Antibiotic Resistance Relevance to Dentistry

Yuwono,MD., PhD.

Resistance and Susceptibility

Determined by in vitro activity, pharmacologic characteristics, and clinical evaluation. The minimal inhibitory concentration (MIC) can be comfortably exceeded by doses tolerated by the patient. Susceptible - implies their MIC is at a concentration attainable in the blood or other body fluid at the recommended dose. Resistant - MIC is not exceeded by normally attainable levels

Mechanisms of Resistance
1) Accumulation barriers to an antimicrobic due to impermeability or active efflux 2) Alterations of an antimicrobic target which render it insusceptible 3) Inactivation of an antimicrobic by an enzyme produced by the microorganism

Cell Wall Barriers

Gram negative cell walls present a large barrier Porins allow access into the cell but these proteins can become mutated making the cell less susceptible

Influx/Efflux
Bacteria such as streptococci, enterococci, and anaerobes lack the necessary oxidative pathways for transport of aminoglycosides. Some bacteria have energy-dependent efflux mechanisms that pump either tetracyclines or fluoroquinolones from the cell

Altered Target
Antimicrobics act by binding and inactivating their target, which is typically a crucial enzyme or ribosomal site. Substitutions of one amino acid in a protein can alter its binding. First generation aminoglycosides and quinolones only bind one site. Newer agents bind at multiple sites on their target making resistance improbable.

An important example : -lactam family

In widely divergent gram-pos and gram-neg species changes in one or more of peptidoglycan transpeptidase penicillin-binding proteins (PBP) have been correlated with decreased susceptibility to multiple -lactams Causes: point mutations, substitutions of amino acid sequence, and synthesis of a new enzyme.

Enzymatic Inactivation
Most powerful and robust of resistance mechanisms -Lactamases - 100s of enzymes with variable activity against - lactam substrates Typically demonstrate high-level resistance with MICs above therapeutic rang

Genetics of Resistance
Intrinsic Acquired Mutational Plasmids and Conjugation Transposons and Transposition

Emergence of antibiotic resistant Streptococcus sanguis in dental plaque of children after frequent antibiotic therapy Pamela Erickson, DDS, PhD Mark Herzberg, DDS, PhD Pediatric Dentistry 21:181-185, 1999

Methods:
25 patients randomly chosen from pool of children between ages three and six who recently completed 10 days of antibiotic therapy for otitis media with amoxicillin, Septra (trimethoprim-sulfamethoxazole) or erythromycin-sulfisoxazole. Children in the control group had received no antibiotics within the past 24 months.

Samples of supragingival dental plaque were collected

from the buccal surfaces of both mandibular first primary molars using sterile cotton swabs. Antibiotic gradient plates were prepared with THB agar and used to precisely determine the level of antibiotic resistance. The same antibiotics were used at different gradients and those colonies whose MIC was greater than the expected blood levels were considered resistant.

All strains of S. Sanguis were tested for interactions with human platelets.

There was no effect on the ability of the S. Sanguis isolates to advere to or induce aggregation of heterologous human platelets.

There was no difference in frequency of isolation of strains of S. sanguis between otitis media and healthy controls

Antibiotic resistance: 60% of all isolates in the experimental group were resistant to at least one antibiotic 32% amoxicillin resistant 24% penicillin resistant Resistance to penicillin and amoxicillin is inversely related to the age Of the child and length of time since exposure.

60% of children harbor antibiotic resistant S. sanguis While antibiotic therapy was associated with the isolation of resistant strains it was not associated with a significant long-term change in the oral flora of these children

Studies in children have found that 78 - 81% of rheumatic children on oral penicillin prophylaxis harbored penicillin resistant Streptococci(Naiman RA, Barrow JG). The frequency of resistance decreased with the time since cessation of therapy and the age of the child (Sprunt et al). In 1997 the American Heart Association suggests that if patients are receiving antibiotics for otitis media or another problem the dental practitioner should observe an interval of time between procedures to reduce the emergence of resistance and for the mouth to repopulate with antibiotic-susceptible flora.

Antimicrobial susceptibility of 800 anaerobic isolates

from patients with dentalveolar infection to 13 oral antibiotics. Williams, Yanagidawa, Iwahara, Shimizu, Nakagawa Oral Microbiology Immunology 2007: 22: 285-288

A total of 800 Isolates from patients with dentoalveolar infection were

tested for their susceptibility to amoxicillin, amoxicillin/clavulanate, cefaclor, cefuroxime, cefcapene, cefdinir, erythromycin, azithromycin, Telithromycin, minocycline, levoflaxacin, clindamycin, and metronidazole Using an agar dilution method.

With Prevotella species, resistance to amoxicillin occcurred in 34% of isolates and all of these resistant

strains were found to produce -lactamase. Amoxicillin/Clavulanate, telithromycin, clindamycin, and metronidazole exhibit high antimicrobial activity against amoxicillinresistant strains of Prevotella species Cervical necrotizing fasciitis: 8-years experience Of microbiology V. Fihman, L. Raskine, F. Peptitpas, J. Matco Journal of Clinical Microbiology and Infectious Disease 2008

158 consecutive patients were admitted for CNF between December 1998 and June 2007 to a tertiary care center dedicated to adult ear-nose-throat emergencies. S. Oraalis and Prevotella are more frequent in dental CNF, whereas S. aureus is only found in pharyngeal CNF.

The majority of CNF patients received at least one

Antimicrobial therapy before admission: Resistance: Penicillin 18% Penicillin plus beta-lactamase inhibitor 26% Cephalosporin 14% Macrolide or strepogramins 11% Metronidazole 17% No difference was seen with treating with antibiotic before sampling or at the origin of the infection

Antibiotic resistance in general dental practice-a cause for concern?

Louise Sweeney, Jayshree Dave, Philip Chambers and John Heritage Journal of Antimicrobial Chemotherapy (2004) 53, 567-576 University of Leeds, UK 1998 Standing Medical Advisory Committee - Dentists account for 7% of all community prescriptions of antimicrobials. -lactams and erythromycin have higher concentrations in the serum than in the saliva. Azithromycin has higher concentrations in saliva than serum but depresses the effects of NSAIDs

Oral Flora
-hemolytic streptococci are the most frequent Potentially pathogenic: S. aureus, Enterococcus Faecalis, S. pneumoniae, S. pyogenes, Neisseria Meningitis, Haemophilus influenzae, and actinomyces

Aminopenicilliins
Amoxicillin resistance has been described in Veillonella and Prevotella denticola isolated from root canals. Resistance to amox is not widespread among anaerobes in deeper sites of the oral cavity (Fosse et al). Prevotella susceptibility is enhanced when amoxicillin is combined with clavulanic acid (Fosse et al).

Penicillins

 207 isolates of nine species of -hemo strep include S. mutans, S. salvarius, S. oralis, and S. mitis only S. mutans was universally susceptibile to PCN (Teng et al). S. oralis and S. mitis show the highest resistance among -hemo strep S. pneumoniae can transfer resistance as mosaic genes

Metronidazole
Dentist are the most frequent prescribers, ususally used in combination with other antibiotics Eight of 97 isolates form odontogenic abscesses were resistant (Roche & Yoshimori) Aa - 50 strains tested and 72% were resistant (Madinier et al) hemolytic strep have a high resistance to Cephalosporins Tetracycline resistance is encoded on the tet gene Of - hemolytic strep isolated from the oropharynx of children 23% were resistant, majority being S. mitis (Konig et al). Carriage of both tet(Q) and erm(F) is common Of the isolates resistant to tetracycline 67% were resistant to erythromycin Tetracycline resistance is widespread and infrequently used in dentistry

Chlorhexidine

Application for more than one week can cause an increased resistance in S. mutans and S. sobrinus

Antibiotic prescriptions
Most frequently prescribed for infections: Pen VK 60%, erythromycin 14%, amoxicillin 12%, metornidazole 8% Amoxicillin = 66% for prophylaxis Lonks et al report a case of endocarditis caused by isolate of S. mitis resistant to pcn and cefotaxime

Moral of the Story..

Avoid broad spectrum antibiotics if able Prescribe antibiotics judiciously Prescribe for the appropriate amount and duration