Question

Recent headlines have highlighted the spread of MRSA infection in the United States. Accoridng to the CDC, MRSA is responsible for over 90,000 serious infections and over 18,000 hospital stay-related deaths per year in the United States. These MRSA strains are responsible for many serious skin and soft tissue infections, as well as pneumonia. One major problem with MRSA is that occasionally the skin infection can spread to other organs of the body with more severe, life threatening symptoms, including necrotizing fasciitis and necrotizing pneumonia, followed by sepsis and toxic shock, and then death in up to 50% of cases. A striking finding about these infections is that they occur in young immunocompetent patients who were previously healthy. MRSA is resistant to several commonly prescribed antibiotics that are usually effective against gram-positive bacteria (methicillin, penicillin, and cephalosporins), and an infection with MRSA strain can be deadly if left untreated. MRSA is subcategorized as community aquired or hospital aquired, depending on how the infection is usually aquired. Most community aquired MRSA strains are still sensitive to many antibiotics, such as trimethoprim, tetracycline, and clindamycin, but hospital aquired MRSA strains are often resistant to these drugs will still sensitive to vancomycin and linezolid.

A) Provide common mechanism that accounts for the observed resistance of MRSA to methicillin, penicillin, and cephalosporin. Provide two different strategies that could be used to overcome this particular resistance.

B) For each of the antibiotics trimethoprim, tetracycline, and clindamycin, provide a possible mechanism to account for the observed resistance of HA-MrSA to the antibiotic. Provide a strategy that could be used to treat patients infected with HA-MRSA resistant to these antibiotics.

C) Why would HA-MRSA strains that are resistant to methicillin, penicillin, cephalosporins, trimethoprim, tetraculine and clindamysic still show sensitivity to vancomycin and linezolid?

D) Although CA-MRSA is resistant to clindamycin, treatment with clindamycin in combination with rifampin results in an increase in the 50% lethal dose (LD50) value from 10 without antibiotic treatment to 10^4 with rifampin to 10^8 for combined treatment with clindamycin and rifampin. In addtion, treatment with clindamycin enhanced opsonization of CA-MRSA by macrophages. What possible mechanism(s) could account for these observations (i.e., change in the LD50 value and enhanced opsonization)? Provide your rationale. Provide an experiment that could be performed to confirm your hypothesis.

Answer 1

a) all the three antibiotics belong to a group called ?-lactams. These have a resemblance to D-alanyl-D-alanine of the pentapeptide that cross-links the cell wall. These pentapeptides are synthesized by penicillin-binding proteins (PBP) and ?-lactams bind it to inhibit its activity. Resistance is acquired by acquiring foreign PBP2a protein that is resistant to binding of ?-lactams.

?-lactams inhibit only transpeptidase, inhibition of transglycosylase activity of PBP2 can decrease resistance. Inhibiting pentaglycine synthesis helps in reducing the resistance against ?-lactams.

b) trimethoprim- altered chromosomal DHFR results in resistance

tetracycline- efflux and ribosomal protection

clindamycin- methylation of the target site on the ribosome

Reversal of trimethoprim resistance- reduced use

Reversal of tetracycline resistance- administering non-toxic synthetic bis tryptophan

Reversal of clindamycin resistance- none

c) Most MRSA patients resistant to many antibiotics die because of septicemia and multiorgan failure, because of this they fail to develop resistance against Vancomycin and linezolid

d) A change in surface molecules of the cells upon treatment with clindamycin could be responsible. Surface lipid, proteins or polysaccharides can be profiled.