Antibiotic Resistance

Antibiotic Resistance and Maxillofacial Pathogens: Emerging Treatment Issues

The practice of using antibiotics to treat and control microbial infections is a little more than 50 years old. Widespread administration of multiple classes of antibiotics over the years has had the unfortunate secondary effect of inducing the emergence of an increasing array of drug-resistant microbial strains. This article will discuss the evolution of certain forms of antibiotic resistance, as well as the mechanisms by which bacteria render numerous antimicrobials ineffective. Special emphasis is placed on emerging issues relating to organisms making up portions of the normal oral microflora.

The introduction of antibiotic chemotherapy for the treatment and prevention of microbial infections in the 1940s represented a historical milestone for modern medicine. Documented clinical successes with penicillin, sulfonamide, and streptomycin regimens were viewed as early indicators of an ensuing "golden age" of antimicrobial chemotherapy. For the remainder of the 1940s and through a major portion of the 1950s, infections caused by many common bacterial pathogens were successfully treated in both hospitalized patients and outpatients. Prominent on the list of susceptible microorganisms were strains of Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, and Mycobacterium tuberculosis.

With widespread antibiotic use, and the sometime misuse of readily available drugs, subsequent observed patterns of infectious disease were very different from those previously studied. Unfortunately, a subtle characteristic of microbial life was asserting itself at the same time that dramatic cures were being chronicled against microbial infection -- the incredible potential for microorganisms to adapt to and survive adverse environmental conditions. Early manifestations of bacterial adaptability to antibiotics were apparent soon after the introduction of penicillin G. Certain strains of E. coli and S. aureus were found to develop an adaptive mechanism aimed at surviving exposure to this bactericidal agent. A bacterial enzyme, termed penicillinase, was synthesized by bacteria that had acquired resistance to penicillin G. This adaptive product was capable of inactivating a core structural component (the beta-lactam ring) of the antibiotic.^1,2 At present, more than 90 percent of S. aureus strains are resistant to penicillin G, with a significant percentage also resistant to later generation beta-lactamase-resistant penicillins.

By the mid-1960s, resistance to penicillins and numerous other antibiotics was also well-documented among Pseudomonas aeruginosa, Haemophilus influenzae, Klebsiella pneumoniae, and other gram-negative bacilli. Among these important findings was the observation that gram-negative bacteria synthesize a greater variety of penicillin-inactivating beta-lactamases than do gram-positive bacteria.^3,4 With continued discoveries of emerging resistant bacteria, viruses, and mycotic organisms, certain common antimicrobials became less viable treatment choices or were eliminated altogether as treatment considerations for many hospital- and community-acquired infections (Table 1).⁵ The developmental significance of these resistance mechanisms cannot be overstated, as therapeutic approaches during medical encounters with nosocomial infections had to be dramatically modified. As a result, people presenting with infections harboring resistant microorganisms are more likely to require hospitalization, remain hospitalized longer, and have higher mortality rates than are patients with more antibiotic-susceptible strains.^6-8 Even after successful treatment of clinical infection, some patients become carriers, where antibiotic-resistant organisms remain as components of the host's resident microflora. Depending on the primary carrier site within the host's system, the potential exists for later infections demonstrating very different antibiotic sensitivity profiles.

Mechanisms of Acquired Resistance

A common misunderstanding among health profession students is that exposure of infectious microorganisms to antibiotics in affected tissues will typically destroy all of the invaders. In the world of clinical infections, however, administration of even the most appropriate microbiocidal agent can still induce a small percentage of target organisms to mutate, develop acquired resistance, and survive. The strong selective pressures exerted by antimicrobial agents will by necessity tend to eliminate weaker organisms rather quickly, while at the same time allowing the more resistant forms to remain viable for extended periods. Destruction and elimination of the latter microbes is then largely determined by the efficiency of the patient's innate and specific immune defenses. Since acquired drug resistance can be genetically transferred between members of the same strain, species, genus, or even between different genera, subsequent infections caused by surviving, cross-infected microorganisms may be more difficult to treat. In a very simplified sense, whatever does not kill pathogenic microorganisms can make them stronger and more difficult to destroy later.

Investigation of how acquired resistance develops has been a major focus of chemotherapy research since the early demonstrations of penicillinases, and several distinct mechanisms have been described (Table 2).^7-10 It is important to note that even as more-sophisticated techniques are used to investigate specific genetic alterations and stable passage of nucleic acid segments between microorganisms, decades of accumulated scientific information continues to reinforce a few basic trends:

* Bacteria eventually develop resistance to every new antibiotic. Acquisition and the extent of resistance is a matter of degree.⁹

* Selective pressure is exerted on microbial populations by antimicrobials. Early spontaneous mutations provide survivors with a growth advantage over susceptible targeted members of the population.

* Repeated antibiotic use to treat multiple infections in hospitalized patients is more efficient in selecting for emergence of resistant microorganisms. In some cases, multiple-drug resistance will develop in a species.

Antibiotic Resistance and Maxillofacial Pathogens

As can be seen in Table 2, some bacterial groups responsible for the onset and progression of a variety of maxillofacial infections have also developed resistance against commonly used antibiotics. This situation continues to create increased concerns and challenges for attending physicians, dentists, and infectious disease specialists alike on multiple fronts, including treatment of symptomatic infections, colonization and development of asymptomatic microbial carrier conditions, and cross-infection of susceptible people via carriers.

The presence of antibiotic-resistant pathogens in intra- and/or extraoral infections can complicate antibiotic therapy subsequent to drainage and debridement of symptomatic tissues. This may be more of a potential problem in the increasing percentage of patients with a variety of chronic immunosuppressed conditions. Multiple microbial groups listed in Table 2 have been shown to present this therapeutic dilemma; two will be briefly discussed -- S. aureus and anaerobes such as members of the genus Bacteroides.

Figure 1. Drainage of mandibular abscess. Analysis of bacterial cultures revealed methicillin-sensitive S. aureus as the major microbial species.

The ability of S. aureus to develop acquired resistance mechanisms against multiple generations of antibiotics has allowed this adaptive, gram-positive coccus to be among the most common causes of life-threatening hospital and community infections.¹⁰ Documented staphylococcal resistance against many antibiotic groups has made this a formidable adversary in nosocomial infections. While not a common etiology of intraoral infections, S. aureus is often isolated from exudates of many maxillofacial soft tissue and osteomyelitis infections. Fortunately, drainage and debridement of localized abscesses (Figure 1) can mechanically remove much of the infectious microbial population, thereby making prescribed antibiotic therapy more efficient against remaining pathogens in tissues. Where S. aureus is determined to be the primary microbial type, care must be taken in administering antibiotics. The antibiotic sensitivity profile of the isolates provides very important treatment information. Antistaphylococcal penicillins (beta-lactamase-resistant penicillins), such as nafcillin, oxacillin, and methicillin, have been effectively used to eradicate many of these soft tissue and bone infections.

Figure 2. Gram stain of a suppurative exudate smear taken from a periodontal abscess. The predominance of polymorphonuclear leukocytes as acute inflammatory cells is evident, as well as the presence of a mixed microbiota. Aerobic and anaerobic cultures of collected fluid specimens revealed streptococcal and staphylococcal species, along with multiple strict anaerobes, including Fusobacterium, Bacteroides, Prevotella, and Porphyromonas species. Clindamycin chemotherapy was successful in resolving the infection after appropriate debridement of the infection site.

With regard to antibiotic resistance in anaerobic bacteria, many infections of the oral cavity and most odontogenic infections involve anaerobes. Since anaerobes are among the most sensitive bacteria to environmental conditions and the metabolic activities of other bacteria, multiple facultative microbial forms will also be routinely found in cultured specimens (Figure 2). Presence of the latter, such as staphylococci and alpha- and nonhemolytic streptococci, typically provide conditions necessary for subsequent colonization and growth of the more fastidious strict anaerobes. Because necrosis and abscess formation are characteristic of most anaerobic infections, surgical drainage and/or debridement is the cornerstone of treatment. Antimicrobial chemotherapy is an important adjunct treatment modality, with a narrow-spectrum penicillin being a historically useful choice. However, treatment failures with these antibiotics have been reported,¹¹ with an increasing prevalence of beta-lactamase-producing anaerobes suspected as major causes. Strains of Bacteroides fragilis and Prevotella melaninogenica, among others, have become relatively penicillin-resistant due their acquired ability to produce beta-lactamases.¹² For example, in one study, more than 70 percent of 43 non-fragilis strains of Bacteroides were found to be penicillin-resistant.¹³ In addition, a gradual increase (20 percent to 40 percent) in beta-lactamase-synthesizing strains of P. melaninogenica has been noted in orofacial infections.¹⁴ Although decreasing effectiveness of other beta-lactams, such as cefoxitin, has been noted with members of the Bacteroides fragilis group,¹⁵ clindamycin resistance continues to remain relatively low.¹⁶ As a result, when traditional beta-lactam agents such as penicillins or cephalosporins are not options because of patient allergic reactions or bacterial resistance, clindamycin and metronidazole or new generations of beta-lactams with clavulanic acid have proven to be efficacious treatment alternatives.^17,18

Summary

The emergence of increasingly resistant microorganisms requires constant vigilance on the part of health care professionals with regard to utilizing alternative antimicrobial treatment approaches. As the number of hospitalized patients and outpatients presenting with infections containing drug-resistant strains rises, careful identification of etiologic organisms and their sensitivity profiles will continue to take on increased importance in ensuring successful treatment. What was once thought primarily to be a medical issue in hospitals has gradually involved more oral surgeons, periodontists, endodontists, and other dentists. In addition to symptomatic infections, affected patients may become colonized as short-or long-term carriers of strains of multiple-drug-resistant S. aureus or other potentially dangerous pathogens. It should also be remembered that colonization is much more common than clinical infection and also more difficult to eliminate. Judicious use of antibiotics only when needed and strict adherence to routinely effective infection control practices have been shown to reverse some of the described trends, and these approaches need to be expanded.

Author

John A. Molinari, PhD, is a professor and chairman of the Department of Biomedical Sciences at the University of Detroit Mercy School of Dentistry.

References

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To request a printed copy of this article, please contact/John A. Molinari, PhD, Department of Biomedical Sciences, University of Detroit Mercy School of Dentistry, 8200 W. Outer Drive, Detroit, MI 48219-0900.