KING EDWARD MEMORIAL HOSPITAL

Seth Gordhandas Sunderdas Medical College

Acharya Donde Marg, Parel,
Mumbai 400 012. India.
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Did U Know

We present fortnightly updates of select topics of interest in Microbiology

Topic of the fortnight:

Newer Beta Lactamases

 

Newer Beta Lactamases

The “new” β-lactamases, include extended spectrum ß-lactamases (ESBLs), plasmid mediated Amp C enzymes and carbapenem hydrolyzing β-lactamases (carbapenemases). Such enzymes are produced both by gram positive as well as gram negative bacteria. Each enzyme has a specific substrate (antibiotic) which it renders ineffective.

Chronologically, the serine beta lactamase SHV and TEM arose first in late 1960s, to render ampicillin and similar penicillins ineffective. To increase the spectrum of activity, third generation cephalosporins were introduced in early 1980s. Very soon (1983 – 1988), mutations in SHV and TEM were observed which rendered the organism capable of hydrolysing even the third generation cephalosporins such as cefotaxime, ceftriaxone and ceftazidime. These came to be known as extended spectrum beta lactamases or ESBLs. ESBLs hydrolyse (render ineffective) all third generation cephalosporins and monobactams but have no action on cephamycins . They are susceptible to beta lactamase inhibitors such as clavulanic acid > sulbactum > tazobactam. They are also susceptible to carbapenems. Unless therapy is started early with the right antibiotic, infection with ESBL producing strains are associated with treatment failure and higher rates of morbidity and mortality as compared to the non ESBL producers. Also, ESBL producing strains demonstrate additional resistance to other families of antimicrobials

The next enzyme to be recognised was CTX-M-1 which specifically hydrolysed Cefotaxime and has a worldwide distribution.

Subsequently, Amp C beta lactamases were recognised. AmpC β-lactamases are cephalosporinases whose preferred substrates are cephalosporins including cephamycins (cefoxitin and cefotetan) and are poorly inhibited by clavulanic acid. Thus, these enzymes have a spectrum similar to ESBL . In addition , they are resistant to beta lactamase inhibitors leaving carbapenems as the only drug of choice for treatment from the beta lactam group. The plasmid encoded Amp C beta lactamases are also being reported from many areas and in many bacterial species. In an organism that carries both ESBL and Amp C enzymes, it has been observed that over production of Amp C Can mask the presence of ESBL during laboratory testing.

For all these resistance mechanisms, risk factors include prior exposure to the same antimicrobial class, prolonged hospital stay, presence of indwelling devices and catheters , and severity of illness .

The increasing prevalence of ESBL and Amp C producing strains worldwide and the resultant increase in the usage of carbapenems has given rise to carbapenem resistant strains of enterobacteriaeceae especially Klebsiella pneumoniae , Enterobacter cloacae and Escherichia coli, a phenomenon previously restricted only to Pseudomonas and Acinetobacter species. Resistance to carbapenems could be mediated by carbapenemases , metallo beta lactamases , OXA enzymes, through porin loss or increased efflux. Of recent interest are the carbapenemase producing Klebsiella pneumoniae (KPC) and the metallo betalactamase producing Escherichia coli ( the New Delhi metallo beta lactamse NDM-1 is such a type) . KPC enzymes are now being recognised in other species as well and being reported from many countries including India . The presence of KPC renders all beta lactams ineffective. Class B Metallo-β-lactamases (MBL) render ineffective carbapenems, penicillins and extended spectrum cephalosporins but not aztreonam.

References and Further Reading

  • Jacoby GA & Munoz-Price L S. Mechanisms of disease-The new β-lactamases. NEJM.2005; 352:380-91
  • Hawkey PM. The growing burden of antimicrobial resistance. J Antimicrob Chemother.2008 Sep;62 Suppl 1:i1-9.
  • Sohei Harada, M.D.1,2, Yoshikazu Ishii, M.D.1, and Keizo Yamaguchi, M.D.
    Extended-spectrum β-Lactamases: Implications for the Clinical Laboratory and Therapy Korean J Lab Med 2008;28:401-12
  • Robert E Siegel Emerging Gram-Negative Antibiotic Resistance: Daunting Challenges,Declining Sensitivities, and Dire Consequences RESPIRATORY CARE APRIL 2008 VOL 53 NO 4

 

Archives

 

Topics – Archives

Presenting topics formerly discussed

Apoptosis

Apoptosis

For every cell, there is a time to live and a time to die.

There are two ways in which cells die:

  • they are killed by injurious agents
  • they are induced to commit suicide

Death by suicide

Cells that are induced to commit suicide:

  • shrink
  • have their mitochondria break down with the release of cytochrome c
  • develop bubble-like blebs on their surface
  • have the chromatin (DNA and protein) in their nucleus degraded
  • break into small, membrane-wrapped, fragments

The phospholipid phosphatidylserine, which is normally hidden within the plasma membrane is exposed on the surface.This is bound by receptors on phagocytic cells like macrophages and dendritic cells which then engulf the cell fragments. The phagocytic cells secrete cytokines that inhibit inflammation.

The pattern of events in death by suicide is so orderly that the process is often called programmed cell death or PCD. The cellular machinery of programmed cell death turns out to be as intrinsic to the cell as, say, mitosis. 

Programmed cell death is also called apoptosis.

CME – Aflatoxins

 

CME – Aflatoxins

1. Name two fungal species producing aflatoxins .
The aflatoxins are a group of structurally related toxic compounds produced by certain strains of the fungi Aspergillus flavus and A. parasiticus.

2. The most severe contamination occurs in which food/feeds?
The most pronounced contamination has been encountered in tree nuts, peanuts, and other oilseeds, including corn and cottonseed.

3. Which is the most predominant and toxic aflatoxin ?
Aflatoxin B1 is usually predominant and is the most toxic.

4. How are the aflatoxins designated ?
The major aflatoxins of concern are designated B1, B2, G1, and G2.

5. Which aflatoxins fraction is excreted in the milk of dairy animals which have consumed aflatoxins contaminated food?
Aflatoxin M a major metabolic product of aflatoxin B1 in animals and is usually excreted in the milk and urine of dairy cattle and other mammalian species that have consumed aflatoxin-contaminated food or feed.

6. Which system of the body do these aflatoxins affect?
Aflatoxins produce acute necrosis, cirrhosis, and carcinoma of the liver

7. Which of the aflatoxins is a potent carcinogen?
Aflatoxin B1 is a very potent carcinogen in many species

8. Which country has reported aflatoxicosis in humans?
One of the most important accounts of aflatoxicosis in humans occurred in more than 150 villages in adjacent districts of two neighboring states in northwest India in the fall of 1974.

9. What was the source in this outbreak?
Contaminated corn

10. Aflatoxicosis was initially called by which name?
In the 1960 more than 100,000 young turkeys on poultry farms in England died in the course of a few months from an apparently new disease that was termed “Turkey X disease”. They were all associated with feeds, namely Brazilian peanut meal.

11. How is the name aflatoxin derived?
The toxin-producing fungus was identified as Aspergillus flavus (1961) and the toxin was given the name Aflatoxin by virtue of its origin (A.flavis-> Afla).

12. Why are the aflatoxins designated as B,G or M?
The aflatoxins M1 and M2 were first isolated from milk of lactating animals fed aflatoxin preparations ; hence , the M designation . Whereas the B designation of aflatoxins B1 and B2 resulted from the exhibition of blue fluorescence under UV-light , while the G designation refers to the yellow-green fluorescence of the relevant structures under UV-light .

13. What is the relation of AFB to aflatoxin?
Urine samples collected after exposure to alfatoxins were found to contain 2,3-dihydroxy-2-(N7-guanyl)-3-hydroxyaflatoxin B1, trivially known as AFB-Gual .

14. Enumerate food detoxification strategies.
Because aflatoxin contamination is unavoidable, numerous strategies for their detoxification have been proposed. These include physical methods of separation, thermal inactivation, irradiation, solvent extraction, adsorption from solution, microbial inactivation, and fermentation. Chemical methods of detoxification are also practiced as a major strategy for effective detoxification .

15. Name a few other poisonous substances produced by fungi?
Some of the poisonous substances made by fungi, such as alpha-amanitin, and phalloidin from the death cap mushrooms, muscarine from the fly agaric, orellanine from the false chanterelle, and lysergic acid from ergot of rye have been purified and have found scientific and medical uses.

16. Trichothecenes are obtained from which fungus?
Disease of cereals known as “scab” had first been characterized in the 19th Century. The diseases were caused mainly by fungi of the genus Fusarium

17. Approximately how many research papers have been published on aflatoxins?
5000

18. Which other fungal genera produce aflatoxins?
Aflatoxins are produced by different species of Aspergillus, particularly flavus and parasiticus, as well as members of the Genera Penicillium and Rhizopus

19. What were the presenting clinical features of the Indian outbreak?
The illness was characterized by jaundice, rapidly developing ascites, portal hypertension and a high mortality rate.

20. What is Reye’s syndrome and how is it associated with aflatoxins?
Reye’s syndrome is characterized by symptoms of encephalopathy and fatty degeneration of the viscera. It occurs in children under 16 and is believed to follow nonspecific viral illness, influenza B and varicella. Abnormalities are present in mitochondrial structure and function, including defective oxidative phosphorylation. Aflatoxins have been reported to be associated with a Reye-like Syndrome in Thailand, New Zealand, Czechoslovakia, the United States, Malaysia, Venezuela, Europe.

 

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