]
For a long time it has been thought that for a microorganism to become resistant to an antibiotic, it must be in a large population. However, recent findings show that there is no necessity of large populations of bacteria for the appearance of antibiotic resistance. We know now, that small populations of E.coli in an antibiotic gradient can become resistant. Any heterogeneous environment with respect to nutrient and antibiotic gradients may facilitate the development of antibiotic resistance in small bacterial populations and this is also true for the human body. Researchers hypothesize that the mechanism of resistance development is based on four SNP mutations in the genome of E.coli produced by the gradient of antibiotic. These mutations confer the bacteria emergence of antibiotic resistance.
A common misconception is that a person can become resistant to certain antibiotics. It is a strain of microorganism that can become resistant, not a person’s body.[79][80]
Combine the above with airplanes and you get this:
Kiwi contracts superbug resistant to every antibiotic
Brian Pool’s twin sister Maureen Dunn said they were not even able to take him outside. Photo / File
A Wellington teacher is believed to be the first New Zealander to have contracted a superbug resistant to every antibiotic.
Brian Pool died in July from complications caused by a stroke, but doctors say his immune system was weakened from fighting the bacteria, Fairfax reported.
It was believed the 68-year-old picked up the bug while travelling overseas.
In January, while he was teaching English in Vietnam, Mr Pool suffered a brain haemorrhage and was operated on in a Vietnamese hospital.
He was flown to Wellington Hospital where tests found he was carrying the strain of bacterium known as KPC-Oxa 48 – an organism that rejects every kind of antibiotic.
Wellington Hospital clinical microbiologist Mark Jones told Fairfax: “Nothing would touch it. Absolutely nothing.
“It’s the first one that we’ve ever seen that is resistant to every single antibiotic known.
“This man was in the post-antibiotic era, and this is why so many agencies over the world are raising alarm bells.”
After the diagnosis, Mr Pool spent that last six months of his life in quarantine unable to leave his room.
His twin sister Maureen Dunn said they were not even able to take him outside.
“He just wanted to get out in the sun, and we couldn’t take him out.”
Ms Dunn said the family was frightened, and even doctors did not seem to know how the bug would affect others.
“They were s**t scared, to put it bluntly, in case these bugs were transferred to another patient or taken out into the community.”
Earlier this year, British chief medical officer Sally Davies described resistance to antibiotics as a “catastrophic global threat” that should be ranked alongside terrorism.
Wellington Hospital infectious disease physician Michelle Balm said Mr Pool’s superbug could have been contracted when he was in hospital in Vietnam, or a few years earlier when he had hernia surgery in India.
We are down to the drugs of last resort unless the Pharma industry can come up with something new.
A drug of last resort is a common name for a pharmaceutical agent that is tried after all other treatment options have failed to produce an adequate response in the patient. Such an alternative may be outside of extant regulatory requirements or medical best practices. It can also refer to situations in which only a single medication exists to treat a particular condition.
The use of a drug of last resort may be based on agreement among members of a patient’s care network, including physicians and healthcare professionals across multiple specialties, or on a patient’s desire to pursue a particular course of treatment and a practitioner’s willingness to administer that course. Certain situations such as severe bacterial related sepsis or septic shock can more commonly lead to situations in which a drug of last resort is used.
Therapies considered to be drugs of last resort may at times be used earlier in the event that an agent would likely show the most immediate dose-response related efficacy in time-critical situations such as high mortality circumstances. Many of the drugs considered to be of last resort fall into one or more of the categories of antibiotics, antivirals, and chemotherapy agents. These agents often exhibit what are considered to be among the most efficient dose-response related effects, or are drugs for which few or no resistant strains are known.
With regard to antibiotics, antivirals, and other agents indicated for treatment of infectious pathological disease, drugs of last resort are commonly withheld from administration until after the trial and failure of more commonly used treatment options to prevent the development of drug resistance. One of the most commonly known examples of both antimicrobial resistance and the relationship to the classification of a drug of last resort is the emergence of methicillin-resistant Staphylococcus aureus (MRSA) (sometimes also referred to as multiple-drug resistant S. aureus due to resistance to non-penicillin antibiotics that some strains of S. aureus have shown to exhibit). In cases presenting with suspected S. aureus, it is suggested by many public health institutions (including the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC) in the United States) to treat first with empirical therapies for S. aureus, with an emphasis on evaluating the response to initial treatment and laboratory diagnostic techniques to isolate cases of drug resistance.
Due to the possibility of potential severe or fatal consequences of resistant strains, initial treatment often includes concomitant administration of multiple antimicrobial agents that are not known to show cross-resistance, so as to reduce the possibility of a resistant strain remaining inadequately treated by a single agent during the evaluation of drug response. Once a specific resistance profile has been isolated via clinical laboratory findings, treatment is often modified as indicated.
Vancomycin has long been considered a drug of last resort, due to its efficiency in treating multiple drug-resistant infectious agents and the requirement for intravenous administration. Recently, resistance to even vancomycin has been shown in some strains of S. aureus (sometimes referred to as vancomycin resistant S. aureus (VRSA) or vancomycin intermediate-resistance S. aureus (VISA)) often coinciding with methicillin/penicillin resistance, prompting the inclusion of newer antibiotics (such as linezolid) that have shown efficacy in highly drug-resistant strains. There are also strains of enterococci that have developed resistance to vancomycin referred to as Vancomycin resistant enterococcus (VRE).
Agents classified as fourth-line (or greater) treatments or experimental therapies could be considered by default to be drugs of last resort due to their low placement in the treatment hierarchy. Such placement may result from a multitude of considerations, including: greater efficacy of other agents, socioeconomic considerations, availability issues, unpleasant side effects or similar issues relating to patient tolerance. Some experimental therapies might also be called drugs of last resort when administered following the failure of all known and currently accepted treatments.
Despite the fact that most of the notable drugs of last resort are antibiotics or antivirals, other drugs are sometimes considered drugs of last resort, such as cisapride.[1]
Examples
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