Antibiotic resistance

When the early antibiotics such as penicillin and streptomycin went into use, individual general and species of bacteria tended either to be susceptible to them, or the drug had no effect. As antibiotics have been widely used, broadening the definition to include antiprotozoal, antifungal and antiviral drugs, organisms once exquisitely sensitive to specific drugs are no longer effective. In some cases, there may be partial resistance, so extremely high dosage levels, usually parenteral, may work, but in such cases, it is probably a matter of time until fully resistant forms emerge.

Given that resistant strains are developing faster than new antibiotics, resistance is a worldwide threat, according to U.S. intelligence analysis of patterns of infectious diseases and impacts. The first antibiotics became available a little more than a half-century ago, and antivirals are quite recent — yet a challenge of HIV therapy is the constant appearance of resistant viral strains. Multidrug resistant tuberculosis is a worldwide problem, given that any treatment of this disease is prolonged.

Development of resistance

At the microbial level, this may be due either to the antibiotic therapy allowing the survival of naturally resistant organisms of the species, or of the transfer of resistance genetic factors among bacteria. It is not, as once thought, a matter of natural selection, where a few organisms within a species randomly mutate, become resistant, and thus become better equipped for survival.

After a patient uses an antibiotic, the risk of resistant organisms is greatest after one month, but the risk may continue for one year.

Other mechanisms, not yet fully understood in the ecology, include the transfer of resistance genes among totally different species.

Human activities promoting antibiotic resistance

A number of organisms have developed resistance to antibiotics resistant to them. Assorted human actions cause much of the development of resistance, with reasons ranging to overprescribing antibiotics in situations where they are unlikely to help, to patients stopping therapy when they feel better but still have an active bacterial infection, to the use of antibiotics as agricultural growth stimulants.

Slowing the development of resistance

Interventions to reduce overprescribing have been systematically reviewed. One study on respiratory tract infections found "physicians were more likely to prescribe antibiotics to patients who they believed expected them, although they (the physicians) correctly identified only about 1 in 4 of those patients". The use of antibiotics varies among countries. Multifactorial interventions aimed at both physicians and patients can reduce inappropriate prescribing of antibiotics. Delaying antibiotics for 48 hours while waiting on improvement of respiratory tract infections or cystitis may reduce antibiotic usage; however, this strategy may reduce patient satisfaction.

Normal c-reactive protein levels have been used to help health care providers reduce antibiotic use.

Normal procalcitonin levels have been used to help health care providers reduce antibiotic use.

Antibiotic stewardship

At the Centers for Disease Control, a program called Get Smart for Healthcare has been instituted under Arjun Srinivasan, Associate Director of Healthcare-associated Infection Prevention Programs, One of its tenets is a three-step concept of responsible antibiotic use, called antibiotic stewardship:

1. "All antibiotic orders should have 3 pieces of information -- a dose, duration, and indication...it is certainly harder to stop therapy if you don't know why it was started in the first place. This challenge is compounded in today's healthcare system where the primary responsibility for patient care is frequently transitioned from one clinician to another.
2. "When placing orders, make certain that they include getting microbiology cultures. Knowing the susceptibility of the infecting organism can allow you to narrow a broad spectrum therapy, change the therapy to better treat resistant pathogens, or stop antibiotics when the cultures results suggest an infection is unlikely."
3. "When your culture results come back in 24-48 hours, let's take an antibiotic time-out. Stop and reassess therapy. Antibiotics are generally started before a patient's full clinical picture is known. Now that you have additional information including microbiology, radiographic and clinical information, ask yourself -- Is this antibiotic still warranted? Or more importantly, is this antibiotic still effective against this organism?"

Treating resistant forms

When a form was found resistant, especially if the mechanism of resistance was known, a variant of the same class of antibiotics might be useful.

Bacterial resistance to the penicillins

For example, the earliest example of bacterial resistance to penicillins was bacterial production of an enzyme called penicillinase, or, more precisely, penicillin beta-lactamase, which breaks a chemical bond in the key lactam structure of penicillin molecules.

Among the first responses were the synthesis of penicillins, such as methicillin, which protected this bond. In time, however, methicillin did not work on some bacteria, beginning with Staphylococcus aureus. Since S. aureus is an important pathogen, common in wound infection but also appearing in systemic disease, methicillin-resistant staphylococcus aureus ('MRSA) became a matter of close surveillance by infectious disease specialists.

Another approach was to co-administer a penicillin with a penicillinase inhibitor, such as clavulanic acid.

In serious infections with MRSA, the "last resort" tended to be vancomycin. Since vancomycin, for systemic infections, must be administered intravenously, it was relatively easy to restrict it to controlled hospital use, only for specific strains. Eventually, vancomycin resistance was seen among staphylococci; acquired resistance was first observed in Enterococci.

Bacterial resistance to the tetracyclines

Glycylcyclines were developed to "evade" resistance mechanisms of tetracyclines.

Multiple antibiotic therapy

A desperately ill patient may be treated with "shotgun" therapy before there is a firm diagnosis, using several antibiotics of which one or more reasonably may be expected to be effective. Cultures are taken before therapy begins, and the drugs changed when sensitivity results are back.

Several antibiotics are always given together for synergistic effect, such as trimethoprim-sulfisoxazole. In other cases, multiple antibiotics are given to avoid resistance formation in certain species, such as Mycobacteria. Quinupristin-dalfopristin, however, are a pair of streptogramin-class indicated for critical resistant forms, such as MRSA.