Antibiotic

If one antibiotic is good, two should be better - discuss.

Antibiotics are used in the treatment of bacterial infections and can be administered orally, topically or intravenously. They can act in two ways, by either preventing bacterial growth or by causing the death of bacterial cells; these are termed bacteriostatic and bactericidal respectively. Antibiotic doses are decided according to their minimum inhibitory concentration (MIC), and it is important that this value is as low as possible due to possible toxicity and resistance that could arise. In most cases of bacterial infection involving the use of antibiotics monotherapy is preferred, but in some instances the need for multiple antibiotics is essential. Administering a patient with two antibiotics concurrently is termed antibiotic combination or combination therapy. But the notion that two antibiotics are better than one is not as simple as it sounds, as this combination therapy can have its disadvantages.

Combination therapy is commonly used empirically to cover seriously ill patients suffering from a disease of unknown origin, until the disease causing agent is identified. It can also be used for the treatment of infection where the causative bacteria have acquired resistance, but this tends to be less common (Steenbergen et al 2009). The exploitation of combination therapy can decrease the frequency of resistance in the bacterial population causing disease. For example, if the patient was given daptomycin and ceftriaxone, which has recently been reviewed by Steenbergen et al 2009, to treat enterococcal infection, then the organisms resistant to daptomycin will be eradicated by ceftriaxone and vice versa. The organisms resistant to both will be the only bacteria that survive but these will be at such a low level that they will be of no threat to the patient. This means the incidence of emerging resistance due to the use of a combination of antibiotics will be the sum of the frequency of resistance from each individual antibiotic. However, if the bacteria were resistant to one of the antibiotics, e.g. daptomycin, it could be of detriment to the patient as only the second antibiotic, e.g. ceftriaxone, would be active against the bacteria and the chance of resistance to the antibiotic would be as high as using the antibiotic alone (Lancini et al 1982).

In clinical practice, it is common for multiple antibiotics to be used when a patient presents with a polymicrobial infection where the range of micro-organisms causing disease will have different susceptibilities to each antibiotic, for example, Otis media, abscesses and peritonitis (Slinger et al 2006, Montravers et al 1998). By administering multiple antibiotics for this reason the spectrum of the antibiotic treatment is much wider than the use of a single antibiotic.

The use of some antibiotics for monotherapy has unpleasant side effects and the MICs have to be very low to prevent any adverse effects on the host. This is observed with the treatment of MRSA with linezolid and due to these side effects is not recommended for use over 28 days in the USA (Nguyen & Graber 2009). By combining low doses (MIC) of two antibiotics administered, a decrease in toxicity could be observed, whilst having the same effectiveness as full dose monotherapy. This could be a solution for the treatment of MRSA with linezolid as discussed above and as there are various antibiotics whose toxicity poses a problem in treatment.

The use of combination therapy can result in three outcomes: synergism, additivity or antagonism, which are not possible with the use of monotherapy.

When a combination of antibiotics acts synergistically, the effects are larger than that of the sum of the antibiotics acting alone. Streptogramins are a good example of this as two groups, A (quinupristin) and B (dalfopristin), are combined to act synergistically to give the antibiotic synercid. Quinopristin and dalfopristin both bind to the 50S ribosome subunit at different points, with quinupristin inactivating peptidyltransferase and dalfopristin preventing peptidyl-tRNA positioning and therefore inhibiting the formation of a peptide bond. Used separately, these streptogramins have a bacteriostatic effect but when used in combination their effect is bacteriosidal. This combination of antibiotics has been effective in the treatment of many Gram positive bacteria that have resistance to multiple antibiotics, for example MRSA (Moellering et al 1999).

However, the theory of synergism may be difficult to credibly demonstrate as the two antibiotics may not always be present at the optimum ratio at the site of infection within the host (Hugo et al 1998). This could be due to factors such as poor of absorption into the bloodstream, which is known to occur with rifaximin (Scarpignato &Pelosini 2005).

Additivity occurs when the combination of antibiotics have an equivalent effect to that of the sum of the effects of the antibiotics acting alone. Therefore the use of the drugs in combination would be of no extra advantage to the patient and the potential cost of the therapy would not merit the outcome.

Occasionally using combination therapy can result in antagonism, where the combined effect of the antibiotics is less than that of the more potent drug alone. This was shown by H. K Johansen et al (2000) where the combination of penicillin and erythromycin was used against pneumococci. Their results showed that the bactericidal activity of penicillin was entirely inhibited by erythromycin. This is due to the fact that penicillin requires the micro-organism to undergo active growth as it prevents cross linking in the final stage of the peptidoglycan biosynthesis pathway. If erythromycin prevents the growth of the bacteria due to its bacteriostatic properties, then this renders the penicillin ineffective.

Eliopoulos and Eliopoulos (1988) suggest that, at that time, if new suitable antibiotics became available with a much broader spectrum, then combination therapy could become redundant. This does not seem likely due to the frequency of resistance observed in bacterial populations in relatively short time frames.

In conclusion, although combination therapy is an indisposable tool in the fight against disease, monotherapy is still the most common choice of treatment overall. If an infection can be treated with just a single antibiotic then this would be least expensive and the use of a combination would be pointless. Combination therapy has its advantages including synergism and reduction of toxicity but it also had disadvantages, for example antagonism which is not possible with monotherapy. Therefore, although it would seem that two antibiotics should be better than one, this is not always the case.

References

Eliopoulos, GM & Eliopoulos, CT, (1988). Antibiotic Combinations: Should They Be Tested? Clinical Microbiology Reviews, 1(2), 139-156.

Goering, RV, Dockrell, HM, Zuckerman, M, Wakelin, D, Roitt, IM, Mims, C & Chiodini, PL (2008) Mim's Medical Microbiology. 4th Edition. Elsevier, China.

Hugo, WB & Russell, AD, (1998). Pharmaceutical microbiology. Blackwell science, UK.

Moellering, RC, & Weinberg, AN, (1971). Studies on antibiotic synergism against enterococci. II. Effect of various antibiotics on the uptake of 14 C-labelled streptomycin by enterococci. Journal of Clinical Investigations,50, 2580-2584.

Moellering, RC, Linden, PK, Reinhardt, J, Blumberg, EA, Bompart, F & Talbot, GH (1999). The efficacy and safety of quinupristin/dalfopristin for the treatment of infections caused by vancomycin-resistant Enterococcus faecium. Journal of Antimicrobial Chemotherapy. 44: 251-261

Johansen, HK, Jensen, TG, Dessau, RB, Ludgren, B & Frimodt-Moller, N (2000). Antagonism between penicillin and erythromycin against Sterptococcus pneumonia in vitro and in vivo. Journal of Antimicrobial Chemotherapy. 46: 973-980.

Lancini, G & Parenti, F (1982). Antibiotics: an integrated view, Springer-Verlag, New York.

Montravers, P, Mohler, J, Maulin, L & Carbon, C (1998). Early bacterial and inflammatory responses to antibiotic theapy in a model of polymicrobial peritonitis in rats. Clinical Microbiology and Infection. 4: 701-709

Scarpignato, C & Pelosini (2005). Rifaximin, a Poorly Absorbed Antibiotic: Pharmacology and Clinical Potential. International Journal of Experimental and Clinical Chemotherapy. 51(suppl 1): 36-66

Steenbergen, JN, Mohr, JF & Thorne, GM (2009). Effects of daptomycin in combination with other antimicrobial agent: a review of in vitro and animal model studies. Journal of Antimicrobial Chemotherapy. 64: 671-884.

Walsh, C, (2003). Antibiotics: actions, origins, resistance. ASM press, Washington DC.

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