Write short notes on antimicrobial resistance with reference to:

(a)	Tuberculosis
(b)	Malaria
(c)	Staphylococcal infection

Outline:
•	Mechanism of resistance
•	Drugs in which resistance has developed
•	Alternative drugs

Suggested Answer:

(a)	Multiple-drug resistance (MDR) explains the reason in the emergence of resistant strains of mycobacteria in up to 70% of patients after 3 months of therapy. Multiple-drug resistance in mycobacteria is apparently the result of the step-wise accumulation of resistance to individual drugs. For example, mutations in the catG and inhA genes are associated with isoniazid resistance, while the rpoB gene responsible for RNA polymerase is altered in many clinical isolates resistant to rifampin. The threat of drug-resistant tuberculosis has made susceptibility testing mandatory for all initial isolates. Antimicrobial resistance to tuberculosis is often the result of non-compliance of patients which allow drug-resistant strains to survive and grow at a later date. Directly observed therapy (DOT) has been instituted in high prevalence areas, especially among recalcitrant patients, as the only reliable means of ensuring that patients complete their treatment successfully. Resistance to the first-line drugs of isoniazid, ethambutol, rifampicin and pyrazinamide is common and second-line drugs such as ethionamide, amikacin, ofloxacin and cycloserine may have to be used. 

(b)	Resistance of malaria parasites to antimalarials may be complete or relative; relative resistance can be overcome by raising the dose of the antimalarial. The choice of blood schizonticide depends upon the clinical condition of the patient, infecting species and possibility of drug resistance. Parenteral therapy is reserved for patients unable to take medications by mouth and for those with complicated malaria. Chloroquine-resistant P falciparum is widespread and currently exists in all malarious areas of the world except Mexico, Central America, the Caribbean and parts of the Middle East. P falciparum resistant to multiple drugs is most prevalent in S.E. Asia but is also present in Africa and Brazil. Therapy of chloroquine-resistant P falciparum is complicated and depends primarily on area of disease acquisition. Patients with uncomplicated disease acquired in areas of chloroquine resistance can be treated with one of several regimens effective against chloroquine-resistant parasites: mefloquine alone, or quinine, plus doxycycline or pyrimethamine/sulfadoxine (FansidarR). Other effective drugs include halofantrine, artemisinin (qinghaosu) derivatives, and clindamycin. Chloroquine-resistant P vivax is prevalent on the island of New Guinea. Primaquine-resistant P vivax is most prevalent in S.E. Asia and Oceania and is reported from other areas. Halofantrine, and chloroquine plus primaquine are highly effective against these resistant strains. Drug resistance has not been reported for P ovale or P malariae. If ever in doubt as to infecting species or presence of resistance, clinicians should assume the infection to be chloroquine-resistant P falciparum. Such therapy will cover all malaria species, although side effects may be more common. 

(c)	Most staphylococci strains are now resistant to penicillin by producing a bete-lactamase enzyme which destroys penicillin. Alternative antibiotics such as cloxacillin, nafcillin, erythromycin and cephalosporins have been used to treat staphylococcal infection. However, hospital strains of S aureus are often resistant to many different antibiotics. Indeed strains resistant to all clinically useful drugs, apart from the glycopeptides vancomycin and teicoplanin, have been described. The term MRSA refers to methicillin resistance and most methicillin-resistant strains are also multiply resistant. Plasmid-associated vancomycin resistance has been detected in some enterococci and the resistance determinant has been transferred from enterococci to S aureus in the laboratory and may occur naturally. S epidermidis nosocomial isolates are also often resistant to several antibiotics including methicillin. In addition, S aureus expresses resistance to antiseptics and disinfectants, such as quaternary ammonium compounds, which may aid its survival in the hospital environment. 
Since the beginning of the antibiotic era S aureus has responded to the introduction of new drugs by rapidly acquiring resistance by a variety of genetic mechanisms including acquisition of extrachromosomal plasmids or additional genetic information in the chromosome via transposons or other types of DNA insertion and by mutations in chromosomal genes. 
There are essentially four mechanisms of resistance to antibiotics in staphylococci: enzymatic inactivation of the drug, alterations to the drug target to prevent binding, accelerated drug efflux to prevent toxic concentrations accumulating in the cell, and a by-pass mechanism whereby an alternative drug-resistant version of the target is expressed. Numerous approaches have been tried to prevent the spread of antibiotic resistance such as isolation of patients with resistant organisms, use of narrow-spectrum antimicrobial agents and rotating the range of agents available.