Avoidance and Disciplined
Use of Antimicrobials

Alexander G. Vandevelde, M.D., Division of Infectious and Communicable Diseases, Department of Medicine, University of Florida Health Science Center/Jacksonville and The Duval County Health Department
 
Among microbes, the Darwinian evolution is alive and well. The fittest organisms, the survivors became resistant to antimicrobial drugs. By now the environment is so polluted with antibiotics that many original, wild microbes have been driven into hiding by their mutated relatives or replaced all together by different, more resistant species. Since mutations - for the most part - are injurious to the microbe or demand extra energy to stay in existence, a less polluted ecology will allow a return of the wild-type microbes. Exchanges of resistance factors among the microbes and mutations took time to occur before arrival into the present predicament. Recalling the "friendly," less resistant bugs will take time as well.

Of course, antibiotics are major elements in our armamentarium for the fight against infections. They save a lot of lives, but there is only a limited window when antibiotics are effective. Their indiscriminate use is closing that window rapidly. The trick then is to use indicated antibiotics as little and for as short a time as possible. That will take courage and discipline.

Inappropriate antibiotic usage is mostly seen in respiratory infections, particularly in children. It is easier to write a prescription than to try to persuade a patient or parent that antimicrobials are to no avail in many situations. For any antibiotic use, indicated or not, one has to pay a price. Because of microbial resistance, cheaper generic antibiotics don't work anymore and have to be replaced by expensive proprietary drugs. Through its side-effects any antibiotic is always deleterious to a certain extent, sometimes to a severe extent: allergies, organ toxicity, damage to the normal flora of the recipient and superinfections.

How can we diminish the inappropriate use of antimicrobials and what are the options for control of resistance? One should approach the problem from several angles (Table I).

1/ Sanitation, behavior modification and vaccinations

Prevented and killed bugs never become resistant! Avoidance of infections can be accomplished by food sanitation and a behavior that is modified according to the circumstances. When eating abroad in developing countries, the old adage "boil it, cook it, peel it, or forget it," should be heeded. We should overcome our unjustifiable fear of food radiation and accept this effective sterilizing procedure for easily contaminated products that are industrially produced in large quantities, such as ground beef. Avoiding crowds during an influenza pandemic will prevent an exchange of the virus. If pathogenic microbes are unavoidable, vaccinations, if available, not only protect the vaccinee but also the population at large. The oral polio vaccine - now passé - benefited the entire population. Eliminating Haemophilus influenzae type b infections in children by the conjugated vaccine has engendered less frequent infections due to that same microbe in adults also. 1

2/ Prevention of the spread of resistant bacteria by hand hygiene

Infection control measures should be implemented not only in the hospital setting, but also in long-term facilities and at home. When one encounters patients with nosocomial infections due to bacteria that tend to be resistant, the healthcare worker should do his/her best to prevent the spread of these microbes to other patients. Isolation precautions, gloving when touching heavily colonized patients and hand hygiene (handwashing supplemented with alcohol-based hand disinfectants) are the mainstays for such prevention. Within the family, one should try to prevent the spread of diarrheal or upper respiratory infections from one member to another by hand hygiene, the use of disposable handkerchiefs, household disinfectants, repeated laundering and, if possible, a separate bedroom.

3/ Treatment of common infections by non-antimicrobial means

Every upper respiratory infection not only involves the rhinopharynx, but also the sinuses (viral rhinosinusitis).2 Because of the high pressures, nose blowing aggravates such sinus involvement. 3 Sneezing and sopping the nasal secretions will not squeeze more virus into the sinuses. Decongestants relieve the symptoms and avoid bacterial overgrowth by keeping the sinus ostia open. Acute bacterial rhinosinusitis is almost always preceded by viral rhinosinusitis, but it only complicates viral sinusitis in less than 2%. The diagnosis of acute bacterial sinusitis is easily made clinically, when the signs and symptoms have lasted more than 10 days or have worsened after a week. Antimicrobials prolong the carriage of Salmonella species in the gastrointestinal tract because protection from the normal gut flora is diminished. More dangerous than a simple colonization is the fact that antibiotics may increase the risk for hemolytic-uremic syndrome in patients with E. coli O157:H7. Here, the presumption is that cytotoxins are released in greater quantities during the killing process of the microbes. 4

4/ Disciplined use of antibiotics:

Prophylaxis

It is in the field of surgical prophylaxis that prolonged use of antibiotics is rampant. Yet, it has been proven that the administration of antimicrobials for the prevention of surgical site infections beyond 24 hours is wasted and leaves the door open for the development or the intrusion of microbes that are resistant to the prophylactic drug and others as well.

Empiricism

When confronted by an possible infectious disease syndrome of which the etiology is not known but demands immediate treatment, the choice of therapeutic drugs is a clinical, judgmental decision. It is wise to stay away from antimicrobials that are known to derepress inducible beta-lactamases 5,6,7. Many cephalosporins possess this effect to a certain extent, but ceftazidime, cefoxitime, as well as imipenem and the clavulanates (Augmentin® and Timentin®) are the main derepressing drugs. They can bring about resistances not only to themselves, but also to other b-lactams, thereby greatly limiting these valuable therapeutic tools and treatment options.1

Empiric antibiotics should be adjusted after the microbiologic data are back. At that moment the antimicrobial spectrum to kill the microbes should be made as narrow as possible to proctect the normal flora. Conversely, if after three days there is still no clinical evidence of infection, e.g. a pulmonary infiltrate in a patient on the ventilator without fever, purulent sputum, nor leukocytosis, one can safely discontinue empiric antimicrobials. Three days should be enough time to clear up the initial uncertainty. 8

Rapidly killing the etiologic agent

One should consider two or more antimicrobials under certain circumstances: for synergy and when dealing with polymicrobial infections or agents that become resistant rapidly. A point can be made also in patients who suffer from immunodeficiency where large numbers of microbes are anticipated and many are already resistant to any chosen drug before the start of therapy.

Experience has taught us where such strategy would be work. It does not mean that the use of multiple antibiotics has to be kept up for the duration of therapy. For example, if one treats a non-endocarditis or non-boney infection due to Pseudomonas sp. with a penicillin plus an aminoglycoside, the aminoglycoside can easily be dropped after 5 to 7 days. Indeed, the microbe is either killed after that period or it has become resistant to the drug.

Pulse therapy in chronic or recurring infections
and taking advantage of the post-antibiotic effect

Recurring infections, such as erysipelas in an extremity made edematous by surgery or varicosities, can be treated and then prevented with short periods of antibiotics. Rather than treating for many weeks, it is advantageous to treat to completion at first for about 14 to 21 days. Then, stop for several weeks and retreat any potential incubating recurrence like for 10 days each month. Other than the practicality of taking less antimicrobials and driving down the cost, the "drug holiday" will allow for some return of the normal flora, and make side-effects more tolerable for the patient. After an initial treatment period of six to twelve weeks for chronic osteomyelitis, an identical pulse strategy can be used if one is dealing with bacteria that are notorious to return after many weeks of dormancy and if effective oral drugs are available. Pulse-treating tuberculosis with two or three antibiotic administrations per week makes directly observed therapy possible. Although no studies are in the literature confirming the efficacy of such strategy, my experience is that it works very well.

Not treating treatable microbes

Patients suffering from chronic bronchitis do not always have to be treated for a flare-up of their bronchitis after a viral respiratory illness. As mentioned above, viral sinusitis during an upper respiratory infection is par for the course and can be treated with decongestants. Minor wound infections only require local care without systemic antimicrobials.

5/ Educating colleagues, patients and the public

Fortunately, patients are beginning to realize that viral infections cannot be treated with antibacterial antimicrobials and that bacterial complications of viral diseases cannot be prevented either. Physicians should continue educating their patients about the benefits and disadvantages of antimicrobials.

Agriculture consumes about 40% of all U.S. antibiotics. 9 Crowded conditions of livestock demand that when one chicken or one cow is sick, the whole flock or herd is to be treated. Since antimicrobials have been found to promote growth as well, treating the whole house is a combination of therapy and growth promotion. Direct transmission of pathogens, such as Salmonella sp. and Campylobacter sp., to humans, first as colonizers, than as disease agents can have dire consequences especially in immunocompromised patients. Furthermore, resistance factors on plasmids, transposons or through conjugation are being exchanged among different species, even non-related species from agricultural microbes to our own microbiota. Vancomycin-resistant enterococci appeared this way through the use of avoparicin, a congener of vancomycin used in Europe.

What can be done to avoid this antibiotic pollution of animals and the environment? It may be impossible to remediate the problem in a free-market environment until we find drugs that are only used in agriculture and do not cause resistance against drugs used in humans. In the meantime, we should avoid exposure to live bacteria from farm animals by scrupulous food hygiene and thorough cooking of all meats. Eating raw animal protein is dangerous for several reasons which includes the transfer of microbes.

Intense use of antimicrobials in long-term-care facilities is a fact and much of that use is inappropriate. Some of the worst resistances in microbes are encountered in patients transferred from such a facility to the hospital. The Society for Healthcare Epidemiology of America (SHEA) just published its position paper on this matter. Rather than a shotgun approach, a minimum of diagnostic studies are recommend in order to narrow the choice of antibiotics (Table II). 10

Conclusion

Antibiotics are double-edged swords. Even with disciplined antibiotic usage, certain resistances are unavoidable. With the right combination of strategies, however, we should be able to give our "friendly" microbes a change of survival and return. Prevention of infection is best of all. Next best is denying the spread of resistant microbes with precautions that do not involve the use of antibiotics. Whenever antimicrobials have to be used, let it be in situations where the duration of use is short, and the spectrum of activity is narrow. Prophylactic and empiric antibiotics should only be used for 24 and 72 hours respectively. Educating our colleagues, patients and the population at large in how to change antibiotic habits can be a disheartening task.

References

  1. Perdue DG, Bulkow LR, Gellin BG, Davidson M, Petersen KM, Singleton RJ and Parkinson AJ. Invasive Haemophilus influenzae disease in Alaskan residents aged 10 and older before and after infant vaccination programs. JAMA. 2000;283:3089-94.
  2. Gwaltney JM Jr, Phillips CD, Miller RD, Riker DK. Computed tomographic study of the common cold. N Engl J Med. 1994;330:25-30.
  3. Gwaltney GM, Hendley JO, Phillips CD, Bass CR, Mygind N, and Winther B. Nose blowing propels nasal fluid into paranasal sinuses. Clin Infect Dis. 2000;30:387-91.
  4. Wong CS, Jelacic S, Habeeb RL, Watkins SL and Tarr PI. The risk of the hemolytic-uremic syndrome after antibiotic treatment of Escherichia coli O157:H7 infections. N Engl J Med. 2000;342:1930-36.
  5. Pitout JD, Moland ES, Sanders CC, Thomson KS and Fitzsimmons SR. Beta-lactamases and detection of beta-lactam resistance in Enterobacter spp. Antimicob Agents Chemother. 1997;41:35-9.
  6. Sanders CC and Sanders WE. b-Lactam resistance in gram-negative bacteria: global trends and clinical impact. Clin Infect. Dis 1992;15:824-39.
  7. Patterson JE, Hardin TC, Kelly CA, Garcia RC and Jorgensen JH. Association of antibiotic utilization measures and control of multiple-drug resistance in Klebsiella pneumoniae. Infect Control Hosp Epidemiol. 2000;21:455-458.
  8. Singh N, Rogers P, Atwood CW, Wagener MM and Yu VL. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit: a proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med. 2000;162:505-11.
  9. Rosenthal M. Agribusiness contributes to growing problem of antibiotics resistance. Infect Dis News 2000;13(8):9-12.
  10. Nicolle LE, Bentley DW, Garibaldi R, Neuhaus EG, Smith PW and SHEA Long-Term-Care Committee. SHEA Position Paper: Antimicrobial use in long-term-care facilities. Infect Control Hosp Epidemiol. 2000;21:537-545.

NOTE: The plasmid-borne genes for b-lactamases in gram-negative bacteria, especially in E.coli and Klebsiella spp., can undergo further mutations. They produce novel molecules that are capable of hydrolyzing practically all extended cephalosporins, the penicillins and aztreonam. Such enzymes are referred to as extended spectrum b-lactamases (ESBLs). An encounter with ESBLs will limit the choices of antimicrobials since none of the b-lactam antibiotics can be used with the exception of the carbapenems (imipenem and meropenem). To make matters worse, on many occasions the ESBL is linked to plasmids that carry resistance genes against other antimicrobials as well, such as the aminoglycosides. For the time being at least, these ESBL enzymes are still neutralized by b-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam).

February, 2001/ Jacksonville Medicine

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