Enzymes and combination therapy

Doctors fear that if the use of antibiotics is not curtailed we may soon approach a day when untreatable infections will rule the roost, say Dr Anita Joshi, Dr Varsha Shahane, Dr Renu Bharadwaj and Shilpa Risbud

It is said that the discovery of antibiotics and vaccination are two discoveries in microbiology that have added at least 20 years to the average life span of an individual. The first antibiotic to be discovered was penicillin, by Sir Alexander Fleming in 1929. The Wonder Drug Penicillin was extremely useful in controlling staphylococci and streptococci, which are responsible for a significant fraction of infections in human beings from sore throats and scarlet fever to septicaemias and pneumonias and even skin infections.

Later, the second World War served as an impetus for the discovery of more chemotherapeutic agents to combat disease thereby bettering human life. However, it does appear that the golden era of the antibiotics is coming towards an abrupt end. Today almost 70-80 per cent of staphylococcus aureus isolates are said to be resistant to penicillin. Some data from studies in B J Medical College and Sassoon General Hospitals in 2000 (Ghadge et al 2000) and 2004 (unpublished data) clearly highlights the problems of emerging antibiotic resistance.

The overuse and misuse of antibiotics is leading us towards an epidemic of antibiotic-resistant bacteria. Doctors fear that if the use of antibiotics is not curtailed we may soon approach a day when untreatable infections will rule the roost. Clinicians are now confronting bacteria that have built defenses against those very drugs that were once efficacious.

Bacteria that were once treatable have emerged stronger and sometimes more virulent than before. The appearance of multi-drug resistant bacteria is caused partly by the overuse and misuse of antibiotics and partly due to a resilience, which stems from the ingenious biochemistry of the microorganisms themselves.

To survive, microorganisms mutate into resistant strains. Overuse of antibiotics serves as a constant evolutionary selection pressure for resistant bacteria. The resistant members are selected over the susceptible ones.

There are three mechanisms of drug resistance viz. evasion, mutation mediated antibiotic resistance and acquired antibiotic resistance which is the most commonly occurring mechanism.
Consequently, it is extremely important that antibiotics be used judiciously and only when necessary. Treating viral infections with antibacterial agents is unwarranted except under those circumstances where they are employed prophylactically against secondary infections.

Secondly, antibiotics should be employed over the prescribed duration of a treatment. Premature termination of treatment (ie. drop-outs) leads to resistance. Thirdly, antibiotics could be employed together with another drug (combination therapy) such that a bacterium that achieves resistance to one antibiotic will not necessarily achieve simultaneous resistance to the second antibiotic; additionally, two antibiotics administered simultaneously may be capable of effecting synergism.

Combination therapy has been used for Pseudomonas wherein a b-lactam antibiotic and an aminoglycoside are given in combination. For instance, a combination of cefotaxime and ciprofloxacin or norfloxacin are administered. Combination therapy has also been frequently found to be effective against urinary tract infections (Ghadage et al).

On similar lines, a new concept explores the possibility of using novel polyenzyme formulations in combination with currently used antibiotics.

Advanced Bio-chemicals Ltd is an ISO 9002 company. The company is a leader in the enzyme industry as a manufacturer of quality enzymes for several years. The company has been providing enzymes to the pharmaceutical industry. Advanced Bio-chemicals is now into the development of a completely new range of health and disease management products.

Gram Negative bacilli: Percentage resistance among isolates
Antibiotic	2000	2004	Isolates
Ampicillin	90	81.7	Blood
Amikacin	24	41.9	Blood
Cefotaxime	53	61.35	Blood
Ciprofloxacin	42.5	51	Blood
Cotrimoxazole	81.75	72.6	Urine
Norfloxacin	67.5	65.45	Urine

Gram Positive cocci: Percentage resistance among isolates
Antibiotic	2000	2004	Isolates
Penicillin	52	70.6	Blood
Cefotaxime	27	35.15	Blood
Norfloxacin	65	72.5	Urine

The potential of using polyenzyme formulations developed completely from natural sources, as novel drugs, is being tapped with promising results.

In vitro research has revealed that these polyenzyme formulations show antibacterial, antifungal and antitubercular activities.
In vitro research has also revealed that a combination of polyenzymes with currently used antibiotics against several pathogenic fungi and bacteria can effectively reduce the Minimum Inhibitory Concentrations (MIC) of the antibiotic. Thus, lower levels of antibiotics given along with polyenzymes, may prove to be equally effective additionally reducing any toxicities and side-effects associated with the drugs.

Moreover, enzymes being complex molecules, the chances of acquiring resistance to them may be few. In addition, proteolytic enzymes have been shown to be immuno modulators thereby enhancing immune response. Enzymes have been well accepted as dietary supplements over many years and are known to be quite harmless.

Could this be a step in the right direction towards reduced toxicities, reduced side-effects and reduced antibiotic resistance, that too with the help of molecules as basic and as natural as enzymes?

Dr Anita Joshi is a biotechnologist, Dr Varsha Shahane is a lecturer, BJ Medical college Microbiolgy dept, Pune, Dr Renu Bharadwaj is a professor. & head, BJ Medical college, department of microbiolgy, Pune and Shilpa Risbud is with Advanced Biochemicals Ltd, Thane