Appropriate antibiotic prescribing for the general
Posted on Friday, November 06, 2009
While it is important for dental providers to keep current with published antibiotic guidelines (which may represent standards of care), there remains some controversy as to the evidence base for the efficacy of these recommendations. When antibiotics are indicated, their appropriate prescription remains an important challenge for dental and medical professionals alike.
Received: May 27, 2009
Accepted: June 26, 2009
General dentists regularly prescribe antibiotics, both to prevent infections or to manage existing oral or dental infections.1 In dental practice, antimicrobial agents have three major uses: for prophylaxis in patients with compromised immune systems caused by certain diseases or medications, for prophylaxis in patients at risk for developing infective endocarditis (IE), and for treatment of an acute dental infection.2
Given the widespread use of antibiotics, national committees representing authoritative professional groups have made official recommendations pertaining specifically to the indications described above. While the first line of treatment remains rigorous oral hygiene and local debridement as a strategy to decrease oral bacteremia, these organization guidelines help to minimize the negative effects of overprescribing antibiotics, including the development of resistant strains, medicolegal problems for clinicians, allergic reactions to antibiotics, and cost to the health care system.3-5 Understanding the pathogenesis of these infections (including the host immune response to bacteremia), together with the completion of prospective clinical trials, will allow for more evidence-based decisions concerning the continuation of this practice for different patient groups.
This article will focus specifically on the quantities and duration of basic antibiotic prescription. A clinical case report is included to help dentists recognize and manage patients who may be candidates for antibiotic therapy.
Antibiotic prophylaxis guidelines represent best practices and determine medicolegal standards, so it is important for dental providers to stay abreast of current recommendations.6-8 Examples of prophylactic antibiotic guidelines began when the American Heart Association recommended a prophylaxis regimen for bacterial (infective) endocarditis in 1955; the organization’s most current recommendations were issued in 2007.6 The British Cardiac Society and the British Society for Antimicrobial Chemotherapy also have updated their recommendations for IE prophylaxis in the last decade (the former in 2004; the latter in 2006). The ADA and the American Academy of Orthopaedic Surgeons have co-sponsored an advisory statement concerning antibiotic prophylaxis for dental patients with total joint replacements; that statement has been in effect since 2003.9
Although these recommendations were intended to help guide prophylactic antibiotic use, a 2007 review by Lockhart et al evaluated the evidence concerning patients with various medical conditions and devices for whom antibiotic prophylaxis was suggested prior to their undergoing a dental procedure. For many groups of patients, the authors found that no definitive scientific basis existed for the use of prophylactic antibiotics before dental procedures.10
Similarly, Lauber et al reported that “the empiric and broad use of antibiotic prophylaxis is clearly no longer acceptable, but details regarding responsible prescribing remain problematic and in the dental community, there has been a general trend toward overprescribing.”11
Regardless of these controversies, there remains consonance between the most common pathogens of concern and the antibiotics that should be prescribed.12-14
The right drug
When considering the three major uses of antimicrobial agents in the practice of dentistry, it is paramount that dentists understand the most commonly associated pathogens. Clinical effectiveness in treating an infection is based on correctly diagnosing the infecting micro-organism(s) and choosing the most specific and effective antibiotic. Ideally, bacteriologic assessment should be completed before treatment is started. However, certain conditions may prevent this from happening.
For example, treatment for an acutely ill patient cannot be delayed for the 48 hours or more that may be required to learn the results of bacteriologic tests. In such a situation, the choice of antibiotic must be based initially on the dentist’s knowledge of the usual causative micro-organisms in a specific disease entity and the antibiotic to which these organisms normally are susceptible. Table 1 outlines the predominant cultivable flora found in various sites of the oral cavity.
A variety of micro-organisms can cause IE, but staphylococci and streptococci account for the majority of cases. The International Collaboration on Endocarditis-Prospective Cohort Study identified the microbiologic etiology in 1,779 patients from 39 medical centers in 16 countries with definite endocarditis as defined by Duke criteria and reported that staphylococci were the etiologic agent in 744 cases (42%) and streptococci in 712 cases (40%).15 However, although Staphylococcus (a family of Gram-positive cocci) is the most ubiquitous family of organisms in the normal human flora, they account for less than 0.005% of the normal oral flora.15-18 Table 2 more closely associates the potential offending pathogens with the dental indication for antibiotics.19-23
Antibiotics are broadly categorized according to their spectrum of activity (see Table 3). Narrow-spectrum antibiotics are effective against either Gram-positive or Gram-negative micro-organisms but generally are not effective against both. Extended-spectrum agents affect a variety of Gram-positive and Gram-negative bacteria, while broad-spectrum antibiotics inhibit both Gram-positive and Gram-negative bacteria and, frequently, other bacteria as well. Although the susceptibility of a given pathogen may fall within the spectrum of activity for any of several antibiotics, it generally is best to use the most specific narrow-spectrum antibiotic to which the micro-organism is susceptible.
Narrow-spectrum antibiotics frequently are more effective than broad-spectrum agents against specific groups of susceptible micro-organisms. In addition, narrow-spectrum antibiotics produce less alteration of the normal microflora (that is, collateral damage), thereby reducing the incidence of super-infection. It is from these data that the guidelines described above were designed to help dentists select the appropriate antibiotic for treatment (see Table 4).
The right time
Antibiotic timing is defined in terms of when to begin or discontinue an antibiotic; this timing is an important consideration for dental practitioners. Again, consonance exists among published guidelines concerning prophylaxis, indicating that antibiotics should be initiated 30–60 minutes before the start of a dental procedure for patients at risk for IE.6-8 A 1990 study by Berney and Francioli was one of the first to scientifically evaluate the efficacy of single-dose amoxicillin either 30 minutes before or 30–240 minutes after bacterial challenge in rats with catheter-induced aortic vegetations.24 The authors verified that while empiric preoperative antibiotics should be considered the gold standard for IE prophylaxis, the antibiotic was still effective, even when it was administered as late as two hours postoperatively.
When treating an acute dental infection, antibiotics should be started as soon as possible after the performance of any mechanical intervention (such as incision and drainage). Given the guidelines described above, antibiotic selection can be made empirically based on the suspected pathogen(s); however, samples (such as blood, tissue, or sputum) should be obtained prior to starting the antibiotic to confirm a diagnosis via culture and sensitivity testing. This bacteriologic assessment can take up to 48 hours and ideally should be completed before treatment is started; however, treatment for an acutely ill patient cannot be delayed while awaiting the results of bacteriologic tests.
If an appropriate antibiotic was chosen empirically, the patient typically will have defervesced within 48 hours and the culture and sensitivity data will confirm only that an acceptable antibiotic was chosen. If an extended-spectrum or broad-spectrum agent was the initial empirical choice, the dentist may decide to continue therapy or to change to a narrow-spectrum agent. If the patient’s condition has shown no improvement within 48 hours, the results of the bacteriological tests should help guide the prescriber to an alternative therapy.
There are fewer specific indications as to when an antibiotic should be discontinued. While such criteria may seem self-evident (that is, the medication should no longer be necessary once the patient is clear of the infection), patients cannot be relied upon to determine this endpoint independently. Before discussing treatment duration, the term treatment time must be defined: Does it refer to the length of time during which the medication is administered or to the time during which therapeutic concentrations of medications are maintained at the site of infection? If pharmacodynamic models are available to determine treatment periods, the second option is preferred as being clear and measurable. Unfortunately, the science of pharmacodynamics does not supply the necessary answers concerning antibacterial therapy; as a result, the duration of therapy is conventionally described as the amount (length) of time during which the patient receives antibiotic therapy.25
In a 2007 review, Rubinstein reported that most treatment periods that appear in textbooks are not supported by scientific evidence. Similarly, treatment duration recommendations presented in therapeutic guidelines are most commonly based on expert opinion.25 In an era of increasing bacterial resistance and rising hospital costs, the necessary duration of therapies for treating common infections should be re-evaluated. Before resistance acquisition makes these issues obsolete, non-industry-sponsored, multicenter studies need to be conducted to eliminate any potential conflict of interest with the pharmaceutical industry.25
Recent studies have examined circulating biomarkers as surrogates for infections, since the limitations of clinical signs for diagnosing infection are well-known and non-definitive (for example, fever, increased heart rate, and leukocytosis).26 Calorimetry, the multiplex polymerase chain reactions of blood specimens, and biomarkers (especially procalcitonin) can significantly improve the diagnosis of bloodstream infections—possibly before clinical or classical laboratory manifestations—and thus can help dentists to better determine when to start or stop antimicrobial treatment (Chart 1).26 Until such testing becomes more widespread and economically viable, dentists have the option of counseling patients to either stop their antibiotic prescriptions 48 hours after symptom resolution or to take all of the medicine as prescribed until the course of antibiotics is finished.
While instructing patients to stop their prescription 48 hours after symptom resolution is preferable (to limit their exposure to antibiotics), the prescriber may feel that the patient is incapable of determining the exact time of symptom resolution and thus is unable to determine the appropriate time to discontinue therapy. In such instances, patients should be counseled to simply complete the prescription as originally written. In either case, the prescriber must consider the possibility of failure or relapse or the development of resistance, adverse effects, or superinfection when determining the optimal duration of therapy. According to the literature, shorter antibiotic treatment courses are becoming the standard of care, since there is strong evidence to suggest that reduced antibiotic usage results in fewer complications while still providing similar outcomes.25,27
Route and dosing intervals
While the guidelines described above clearly delineate the best choices for either antibiotic prophylaxis or treatment, ranges often are recommended when selecting an individualized dosing scheme. Although standard doses are effective in most patients, interpatient variability in medication response should be considered on a case-by-case basis (Chart 2). Again, when determining the optimal dosing regimen, the prescriber must consider the possibility of failure or relapse versus the development of resistance, adverse effects, or superinfection. For example, using low-dose penicillins to treat respiratory infections for longer periods than necessary is associated with an increased rate of Streptococcus pneumoniae resistance to penicillin.28
The oral cavity is not exempt from bacterial resistance to antibiotics. Although approximately 10% of common antibiotics (including penicillins, cephalosporins, macrolides, and tetracyclines) are prescribed in dental medicine, dentistry’s contribution to the development of antibiotic resistance may be substantial.29 Numerous studies have reported the existence of antibiotic-resistant and even multiresistant oral bacteria.30,31 The emergence of resistance in the oral microflora is almost certainly linked in large part to the improper use of antibiotics, in terms of either dosage (duration of treatment too long or dose too weak) or indication. The literature has demonstrated an association between the prevalence of resistant bacterial strains at subgingival sites and the consumption of antibiotics.32
In most cases, antibiotics for treating periodontitis are prescribed empirically, which may result in inappropriate treatment and lead to the development of bacteria that are resistant to one or more antibiotics. The use of doxycycline, for example, at subantimicrobial concentrations as an adjunct to scaling and root planing also has raised questions with regard to the development of antibiotic-resistant bacterial flora.33-36 Thomas et al reported that long-term use of subinhibitory concentrations of doxycycline did not contribute to a change in the antibiotic susceptibility of the subgingival microflora.37 Additional studies are required to confirm that oral bacteria that are in the presence of subinhibitory concentrations of doxycycline for long periods do not develop bacterial resistance.37
Since the primary goal of antimicrobial therapy is to provide adequate drug concentrations at the site of infection that will achieve bacterial eradication and clinical cure, loading doses often are suggested (for example, administering 600 mg of oral penicillin immediately, followed by 300 mg every six hours). This loading dose (also known as front loading) maximizes drug exposure at a time when the bacterial burden is likely to be high. This practice drives up the 24-hour area under the concentration-time curve to minimum inhibitory concentration (AUC:MIC) ratio, which is the pharmacokinetic/pharmacodynamic (PK/PD) parameter that best predicts the efficacy of most antibiotics.38
Doern and Brown reported that drug exposure can fluctuate greatly among patients receiving the same antibiotic regimen.39 As a result, dosing regimens based solely on mg/kg values may be inadequate for determining the target drug concentrations that best correlate with bacterial eradication and clinical cure.
A more accurate approach for determining appropriate dosing regimens and optimal drug exposure involves integrating the PK/PD parameters of a drug to determine its antimicrobial efficacy. Another important aspect of the integrated PK/PD approach is the ability to more accurately predict whether a dosing regimen is likely to induce bacterial resistance. Typical loading doses usually are twice the antibiotic’s usual dose (for example, 600 mg of clindamycin taken orally immediately, followed by 300 mg taken orally three times per day).
The right patient and the right procedure
This evidence and these guidelines should ensure that dentists select the right drug, in the right dose, at the right time. Ultimately, though, clinicians must determine whether they are treating the right patient. While the individual characteristics described in Chart 2 can help dentists to determine the most effective dose of a medication for a specific patient, other considerations (such as the patient’s pregnancy status, allergy history, ability to manage side effects, socioeconomic status, and level of compliance) all need to be considered.
For example, if a patient is unlikely to comply with the prescription of choice for most dental infections (500 mg of amoxicillin taken orally three times a day), a dentist might better ensure compliance by prescribing 500 mg of azithromycin immediately, followed by 250 mg orally once a day for four days. Some penicillins, such as penicillin V potassium and amoxicillin, generally are considered to be safe for use in non-allergic patients during pregnancy and are frequently used for susceptible organisms commonly encountered in this setting. By contrast, the FDA cited moxifloxacin (Avelox, Bayer Pharmaceuticals) as a pregnancy Category C drug, meaning that no controlled studies have been performed in women, while studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal, or other), or that studies involving women and animals are not available. Such drugs should be administered only if the potential benefit justifies the potential risk to the fetus.40,41
An 88-year-old woman had a chief compliant of “pain and swelling” localized to the left mandibular teeth. Her medical history was significant for depression, hyper-cholesterolemia, and peripheral neuropathy. Her medications included gabapentin (Neurontin, Pfizer, Inc.), sertraline (Zoloft, Pfizer, Inc.), ezetimibe (Zetia, Merck), propranolol (Inderal, Wyeth Pharmaceuticals), amytriptyline (Elavil), celecoxib (Celebrex, Pfizer Inc.), and hydrocodone/APAP (Lorcet). The patient reported no drug allergies but noted a gastrointestinal intolerance to aspirin. Blood pressure taken before treatment was 137/85 mmHg.
The patient’s remaining dentition (teeth No. 21–24) was examined clinically and radiographically (Fig. 1). Tooth No. 22 was sensitive to percussion and palpation and the radiograph showed a perapical radiolucency. Mild swelling of the buccal vestibule associated with tooth No. 22 was noted. After discussing treatment options and receiving informed consent, root canal therapy was initiated and completed without complication. Postoperatively, the patient was given a prescription of amoxicillin (500 mg, to be taken orally three times a day for seven days). A follow-up conversation with the patient confirmed that she had filled the prescription and completed it as indicated without incident.
The patient returned one month later for re-evaluation of tooth No. 22; at that time, she reported mild sensitivity but all other symptoms had resolved following the previous visit. However, six days after the re-evaluation, the patient returned to the office for an emergency appointment, claiming to once again feel extreme pain in the left mandible (Fig. 2). Intraoral swelling of the buccal vestibule adjacent to teeth No. 21–23 was present; in addition, extraoral swelling was present along the patient’s left chin/lower border of the mandible. Clindamycin (300 mg, taken orally) was prescribed immediately; this was to be followed by 150 mg, taken three times a day for 10 days.
Three days after starting the clindamycin, the patient returned to the office, complaining of intolerable pain from the area around tooth No. 22. No significant change was noted in symptoms; intra- and extraoral swelling were still present and the patient reported spontaneous and continuous pain. Local anesthesia was administered in preparation for incision and drainage. Profound anesthesia was difficult to achieve due to obvious signs of infection in the area; however, drainage was achieved and the swelling improved almost immediately after copious amounts of pus and blood were expressed. At this time, the antibiotic regimen was switched to 150 mg clindamycin and 500 mg metronidazole, which were to be taken concurrently four times a day.
Two days after the incision and drainage, the patient was contacted via telephone and reported that the swelling was reduced and her pain could now be controlled with acetaminophen and ibuprofen. Her only complaints were watery diarrhea and stomach discomfort since increasing the frequency of clindamycin. The antibiotic regimen was changed to penicillin V potassium (500 mg, taken four times a day for 10 days). At a two-week follow-up appointment, the patient reported no pain or discomfort and the affected area appeared to be healing within normal limits.
This case report highlights many of the teaching points reviewed in this article. In the case of the patient’s first prescription, empiric therapy with amoxicillin was appropriately prescribed for the suspected pathogens and her symptoms resolved rapidly. The patient also demonstrated excellent compliance with this prescription by taking the medication as prescribed.
When the patient returned a month later with similar symptoms, the dentist chose to prescribe a different antibiotic (clindamycin), perhaps after concluding that this recurrence was due to latent pathogens that had not been cleared by the initial amoxicillin prescription. In fact, amoxicillin is a potent bactericidal antibiotic; given its effectiveness a month earlier, a repeat prescription would have been prudent. By comparison, clindamycin is only bacteriostatic and has a narrower spectrum of activity, which resulted in treatment failure and forced the patient to return within three days complaining of intolerable pain from the area around the tooth.25
After incision and drainage, the antibiotic prescription was amended to increase the frequency of the clindamycin with the addition of metronidazole. This combination offers a wider spectrum of activity (Gram-positive, Gram-negative, and anaerobic coverage) compared to clindamycin alone, coupling two antibiotics that work by different mechanisms of action (metronidazole also is bactericidal). The patient reported being much improved within two days but complained of watery diarrhea and stomach discomfort (potential precursor symptoms of antibiotic-induced colitis). Since the patient had begun to defervesce, the clinician made the final antibiotic change (to penicillin alone) and the affected area healed.
The prescribing guidelines for cases similar to the one presented here continue to emphasize a select few antibiotics as the drugs of choice. A plethora of experience and evidence has helped dentists to define the likely pathogens of concern and bactericidal penicillins such as penicillin V potassium and amoxicillin are still considered the mainstays of therapy for most patients.1,2 Metronidazole is a potent anti-anaerobic antibiotic but it has such a narrow spectrum of activity that it seldom is effective by itself when prescribed empirically. There also is no PK/PD advantage to prescribing this medication more frequently than twice a day for oral infections.43 Similarly, there is no PK/PD advantage to prescribing clindamycin more frequently than three times a day.44
Overprescription practices for certain medical and dental situations, as well as the development of antibiotic-resistant strains of bacteria, could be greatly abated by paying closer attention to basic principles of prescription writing. A review of the current guidelines and evidence to date shows that all dentists should be able to achieve the goal of antibiotic therapy, to assure selection of the right drug at the right time and at the right dose for the right patient and the right procedure.
Dr. Goodchild is a clinical associate professor, Department of Oral Medicine, University of Pennsylvania School of Dental Medicine in Philadelphia, and a clinical assistant professor in the Division of Oral Diagnosis, Department of Diagnostic Sciences, New Jersey Dental School in Newark. Dr. Donaldson is Director of Pharmacy Services, Kalispell Regional Medical Center in Kalispell, Montana; a clinical professor, School of Pharmacy, University of Montana in Missoula; and a clinical assistant professor, School of Dentistry, Oregon Health & Sciences University in Portland.
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