Oral Maxillofacial Surg Clin N Am 15 (2003) 17 38

Antibiotic selection in head and neck infections

Oral and maxillofacial surgeons see patients with infections as part of their everyday practice. It is imperative to understand the mechanisms of antimicrobial resistance, its potential problems, and the means of overcoming it. This situation raises several important questions with respect to antimicrobial therapy for odontogenic infections: 1. Is there a problem of antibiotic resistance? 2. How does antibiotic resistance arise? 3. Is antibiotic resistance the fault of the bacteria or the host or the result of treatment (ie, the medical and surgical community)? 4. What can be done to remedy the problem? The purpose of this article is to examine the problem of antimicrobial resistance in the oral cavity and make recommendations for antibiotic selection in the treatment of head and neck infections.

The acquisition of antibiotic resistance genes by bacteria allows such mechanisms to be implemented. There are four specific mechanisms by which bacteria acquire resistance genes: 1. Spontaneous mutation. This is the original source for all antibiotic resistance, because bacteria have maintained genes that encode for resistance of naturally occurring antibiotics of other species. For example, the DNA encoding of b-lactamases and penicillinbinding proteins have several homologous sequences [1]. 2. Gene transfer. Bacteria can undergo conjugation with a transfer of genes as plasmids, which are a composition of cytoplasmic loops of DNA that encode for antibiotic resistance, and transposons, which are able to insert themselves into the genome of the recipient cell. An example of a plasmid-mediated genetic event is acquisition of the ability to produce b-lactamase by some species. 3. Bacteriophages. Viruses infect bacteria and can insert genetic material and take control of the hosts genetic and metabolic machinery, which may encode for antibiotic resistance mechanisms. 4. Mosaic genes. Bacteria can absorb directly the fragments of the virally altered genome of dead members of related species to form a mosaic genome of genetic material from varying sources. This type of gene derivation is responsible for the non b-lactamase penicillin resistance in Streptococcus pneumoniae and meningococci and ampicillin resistance in Haemophilus influenzae and gonococci [1].

Molecular biology of antibiotic resistance Generally speaking, bacteria acquire antibiotic resistance in one of four ways: 1. 2. 3. 4. Alteration of a drugs target site Inability of a drug to reach its target Inactivation of an antimicrobial agent Active elimination of an antibiotic from the cell

* Corresponding author. Department of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115. E-mail address: [email protected] (T.R. Flynn).

1042-3699/03/$ see front matter D 2003, Elsevier Science (USA). All rights reserved. PII: S 1 0 4 2 - 3 6 9 9 ( 0 2 ) 0 0 0 8 2 - 1

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Antibiotic resistance mechanisms Once the genetic machinery is in place, bacteria exert antibiotic resistance by various pathways that are broadly classified in four ways. Drug inactivation or modification. The destruction or inactivation of the antimicrobial agent is accomplished by the induction of specific drug-inactivating enzymes, such as those that inhibit b-lactams or aminoglycosides. Numerous gram-positive and gram-negative bacteria, such as Staphylococcus aureus, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, H. influenzae, Bacteroides, and many strains of Prevotella have this capability. Another method used by bacteria to withstand antimicrobial attack is the ability to synthesize neutralizing enzymes. The best examples are penicillinase and the methylation of erythromycin and clindamycin. Other antibiotics that are neutralized include vancomycin, sulfonamides, aminoglycosides and rifampin. Bacterial organisms with this capability include S. pneumoniae, S. aureus, Clostridium perfringens, Bacteroides fragilis, Campylobacter species, and Neisseria gonorrhoeae. Alteration of microbial membrane permeability. Alterations in membrane permeability can cause decreased uptake or increased efflux of the antibiotic. The types of antibiotics most often affected by this mechanism are the b-lactams, quinolones, tetracyclines, erythromycin, and the aminoglycosides. The gram-negative rods E. coli, P. aeruginosa, and Salmonella typhimurium also have this capability. Porins within the transmembrane protein matrix are specific for various antibiotics, and the loss of a specific porin confers resistance. Lack of the D2 porin, for example, confers imipenem resistance in P. aeruginosa. Increased efflux of the antibiotic before lethal damage occurs is seen in the Enterobacteriae with the mar, norA, and tetA genes, which convey resistance by pumping tetracycline out of the cells. E. coli and Staphylococcus epidermidis also can resist tetracyclines, macrolides and quinolones by this mechanism [1,2]. Alteration of target site. Enzymes responsible for cell wall synthesis, the transpeptidases, can be altered slightly to produce less affinity for penicillins. These altered penicillin-binding proteins are most often seen in S. aureus and S. pneumoniae [3]. Alteration in the concentration of drug target receptors. Many of the gram-negative rods (ie, E. coli and Proteus, Enterobacter, and Klebsiella species) have the ability to alter the number of drug receptors that bind antibiotics. The sulfonamide family is affected by such a mechanism.

Strategies in the prevention of antibiotic resistance Extending surgical prophylaxis beyond 48 hours and inappropriately low dosing that encourages subpopulations of organisms to survive in increasing concentrations of antibiotics can select for resistant bacteria [3]. Although culture and sensitivity studies are crucial and should not preclude empiric therapy when warranted, there is also the risk that the latter can produce bacterial resistance. A case series to examine the bacteriology of dentoalveolar abscesses in patients who received empiric antibiotic therapy suggested that the polymicrobial nature of the abscess and the administration of empiric therapy with ampicillin or cephalosporins often results in resistant strains [4]. The predominant species were anaerobic (ie, Prevotella and Peptostreptococcus species, both resistant to the therapy initially given). Kuriyama et al [5] examined the relationship between past administration of b-lactamase antibiotics and an increase in b-lactamase producing bacteria in patients with odontogenic infections. The algorithm of treatment derived from their study is a course of b-lactamase antibiotics for 1 to 2 days, but if the infection is unresolved by 3 days or more, one should assume the presence of b-lactamase producing organisms, and treatment should involve a penicillinase-stable b-lactam or a non b-lactam antibiotic. No definitive studies with large sample sizes clearly define ways to manage antibiotic resistance in odontogenic infections, however. The question of whether antibiotic resistance in patients with odontogenic infections who need hospitalization is caused by the therapeutic modality given, the characteristics of the patient population, or the ability to isolate and characterize more carefully the vector of disease is paramount because of the possibility that the increased incidence of antibiotic-resistant strains is an unavoidable direct effect of therapy. Retrospective studies that compared populations decades apart have shown that although no clinically significant differences exist between cohorts examined, there are differences in types of microorganisms in terms of their nomenclature [6,7]. Flynn et al [8] performed a prospective study of 34 hospitalized patients with odontogenic infections and found a 26% rate of clinical failure with penicillin therapy and a 60% rate of penicillin resistance. This finding is exemplified by data on treatment of upper respiratory tract infections. In a study of children with pharyngitis, Brook [9] found a 9% incidence of penicillin resistance in throat swab cultures at the initiation of treatment. After 1 week

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of penicillin therapy, 46% of the subjects and 45% of the subjects parents and siblings harbored resistant strains. The number declined to 27% in the subjects over the ensuing 3 months. Several hospitals have substituted the cephalosporins for penicillin/b-lactamase inhibitor combinations, with or without an aminoglycoside, which in some cases has resulted in dramatic recovery of antibiotic susceptibility rates among pathogens such as Enterobacter cloacae, Klebsiella pneumoniae, P. aeruginosa, and Clostridium difficile [1].

Issues in antibiotic selection The selection of an appropriate antibiotic for a given case can be complex, but usually it is a straightforward process. The factors that must be considered can be categorized into host-specific and pharmacologic factors.

antibiotics in early cases. Another factor is the severity of the odontogenic infection. Flynn et al [8] found a clinical failure rate of 26% for penicillin in hospitalized cases. On the other hand, little or no difference was found between the effectiveness of penicillin and various other antibiotics in outpatient odontogenic infections [11 14]. The clinician must keep in mind the occasional pathogen that is resistant to the usual empiric antibiotic of choice. In odontogenic infections and dog and cat bites, Eikenella corrodens is fairly resistant to the penicillins and completely resistant to clindamycin. The fluoroquinolones have become the antibiotic of choice for this pathogen. E. corrodens should be considered a possible pathogen in treatment failure of odontogenic infections and routinely in animal bite wounds [15]. The usual flora of various types of head and neck infections are listed in Table 1. Allergy or intolerance A history of antibiotic allergy is usually readily obtained from the conscious patient or, alternatively, from the family. Penicillin allergy is common, and macrolide (erythromycin family) intolerance and drug interactions are frequent. The choice of clindamycin, metronidazole, or newer antibiotics may be prudent when anamnestic information is unavailable. The penicillins are the antibiotics most frequently prescribed for infections in the oral cavity. It is not surprising that their use is associated with hypersensitivity reactions. Between 1% and 10% of patients who initially take penicillin develop an allergic reaction, and persons who do not develop a reaction have less than a 1% chance of developing an allergy with reexposure [16]. It is judicious to clarify whether the person has a true allergy to penicillin. Cross-sectional studies of penicillin allergy indicate that in many hospital chartings of penicillin allergy, subsequent skin testing proved that more than 60% of patients were not allergic to either penicillin or other b-lactams, which warrants more careful vigilance by doctors who are recording medical histories and allergies of their patients [17,18]. Fortunately, hypersensitivity reaction to clindamycin, often substituted in penicillin-allergic patients, is a rare event. All clinicians should be aware of the potential for cross-allergy between the penicillins and other members of the b-lactam group. Approximately 10% to 15% of penicillin-allergic patients are also sensitive to the cephalosporins. The cross-allergic group tends to include persons who have had an anaphylactoid reaction to the penicillins. The cephalosporins should be avoided in these patients.

Host factors in antibiotic selection Usual pathogens The type of infection that presents can be characterized by cause and location, and each has its own characteristic flora. Odontogenic infections are generally characterized by a combination of facultative streptococci and oral anaerobes. Within the viridans group of facultative streptococci, the Streptococcus milleri group, which consists of S. anginosus, S. intermedius, and S. constellatus, is most frequently associated with orofacial cellulitis and abscess. This is fortunate because only approximately 3% of the strains of these species are resistant to the penicillins. On the other hand, other members of the viridans streptococci, such as Streptococcus mitis, Streptococcus sanguis, and Streptococcus salivarius, are more frequently found in endocarditis, and they can be highly penicillin resistantup to 58% in one study [10]. Among the anaerobes, anaerobic peptostreptococci and members of the genera Prevotella and Porphyromonas predominate. Although the peptostreptococci remain penicillin sensitive, approximately 25% of strains of Prevotella and Porphyromonas are penicillin resistant [8]. The penicillin-sensitive streptococci predominate during the first 3 days of clinical symptoms, and the more resistant gram-negative obligate anaerobes appear in significant numbers thereafter. This fact suggests the selection of the penicillins over other

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Table 1 Major pathogens of head and neck infections Type of infection Odontogenic cellulitis/abscess Microorganisms Streptococcus milleri group Peptostreptococci Prevotella and Porphyromonas Fusobacteria Streptococcus pneumoniae Haemophilus influenzae Head and neck anaerobes (peptostreptococci, Prevotella, Porphyromonas, fusobacteria) Group A b-hemolytic streptococci Staphylococcus aureus Moraxella catarrhalis Viruses Head and neck anaerobes Aspergillus Rhizopus sp. (mucor) Enterobacteriaceae (especially Pseudomonas, Acinetobacter, Escherichia coli) S. aureus Yeasts (Candida species) Odontogenic flora S. aureus and skin flora in trauma Salmonella in sickle cell disease Actinomyces species Group A b-hemolytic streptococci Regional flora (oral and sinus pathogens in head and neck) Candida species Histoplasma species Blastomyces species Aspergillus Rhizopus (mucor)

Rhinosinusitis

Acute

Chronic Fungal Nosocomial (especially if intubated)

Osteomyelitis of the jaws

Acute

Chronic Necrotizing fasciitis

Fungal

Mucosal or disseminated Soft tissue Sinus

The newer b-lactam antibiotics, the monobactams (aztreonam) and the carbapenems (imipenem and meropenem), have much less frequent cross-sensitivity with the penicillin group. A history of adverse reaction or intolerance of an antibiotic, such as phototoxicity with the tetracyclines or antibioticassociated colitis with clindamycin, would preclude its subsequent use unless strongly indicated.

Immune system compromise Because the immunocompromised patient is less able to kill invading pathogens by host resistance mechanisms, a bactericidal rather than bacteriostatic antibiotic should be selected whenever possible. This stratagem should result in a more rapid clinical response. The bactericidal antibiotics generally interfere with either cell wall synthesis, which causes

lysis, or with nucleic acid synthesis, which arrests vital processes. The bacteriostatic antibiotics interfere with protein synthesis, arresting growth and multiplication. Some antibiotics, such as clindamycin, seem to be bacteriostatic at lower doses and bactericidal at higher doses. HIV-infected individuals seem to be able to handle oral bacterial infections almost as well as noninfected persons. This ability is probably caused by the antibody-mediated immunity provided by the B-lymphocytes, which is largely responsible for combating the extracellular bacterial pathogens of most head and neck infections. Resistance to these common infections remains fairly robust until the terminal stages of AIDS, when all types of lymphocytes are severely depleted. On the other hand, fungal and viral infections, which are resisted by cell-mediated immunity (T cells), are prevalent in poorly controlled HIV-infected individuals.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 2 Bactericidal and bacteriostatic antibiotics Bactericidal b-lactams penicillins cephalosporins carbapenems monobactams Aminoglycosides Vancomycin Metronidazole Fluoroquinolones Bacteriostatic Macrolides erythromycin clarithromycin azithromycin Clindamycin Tetracyclines Sulfa antibiotics

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They are discussed in the section on adverse antibiotic reactions.

Pharmacologic factors in antibiotic selection Antimicrobial spectrum The most important pharmacologic consideration in antibiotic selection is whether it is effective against the likely pathogens. Table 3 describes the general spectrum of selected antibiotics. Table 4 lists the bacteria and fungi most likely to be encountered and the antibiotics of choice for those pathogens. The antibiotics effective against the highly resistant organisms are also included in Table 4. Table 5 lists the antibiotics to which selected highly resistant organisms have become resistant. These data, among others, are used in constructing the recommendations for empiric antibiotics of choice for various head and neck infections, and Tables 4 and 5 especially can be used in selecting an appropriate antibiotic for organisms identified by culture, for which sensitivity data may not be available. Tissue distribution of antibiotics Although abscess cavities are not vascular, some penetration of antibiotics into these spaces does occur. The antibiotic that best penetrates an abscess is clindamycin; the abscess concentration of clindamycin reaches 33% of the serum level [22]. This fact may partially explain the usefulness of clindamycin in odontogenic infections. Bone penetration of antibiotics is an important consideration, especially in osteomyelitis. The antibiotics that best penetrate or even accumulate in bone are the tetracyclines, clindamycin, and the fluoroquinolones. Cerebrospinal fluid penetration, or the ability of an antibiotic to cross the blood-brain barrier, is paramount in the treatment of infections that threaten the central nervous system, as in actual or impending cavernous sinus thrombosis. The antibiotics that can attain therapeutic levels in cerebrospinal fluid when the meninges are inflamed are listed in Table 6. The antibiotics that do not penetrate the cerebrospinal fluid well are clindamycin, the macrolides (including clarithromycin and azithromycin), cefazolin, and most other cephalosporins (except those listed in Table 6), aminoglycosides, amphotericin, itraconazole, ethambutol, and saquinavir. Penicillin G in high doses reaches 5% to 10% of the serum concentration in the cerebrospinal fluid

Table 2 lists common antibiotics by their ability to kill bacteria or merely suppress their growth. Previous antibiotic therapy All antibiotic therapy inherently selects for resistant organisms. Studies of patients who are currently taking or recently have taken antibiotics consistently yield a higher incidence and proportion of organisms resistant to that antibiotic [10,19]. On the other hand, these effects persist for a considerable time after antibiotic therapy and may be permanent [19,20]. The previous use of different antibiotics during the course of an acute infection definitely clouds the bacteriologic picture. In this situation, the clinician has the choice of changing the current antibiotic or increasing its dose, perhaps by using the parenteral route. With penicillins V (oral) and G (intravenous), peak serum blood levels are 5.6 mg/mL and 20 mg/mL, respectively. The dramatic increase in efficacy afforded by the parenteral route of administration may be more advantageous than changing to another antibiotic that is less effective than the penicillins. The penicillin resistance rate of the endocarditisassociated viridans streptococci (S. mitis, S. sanguis, and S. salivarius) is highup to 58% [21] in persons with a history of prior endocarditis. Clindamycin resistance of these bacteria in such patients remains low. In patients with a history of endocarditis, it may be advisable to use clindamycin rather than amoxicillin for endocarditis prophylaxis before oral procedures. This approach, however, has not been tested in a clinical study. Special conditions Certain temporary host conditions may affect antibiotic selection, such as childhood and pregnancy.

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Table 3 Spectrum of selected antibiotics Antibiotic category Natural penicillins Antibiotic Penicillin G and V Susceptible organisms Viridans streptococci Oral anaerobes Actinomyces sp. (penicillin G only) Pasteurella multocida As with natural penicillins, plus enterococci Actinomyces As with amoxicillin, plus S. aureus, not MRSA S. epidermidis, not MRSE H. influenzae M. catarrhalis Klebsiella species E. coli Bacteroides fragilis S. aureus, not MRSA S. epidermidis, not MRSE As with natural penicillins, plus S. aureus, not MRSA S. epidermidis, not MRSE H. influenzae M. catarrhalis Klebsiella species E. coli Bacteroides fragilis Enterobacteriaceae (most) Pseudomonas aeruginosa As with antipseudomonal penicillins, plus Actinomyces (imipenem) Enterobacteriaceae, except Salmonella (no data) and Acinetobacter (resistant) Streptococci S. aureus, not MRSA H. influenzae Klebsiella E. coli As with first generation, plus M. catarrhalis (cefuroxime) Oral anaerobes B. fragilis (cefoxitin) As with first generation, plus M. catarrhalis Oral anaerobes Actinomyces (ceftriaxone) Streptococci Actinomyces Peptostreptococci (azithromycin) Streptococci Oral anaerobes Actinomyces S. aureus, not MRSA Obligate anaerobes S. aureus, not MRSA Enterobacteriaceae (most) (continued on next page)

Semisynthetic penicillins b-lactam/b-lactamase inhibitors

Ampicillin Amoxicillin Amoxicillin/clavulanate Ampicillin/sulbactam

Penicillinase-resistant penicillins Antipseudomonal penicillins

Oxacillin Dicloxacillin Ticarcillin/clavulanate Piperacillin/tazobactam

Carbapenems

Monobactam Cephalosporins

Imipenem Meropenem Ertapenem Aztreonam First generation Cephalexin Cefazolin

Second generation Cefaclor Cefuroxime Cefoxitin Third generation Cefotaxime Ceftriaxone Macrolides Erythromycin Clarithromycin Azithromycin Clindamycin

Clindamycin

Metronidazole Fluoroquinolones

Ciprofloxacin

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 3 (continued ) Antibiotic category Antibiotic Moxifloxacin Susceptible organisms

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Aminoglycosides

Gentamicin Tobramycin

Glycopeptides

Vancomycin Teicoplanin Linezolid

Oxazolidinones

Pristinamycins

Quinupristin/dalfopristin

Ketolides

Telithromycin

Streptococci Oral anaerobes S. aureus, not MRSA Actinomyces B. fragilis Enterobacteriaceae (most) S. aureus, not MRSA Enterococci (gentamicin synergistic with ampicillin) Enterobacteriaceae (many) Pseudomonas Streptococci S. aureus, including MRSA S. epidermidis, including MRSE (vancomycin) Streptococci Staphylococci, including VISA, VRSE, MRSA, MRSE Peptostreptococci Enterococci, including VRE Streptococci Staphylococci, including VISA, VRSE, MRSA, MRSE Legionella Streptococci S. aureus (not MRSA?) H. influenzae M. catarrhalis Legionella

Abbreviations: MRSA, methicillin-resistant S. aureus; MRSE, methicillin-resistant S. epidermidis; VISA, vancomycin-intermediate S. aureus; VRSE, vancomycin-resistant S. epidermidis.

when the meninges are inflamed. In odontogenic infections that threaten the central nervous system, the addition of metronidazole (30% 100% penetration) to ampicillin (13% 14% penetration) is more efficacious than using penicillin G alone [15]. Pharmacokinetics The effectiveness of some antibiotics, such as the fluoroquinolones and aminoglycosides, is concentration dependent, whereas with other antibiotics, such as the b-lactams and vancomycin, it is time dependent. In concentration-dependent antibiotics, efficacy is determined by the ratio of the serum concentration of the antibiotic to the minimum inhibitory concentration (MIC), which is the concentration of the antibiotic required to kill a given percentage of the strains of a particular species, usually 50% or 90%. In time-dependent antibiotics, it is necessary to maintain the serum concentration above the MIC for at least 40% of the dosage interval. It is necessary with time-dependent antibiotics to know the serum elimination half-life (t/2) of the antibiotic to determine its proper dosage interval.

For example, the t/2 of penicillin G is 0.5 hours. During each half hour, 50% of the remaining penicillin is eliminated from the serum. By five half-lives, or 2.5 hours, only approximately 3% of the peak serum level of penicillin remains. Because the MIC-90 of the viridans streptococci (the concentration that kills 90% of the strains) is 0.2 mg/mL and because the peak serum level achieved with 2 million U of intravenous penicillin G is 20 mg/mL, the serum concentration of penicillin after 4 hours (eight half-lives) is approximately 0.15 mg/mL. The serum level will have fallen below the MIC-90 roughly for only the last 15% of the dosage interval. Intravenous penicillin G, 2 million U every 4 hours, should be highly effective against the viridans group of streptococci. Using the same analysis, the peak blood level achieved with amoxicillin, 500 mg orally, is 7.5 mg/mL, and its t/2 is 1.2 hours. The MIC-90 for the viridans streptococci is 2 mg/mL for amoxicillin. Using an 8-hour dosage interval, the remaining serum concentration of amoxicillin should have fallen below the MIC-90 of the viridans streptococci at approximately 2.5 hours, which is only 31% of the dosage interval. Oral amoxicillin therapy may not kill 90% of all the

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Table 4 Antibiotics of choice for head and neck pathogens Pathogen Actinomyces Type +, R, A First choice antibiotics Penicillin G or ampicillin Alternative antibiotics

Bacteroides fragilis

Clostridium species (except C. difficile) Clostridium difficile Eikenella corrodens

Enterococcus faecalis (group D streptococcus) Enterococcus faecium (group D streptococcus: b-lactamase +, aminoglycoside and vancomycin resistant) Escherichia coli

Fusobacterium species Haemophilus influenzae (b-lactamase positive) Klebsiella pneumoniae

Klebsiella pneumoniae (producing extended spectrum b-lactamases: ESBLs) Pasteurella multocida (eg, dog and cat bites) Peptostreptococcus (and former Peptococcus) Black pigmented oral anaerobes (Prevotella and Porphyromonas) Proteus vulgaris (indole +)

Doxycycline Clindamycin Erythromycin , R, AN Metronidazole Clindamycin Cefoxitin, not cefotetan (DOT) Ampicillin/sulbactam +, R, AN Penicillin G F clindamycin Metronidazole Doxycycline Cephalosporin (1st)a +, R, AN Metronidazole p.o. Vancomycin p.o. Bacitracin p.o. , R, A Penicillin G or V Fluoroquinolones Amoxicillin TMP/SMX (avoid Amoxicillin/clavulanate clindamycin) +, C, F Ampicillin F gentamicin Vancomycin (for endocarditis or meningitis Ampicillin/sulbactam Linezolid +, C, F Linezolid + quinupristin/dalfopristin F Teicoplanin + aminoglycoside choramphenicol F doxycycline (van B) For some strains: no effective regimen (I.D. consultation) Meropenem for central nervous system , R, A Ticarcillin/clavulanate Aztreonam Cephalosporins Imipenem TMP/SMX Tobramycin Fluoroquinolones , R, AN Penicillin G or V Metronidazole Clindamycin , R, F Amoxicillin/clavulanate Cefotaxime (if life threatening) Cefaclor Ciprofloxacin Azithro/clarithromycin TMP/SMX , R, A Cephalosporin (3rd)* Tobramycin Fluoroquinolones Ticarcillin/clavulanate Imipenem/cilastatin , R, A Imipenem/cilastatin Meropenem Fluoroquinolones , R, A Penicillin G Amoxicillin/Clavulanate Doxycline Cephalosporin (2nd)a TMP/SMX Clindamycin Doxycline Vancomycin PCN + metronidazole Amoxicillin Cefotetan Tobramycin Imipenem Ticarcillin/clavulanate Aztreonam + ceftazidime Piperacillin + tobramycin Cefepime + tobramycin Chloramphenicol Amoxicillin TMP/SMX (continued on next page)

+, C, AN Penicillin G or V

, R, AN Clindamycin

, R, A

Cephalosporin (3rd) Fluoroquinolones Ciprofloxacin Tobramycin

Pseudomonas aeruginosa

, R, A

Salmonella typhi

, R, A Fluoroquinolones Ceftriaxone

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 4 (continued ) Pathogen Serratia marcescens Type First choice antibiotics Alternative antibiotics Gentamicin Aztreonam

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Shigella Staphylococcus aureus (methicillin sensitive) Staphylococcus aureus (methicillin resistant)

, R, A Cephalosporin (3rd) Imipenem Meropenem Fluoroquinolones , R, A Fluoroquinolones Azithromycin +, C, A Penicillinase-resistant penicillin +, C, A Vancomycin

TMP/SMX + ampicillin Cephalosporin (1st)a Vancomycin Clindamycin Teicoplanin Quinupristin-dalfopristin TMP/SMX (some strains) Linezolid Quinupristin/dalfopristin Linezolid Quinupristin/dalfopristin

Staphylococcus aureus (methicillin and vanco mycin resistant) Staphylococcus epidermidis (methicillin resistant)

+, C, A

No effective regimen Try vancomycin F rifampin Vancomycin (+ rifampin + gentamicin for prosthetic valve endocarditis) Quinupristin/dalfopristin Linezolid Penicillin G or V Ceftriaxone Amoxicillin Vancomycin + Rifampin

+, C, A

Staphylococcus epidermidis +, C, A (methicillin and glycopeptide resistant) Streptococcus pneumoniae +, C, A (Pneumococcus) (penicillin sensitive) Streptococcus pneumoniae +, C, A (Pneumococcus) (multiantibiotic resistant, including high-level penicillin, erythromycin, tetracycline, chloramphenicol, and TMP/SMX) Streptococcus pyogenes +, C, A (b-hemolytic streptococcus) Streptococcus viridans +, C, A (a-hemolytic streptococcus) Fungal organisms Blastomyces Fungus Candida Fungus

Vancomycin (high dose) New fluoroquinolones?b (rapid resistance a problem) Cefuroxime, cefipime Imipenem New fluoroquinolonesb Clindamycin New fluoroquinolones (in vitro)

Penicillin G or V (+ gentamicin if serious group B infection) Penicillin G or V

Cephalosporin (1st)a Erythromycin Cephalosporin (1st)a Macrolides Itraconazole (if surface) Fluconazole (if surface) Nystatin (if surface) Clotrimazole (if surface) Ketoconazole (if surface) Itraconazole (if surface) Fluconazole Amphotericin B Itraconazole (immunocompetent) Itraconazole (immunocompromised) Control underlying systemic disease

Amphotericin B (for systemic cases) Fluconazole Amphotericin B (for systemic cases) Itraconazole Amphotericin B (for systemic or immunocompromised cases) Amphotericin B

Coccidioides immitis Histoplasma Mucormyces

Fungus Fungus Fungus

Abbreviations: A, aerobe; AN, anaerobe; C, coccus; DOT, distasonis, ovatus, and thetaiotamicron group of B. fragilis species; F, facultative; PCN, penicillin; R, rod; TMP-SMX, trimethoprim-sulfamethoxazole. Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2002. 32nd edition. New Hyde Park (VT): Antimicrobial Therapy Inc.; 2002. + = gram positive. = gram negative. a Number in parentheses after cephalosporins refers to generations within the cephalosporin family. b New fluoroquinoles are gati-, gemi-, lero-, moxi-, sparfloxacin.

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Table 5 Highly resistant organisms and the antibiotics to which they are resistant Organism Acinetobacter baumanii Resistant to Penicillins Third generation cephalosporins Antipseudomonal aminoglycosides Fluoroquinolones Imipenem Glycopeptides Streptomycin Gentamicin All b-lactams Glycopeptides Aminoglycosides Glycopeptides Streptomycin Gentamicin all b-lactams Glycopeptides Aminoglycosides Penicillins Third generation cephalosporins Aztreonam Penicillins Cephalosporins Carbapenems Methicillin Methicillin Vancomycin only Vancomycin and teicoplanin (both available glycopeptides) Methicillin Methicillin Glycopeptides Penicillin G

Enterococcus faecalis b-lactamase negative Enterococcus faecalis b-lactamase positive Enterococcus faecium b-lactamase negative Enterococcus faecium b-lactamase positive Klebsiella pneumoniae ESBL positive

strains of the viridans streptococci. Fortunately for oral and maxillofacial surgeons, the Streptococcus milleri group associated with odontogenic infections is highly sensitive to the penicillins, whereas the endocarditisassociated strains are less so. The pharmacokinetics of the clinically available antibiotics have been determined during drug development. It is incumbent on the clinician to prescribe antibiotics within the accepted ranges for dose and interval. Once-daily dosing for the aminoglycosides as a means of reducing their ototoxicity and nephrotoxicity recently has been evaluated in a systematic review [23]. The available well-designed studies indicate that this practice results in a modest increase in therapeutic advantage and possibly a decrease in toxicity. The cost saving of once-daily intravenous dosing makes this approach appealing. Caution is advised in patients with limited volumes of fluid distribution, however. Adverse reactions The adverse reactions and toxicities of the antibiotics commonly used in head and neck infections are generally mild and uncommon. Table 7 lists the major serious adverse reactions of the commonly used antibiotics. The clinician especially should note allergic reactions to the penicillins and cephalosporins, gastrointestinal intolerance of the erythromycins, nephrotoxicity and ototoxicity of the aminoglycosides, and antibiotic-associated colitis with the b-lactam/b-lactamase inhibitor combinations (eg, Augmentin, Unasyn), antipseudomonal penicillins (eg, ticarcillin, piperacillin), cephalosporins, and clindamycin, among others. Special conditions Antibiotics that should be avoided in children include the tetracyclines (under the age of 8), because of permanent intrinsic dental staining, and the fluoroquinolones, because of chondrotoxicity in growing cartilage. Among the carbapenems, imipenem is not recommended because of the risk of seizures. Meropenem is an acceptable alternative. The use of antibiotics in pregnancy almost always involves an evaluation of risk versus benefit. The antibiotics that must be avoided in pregnancy include the antimycobacterial agent, thalidomide, and the antiparasitic agent, quinine, for which the risk clearly outweighs the benefit. Table 8 lists the pregnancy risk categories of selected antibiotics.

Pseudomonas aeruginosa Staphylococcus aureus MRSA S. aureus VISA or GISA

Staphylococcus epidermidis MRSE S. epidermidis VRMRSE Streptococcus pneumoniae penicillin intermediate or resistant S. pneumoniae multi-antibiotic resistant

Penicillins Cephalosporins Aztreonam

Abbreviations: ESBL, extended-spectrum b-lactamase; GISA, glycopeptide-intermediate S. aureus; MRSE, methicillin-resistant S. epidermidis; VRMRSE, vancomycinresistant methicillin-resistant S. epidermidis. Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 6 Selected antibiotics and the blood-brain barrier Cerebrospinal fluid Therapeutic levels achieved Antibiotic Penicillins ampicillin nafcillin penicillin G, high dose ticarcillina piperacillina Cephalosporins ceftazidime cefuroxime ceftriaxone Carbapenem meropenemb Fluoroquinolones levofloxacin ciprofloxacinc Other antibiotics metronidazole trimethoprim/ sulfamethoxazoled vancomycine Antifungal drugs fluconazole flucytosine Antiviral drugs acyclovir foscarnet ganciclovir zidovudine Cephalosporins cefazolin cephalexin Aminoglycosides Macrolides erythromycin clarithromycin azithromycin Clindamycin Antifungal drugs amphotericin itraconazole Antiviral drugs saquinavir zidovudine

27

Antibiotic drug interactions Two important categories of antibiotic drug interaction are interference with the effectiveness of oral contraceptives and interference with the metabolism of drugs, which involves the cytochrome P450 system. These and other selected antibiotic drug interactions are listed in Table 9. Antibiotic interference with the effectiveness of oral contraceptive pills remains a controversial topic. The only antibiotic that has been shown conclusively to interfere with oral contraception is rifampin. The evidence that implicates ampicillin, amoxicillin, dapsone, trimethoprim/sulfamethoxazole, and the antiviral protease inhibitors is less strong. It is important to note that antibiotics do not interfere with injectable or implantable contraceptives. Only oral contraceptives are affected [24]. A possible mechanism for this interaction stems from efforts to decrease the adverse effects, such as thromboembolism and activation of uterine and breast carcinomas associated with older contraceptive formulations that contained higher estrogen doses. Currently, oral contraceptive preparations have minimally effective estrogen doses, and the serum level of the estrogen is supported by enterohepatic recirculation. In this process, the liver conjugates absorbed estrogen with glucuronide, and the estrogen-glucuronide complex is excreted in the bile. In turn, the gut flora breaks the estrogenglucuronide bond, which allows the pure estrogen molecule to be reabsorbed by the gut, thus supporting the serum estrogen level. If an antibiotic kills enough of the gut flora, then the conjugated estrogen is not broken down, and the estrogen-glucuronide complex stays in the intestine until it is excreted. The serum estrogen level falls, which results in breakthrough menstrual bleeding or ovulation and unwanted pregnancy. The cytochrome P450 system is a complex set of drug-metabolizing enzymes that is responsible for the breakdown of many classes of drugs. Enzymes within this system include CYP3A4, CYP2C19, and CYP2D6. Drugs that share this metabolic pathway may interact. The metabolism of one or the other may be either increased or decreased as a result. The adverse affect is usually caused by an increased effect of the drug whose metabolism is inhibited, but in some of the most serious cases, life-threatening or fatal cardiac dysrhythmias, such as ventricular fibrillation and torsade des pointes, have occurred. The most significant interactions involving the cytochrome P450 system are included in Table 9.

Therapeutic levels not achieved

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002. a Levels effective for P. aeruginosa and coliforms may not be reached. b Imipenem is avoided in meningitis because of seizure potential. Meropenem is preferred. c Does not reach adequate cerebrospinal fluid levels for streptococci. d Not adequately effective against Neisseria species and coliforms. e High doses are needed for resistant streptococci.

28

Table 7 Major adverse reactions of selected antibiotics Ampicillin, Penicillin G amoxicillin F and V clavulanate + + + + + + + + + + + + + + + Ticarcillin F clavulanate Gentamicin, Cephalexin, Impenem Meropenem tobramycin cefazolin Cefuroxime Cefoxitin Cefotaxime Cefaclor

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Adverse reactions Local, phlebitis Hypersensitivity Rash Photosensitivity Anaphylaxis Serum sickness Anemia Nausea, vomiting Diarrhea Antibiotic-associated colitis (AAC) Renal: z BUN, creatinine Headache Seizures Hypotension Ototoxicity Vestibular dysfunction Alcohol interaction Red man flushing Drug interactions Pregnancy risk C or D

+ +

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002.

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Table 7 (continued ) Erythromycin Local, phlebitis Hypersensitivity Rash Photosensitivity Anaphylaxis Serum sickness Anemia Nausea, vomiting Diarrhea AAC Renal: z BUN, creatinine Headache Seizures Hypotension Ototoxicity Vestibular dysfunction Alcohol interaction Red man flushing Drug interactions Pregnancy risk C or D Clarithromycin, azithromycin Clindamycin Metronidazole Ciprofloxacin Moxifloxacin Vancomycin + + + Tetracycline, doxycycline Linezolid Telithromycin

+ + + + + + + + + + +

+ + + + + + + + + + + + +

29

30

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Table 8 Pregnancy risk categories of selected antibiotics Antibiotic Penicillins penicillin G and V ampicillin amoxicillin amoxicillin/clavulanate ticarcillin/clavulanate Cephalosporins cephalexin cefazolin cefaclor cefuroxime cefoxitin cefotaxime Carbapenems imipenem meropenem Macrolides erythromycin clarithromycin azithromycin Antianaerobic clindamycin metronidazole Fluoroquinolones ciprofloxacin moxifloxacin Aminoglycosides gentamicin tobramycin Other vancomycin tetracyclines doxycycline linezolid telithromycin Pregnancy risk category B B B B B B B B B B B C B B C B B B C C D D C D D C B Spontaneous abortions in rabbits Fetal toxicity in rodents and monkeys Ototoxicity in human fetuses Ototoxicity in human fetuses Potential ototoxicity in human fetuses Intrinsic dental staining Intrinsic dental staining Fetal toxicity in rodents Spontaneous abortions in monkeys Pregnancy risk

Fetal defects in mice and monkeys

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy, Inc.; 2002. A = Studies in pregnancy; no risk. B = Animal studies no risk, but human studies inadequate or animal toxicity, but human studies no risk. C = Animal studies show toxicity, and human studies inadequate, but benefit of use may outweigh risk. D = Evidence of human risk, but benefits may outweigh risk. X = Risk outweighs benefit.

Cost Although clinical effectiveness and reduction of the morbidity of infection and treatment are of paramount concern in the management of head and neck infections, cost is a factor that should be considered when other factors do not predominate. The costs of oral antibiotic therapy can be compared based on the cost for a standard prescription for the antibiotics of interest, because there is no additional cost of administration, as there is with parenteral antibiotics, espe-

cially by the intravenous route. Table 10 compares the retail cost of a 1-week prescription of the antibiotics listed. The penicillin V cost ratio is calculated by dividing the retail cost of the standard 1-week prescription for the given antibiotic by that of penicillin V. Table 11 compares the cost of intravenous antibiotics. The cost of administration assumes great importance. Each dose requires sterile intravenous administration supplies, professional labor, and hospital sterile processing and drug error prevention systems.In Table 11, these costs are conservatively estimated at

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 9 Selected antibiotic interactions with other drugsa,b Antibiotic Erythromycin, clarithromycin, ketoconazole, itraconazole Second drug Theophylline Adverse effects Seizures, dysrhythmias Mechanism

31

Erythromycin, clarithromycin, ketoconazole, itraconazole

Cisapride

Erythromycin, clarithromycin, ketoconazole, itraconazole

Alfentanil

Erythromycin, clarithromycin, ketoconazole, itraconazole

Bromocriptine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Carbamazepine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Cyclosporine

Erythromycin, clarithromycin, ketoconazole, itraconazole

Felodipine, possibly other calcium channel blockers

Erythromycin, clarithromycin, ketoconazole, itraconazole

Methylprednisolone, prednisone

Erythromycin, clarithromycin, ketoconazole, itraconazole

Lovastatin, possibly other -statins

Erythromycin, clarithromycin, ketoconazole, itraconazole

Triazolam, oral midazolam

Erythromycin, clarithromycin, ketoconazole, itraconazole

Disopyramide

Erythromycin Erythromycin, tetracyclines

Clindamycin Digoxin

Erythromycin, clarithromycin, metronidazole

Warfarin Anisindione

Antibiotic inhibits cytochrome P450 metabolism of second drug; ketoconazole not implicated Dysrythmias (torsades) Antibiotic inhibits cytochrome P450 metabolism of second drug z Respiratory depression Antibiotic inhibits cytochrome P450 metabolism of second drug; ketoconazole not implicated z CNS effects, hypotension Antibiotic inhibits cytochrome P450 metabolism of second drug Ataxia, vertigo, drowsiness Antibiotic inhibits cytochrome P450 metabolism of second drug z Immunosuppression Antibiotic inhibits and nephrotoxicity cytochrome P450 metabolism of second drug Hypotension, tachycardia, Antibiotic inhibits edema cytochrome P450 metabolism of second drug z Immunosuppression Antibiotic inhibits cytochrome P450 metabolism of second drug Muscle pain, rhabdomyolysis Antibiotic inhibits cytochrome P450 metabolism of second drug z Sedative depth and duration Antibiotic inhibits cytochrome P450 metabolism of second drug Dysrhythmias Antibiotic inhibits cytochrome P450 metabolism of second drug # Antibiotic effect Mutual antagonism Digitalis toxicity, Antibiotic kills dysrhythmias, visual Eubacterium lentum, disturbances, which metabolizes hypersalivation digoxin in the gut z Anticoagulation Antibiotic interferes with metabolism of the second drug (continued on next page)

32 Table 9 (continued ) Antibiotic

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Second drug

Adverse effects z Anticoagulation

Mechanism Antibiotic kills gut flora that synthesize vitamin K, which antagonizes the second drug; poor vitamin K intake a factor Antibiotic inhibits acetaldehyde dehydrogenase, causing accumulation of acetaldehyde; ritonavir preparations contain alcohol Antibiotic inhibits lithium excretion by kidney; tetracycline interaction not well established Second drug interferes with absorption of antibiotic; didanosine is formulated with calcium carbonate and magnesium hydroxide buffers Additive effect caused by inherent minor neuromuscular blocking effect of the antibiotic; seen with clindamycin in the presence of low pseudocholinesterase levels and abnormal liver function tests Mutual antagonism Interference with enterohepatic recirculation of estrogen caused by killing of gut flora; rifampin is the only antibiotic in which this has been clinically proven Unknown, possibly caused by hyperuricemia in patients taking allopurinol Additive or potentiating effect Thrombocytopenia Additive effect (continued on next page)

Tetracycline, cefamandole, Warfarin, anisindione cefotetan, cefoperazone, sulfonamides, aminoglycosides

Metronidazole, cephalosporins

Alcohol, ritonavir

Flushing, headache, palpitations, nausea

Metronidazole Metronidazole, tetracyclines

Disulfiram Lithium

Acute toxic psychosis Lithium toxicity: confusion, ataxia, kidney damage

Tetracyclines, fluoroquinolones

Divalent and trivalent cations (dairy, antacids, vitamins) didanosine

# Absorption of antibiotic

Clindamycin, aminoglycosides, tetracyclines, bacitracin

Neuromuscular blocking agents

z Depth and duration of paralysis

Clindamycin Penicillins, cephalosporins, metronidazole, erythromycin, clarithromycin, tetracyclines, rifampin

Erythromycin # Antibiotic effect Estrogen- and progestinContraceptive failure containing oral contraceptives

Ampicillin, amoxicillin

Allopurinol

Rash

Cephalosporins Trimethoprim/sulfamethoxazole Vancomycin

Aminoglycosides Thiazide diuretics Aminoglycosides

z Nephrotoxicity Purpura, bleeding in elderly patients z Renal toxicity

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 9 (continued ) Antibiotic Fluoroquinolones, sulfonamides, chloramphenicol, fluconazole, itraconazole Ciprofloxacin, sulfonamides, chloramphenicol, fluconazole, ketoconazole, itraconazole Sulfonamides Second drug Oral hypoglycemic agents Adverse effects Hypoglycemia Mechanism Antibiotic displaces second drug from plasma proteins Interference with phenytoin metabolism

33

Phenytoin

z Serum level of phenytoin, confusion, delirium z Methotrexate concentration

Methotrexate

Protease inhibitors (ritonavir, amprenavir, saquinavir, nelfinavir, indinavir, and others)

Hydrocodone, fentanyl, alfentanil, amiodarone, lidocaine, anticonvulsants, loratidine, Benzodiazepines b-blockers Calcium channel blockers Cisapride Corticosteroids -statin type antihyperlipidemics Warfarin Codeine, morphine, contraceptives

z Levels of second drug, with possible toxic effects

Protease inhibitors

# Levels of second drug

Delavirdine (Rescriptor)

Cisapride, clarithromycin, protease inhibitors, warfarin

z Levels of second drug, with possible toxic effects

Didanosine (ddl, Videx) Foscarnet (Foscavir)

Metronidazole Ciprofloxacin

z Risk of peripheral neuropathy z Risk of seizures

Antibiotic displaces methotrexate from plasma proteins Serious interaction: avoid using the drugs in bold print Ritonavir has high affinity for various isoenzymes in the cytochrome P450 system and has the most frequent and severe drug interactions among the protease inhibitors Warfarin reaction is only with ritonavir Antibiotic enhances cytochrome P450 metabolism of second drug Antibiotic inhibits cytochrome P450 metabolism of second drug Additive effect Additive effect

From Flynn TR. Update on the antibiotic therapy of oral and maxillofacial infections. In: Piecuch JF, editor. Oral and maxillofacial surgery knowledge update 2001. Rosemont (IL): American Association of Oral and Maxillofacial Surgeons, 2001; with permission. a Interactions among the various anti-HIV antibiotics are frequent and complex. The reader is referred to appropriate sources on the subject. b This list of antibiotic-drug interactions is only partial and selected according to the interests of oral and maxillofacial surgeons. Drug prescribers remain responsible to ascertain the complete drug interactions of any medications they may prescribe.

$4.00 per dose. Even this small additional cost can make an infrequently administered but more expensive antibiotic more economical than a cheaper, more frequently dosed antibiotic. An example of this effect can be found by comparing the cost ratio of penicillin G (analogous to the penicillin V cost ratio) with cefazolin. Table 11 also illustrates the markedly increased cost of combined antibiotic therapy as compared to monotherapy. For example, 1 weeks intravenous therapy of penicillin G plus metronidazole costs $690, whereas 1 weeks treatment with clindamycin costs only $375, a reduction of 46%. On the other hand, the combination approach may be advantageous

in an infection that threatens the brain, for example, because clindamycin does not cross the blood-brain barrier and penicillin does so only to a limited extent. Metronidazole crosses the blood-brain barrier well.

New antibiotics of interest to oral and maxillofacial surgeons New fluoroquinolones Moxifloxacin (Avelox) and gemifloxacin are two new fluoroquinolones whose spectrum includes

34 Table 10 Oral antibiotic costs Antibiotic

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

Usual dose (mg) 500 500 500 875 500 500 500 500 500 500 500 333 250 500 500 250 150 300 300 500 160/800 500 100 125

Usual interval (h) 6 8 8 12 6 6 6 6 8 8 6 6 6 24 12 24 6 6 6 6 12 12 12 6

Pharmacy Cost 01 * * $0.14 $0.31 $3.65 $4.76 $0.66 $1.07 $3.11 $0.52 $7.43 $4.00 $0.36 $0.36 $0.31 $12.39 $3.57 $6.75 $0.98 $1.96 $4.22 $0.72 $0.15 $4.15 $0.08 $5.38

Cost for 24 hours $0.56 $0.93 $10.95 $9.52 $2.64 $4.28 $12.44 $2.08 $22.29 $12.00 $1.44 $1.44 $1.24 $12.39 $7.14 $6.75 $3.92 $7.84 $16.88 $2.88 $0.30 $8.30 $0.16 $21.52

Retail cost for 1 weekd $9.99 $13.89 $104.99 $97.59 $26.69 $24.89 $104.99 $70.59 $199.99 $77.59 $13.89 $16.29 $13.49 $63.99 $71.99 $60.59 $31.29 $54.86 $118.27 $10.02 $11.69 $80.59 $9.99 $187.99

Penicillin cost ratioc 1.00 1.39 10.51 9.77 2.67 2.49 10.51 7.07 20.02 7.77 1.39 1.63 1.35 6.41 7.21 6.07 3.13 5.49 11.84 1.00 1.17 8.07 1.00 18.82

Penicillins Penicillin V Amoxicillin Augmentina Augmentin Dicloxacillin Cephalosporins (generation) Cephalexin caps (1st) Keftabs (1st)b Cephradine (1st) Cefuroxime (2nd) Cefaclor (2nd) Erythromycins Erythromycin base Erythromycin stearate Erythromycin estolate Dirythromycin (Dynabec) Clarithromycin (Biaxin) Azithromycin (Zithromax) Anti-anaerobic Clindamycin (generic) Clindamycin (2 T generic) Clindamycin (Cleocin) Metronidazole (250 mg = $0.08) Other Trimethoprim/sulfamethoprim Ciprofloxacin Doxycycline Vancomycin

Usual doses and intervals are for moderate infections, and are not to be considered prescriptive. From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT): Antimicrobial Therapy, Inc; 2001. a Augmentin = amoxicillin plus clavulanic acid. b Keftab = cephalexin hydrocloride in tablet form (Dista). c Penicillin cost ratio = retail cost of antibiotic for 1 week retail cost of penicillin V for 1 week. d Retail cost/1 week = retail price charged for a 1-week prescription at a large pharmacy chain in the Boston region. Courtesy of Chris Gonzalez, RPh.

the viridans streptococci, oral anaerobes, and actinomyces. They are also effective against sinus pathogens, staphylococci, Enterobacteriaceae, and B. fragilis. Their broad spectrum is a relative disadvantage when the target is a fairly small range of bacteria. These new fluoroquinolones probably should be reserved for situations in which a narrower spectrum alternative antibiotic is not available. Oxazolidinones Linezolid (Zyvox) is the prototype of this new class of antibiotics. It is effective against virtually all

gram-positive pathogens but not against the gramnegative oral anaerobes. Its effectiveness against methicillin- and vancomycin-resistant staphylococci and enterococci indicates that it should be reserved for these highly resistant organisms [25]. Ketolides Telithromycin (Ketek) is the first representative of this new class, which is related to the macrolides. Its spectrum includes the pathogens against which the macrolides have been historically effective, including S. pneumoniae, mycoplasma, H. influenzae, Chlamy-

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 11 Intravenous antibiotic costs Antibiotic Usual doseb Usual interval (hour)b 6 6 6 6 4 4 8 12 8 8 8 24 8 6 6 24 6 12 8 6 12 6 12 Pharmacy cost 00 $1.33 $1.64 $10.18 $2.68 $12.92 $15.40 $1.74 $11.58 $13.93 $21.16 $28.45 $42.00 $16.97 $30.32 $22.16 $23.70 $7.80 $15.60 $13.88 $19.03 $21.07 $16.42 $30.00 Pharmacy cost 01 $1.32 $1.31 $14.45 $5.14 $13.43 $15.20 $1.90 $11.60 $13.80 $26.38 $28.45 $40.18 $16.97 $30.32 $23.00 $24.44 $8.28 $16.56 $13.88 $15.34 $4.16 $16.42 $30.00 Total cost 24 hours $21.28 $21.24 $73.80 $36.56 $104.58 $115.20 $17.70 $31.20 $53.40 $91.14 $97.35 $44.18 $62.91 $137.28 $108.00 $28.44 $49.12 $41.12 $53.64 $77.36 $16.32 $81.68 $68.00 Total cost for 7 days $148.96 $148.68 $516.60 $255.92 $732.06 $806.40 $123.90 $218.40 $373.80 $637.98 $681.45 $309.26 $440.37 $960.96 $756.00 $199.08 $343.84 $287.84 $375.48 $541.52 $114.24 $571.76 $476.00

35

Penicillin G cost ratioa 1.00 1.00 3.47 1.72 4.91 5.41 0.83 1.47 2.51 4.28 4.57 2.08 2.96 6.45 5.08 1.34 2.31 1.93 2.52 3.64 0.77 3.84 3.20

Penicillins Penicillin G 2 mu Ampicillin 1g Unasyn 2g Oxacillin 1g Ticarcillin 3g Timentin 3.1 g Cephalosporins (generation) Cefazolin (1st) 1g Cefotetan (2nd) 1g Cefuroxime (2nd) 1.5 g Cefotaxime (3rd) 2g Ceftazidime (3rd) 2g Ceftriaxone (3rd) 1g Monobactam Aztreonam 1g Carbapenem Imipenem-cilastatin 0.5 g Penicillin allergy Erythromycinc 1g Azithromycin 0.5 g Vancomycin 0.5 g Vancomycin 1.0 g Anti-anaerobic Clindamycin 0.9 g Metronidazole 0.5 g Other Doxycycline 0.1 g Trimethoprim-sulfa 800 mg Ciprofloxacind 400 mg

Total cost of therapy includes $1.00 for infusion materials and $3.00 labor cost, per dose. From Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy 2001. 31st edition. Hyde Park (VT): Antimicrobial Therapy, Inc; 2001. a Penicillin cost ratio = 24-hour cost of antibiotic/24-hour cost of penicillin G. b Usual doses and intervals are for moderate infections and are not to be considered prescriptive. c Only the brand name price is listed in the reference. Price is selected from the lowest available average wholesale price. d Cipro IV is for NPO patients only because of excellent oral absorption.

dia pneumoniae, and Legionella pneumophila. Its most frequent use probably is in respiratory tract infections, especially pneumonia [26,27]. Pristinamycins Quinupristin/dalfopristin (Synercid), a combination of two pristinamycin antibiotics, is especially effective against vancomycin-resistant staphylococci. Its use generally has been reserved for infections caused by these organisms.

Empiric antibiotics of choice for head and neck infections Odontogenic infections Empiric antibiotics are administered before culture and sensitivity test results are available; specific antibiotic therapy is selected based on culture and sensitivity results. Table 12 lists the empiric antibiotics of choice for selected types of head and neck infections, including odontogenic infections.

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T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738

In a prospective case series of 34 cases of odontogenic infection, Flynn et al reported therapeutic failure of penicillin in 26% of cases using the following criteria for failure: allergic or toxic reaction (no cases); failure of swelling, temperature, and white blood cell count to decline after at least 48 hours of intravenous penicillin; and a postoperative CT scan that demonstrated adequate surgical drainage. If inadequate drainage was found on the postoperative CT scan, surgery was repeated. All of the patients with therapeutic penicillin failure (8 of 31 cases initially treated with penicillin) subsequently yielded at least one penicillin-resistant strain when culture and sensitivity test results became available. This finding suggests a correlation between infection severity and penicillin resistance and is the basis for the recommendation of clindamycin as the empiric antibiotic of choice in odontogenic infections serious enough to require hospitalization [8]. On the other hand, penicillin resistance has not yet been shown to be a significant problem in outpatient odontogenic infections [11 14]. Penicillin V remains the empiric antibiotic of choice for outpatient odontogenic infections. Because of their ineffectiveness against the oral anaerobes, the macrolides are no longer considered among the empiric antibiotics of choice for odontogenic infections. Because the oral anaerobic gram-negative rods are fairly resistant to most cephalosporins, especially those in the first generation, the cephalosporins remain secondline choices. Sinus infections Acute rhinosinusitis of odontogenic origin is characterized by the same flora as other odontogenic infections, except that not all of the species found in the periapical infection survive in the sinus location [28]. Non-odontogenic acute rhinosinusitis is frequently caused by S. pneumoniae, H. influenzae, Moraxella catarrhalis, and streptococci. S. aureus is found in only approximately 4% of cases of acute rhinosinusitis [15]. Antibiotic treatment should be reserved for patients who already have been treated for 7 days with only decongestants and analgesics and who have maxillary or facial pain or purulent nasal discharge. Patients with severe pain or fever may need antibiotic therapy sooner, and hospitalization may be required in these cases. If antibiotics have been used in the previous month or if the local incidence of penicillin-resistant S. pneumoniae is more than 30%, amoxicillin and clavulanic acid or a secondor third-generation cephalosporin is prescribed for

two weeks [15]. On the other hand, a recent systematic literature review indicates that penicillin or amoxicillin alone is as effective as the other broader spectrum and more expensive antibiotics [29]. In chronic rhinosinusitis, the flora becomes more anaerobic, including B. fragilis and the peptostreptococci, such as Fusobacterium, Prevotella, and Porphyromonas. Antibiotics alone are not usually effective in these cases, and corrective surgery, usually with otorhinolaryngology consultation, is indicated. Fungal infection of the sinuses should be suspected and treated urgently with antibiotics and surgery in patients with acute rhinosinusitis who have diabetes mellitus with acute ketoacidosis, neutropenia, or previous treatment with deferoxamine. Amphotericin B and surgery are indicated, along with discontinuation of deferoxamine, if applicable. Deferoxamine (Desferal) is an iron-chelating agent used in Alzheimers disease. Mucormycosis has been found in patients who are undergoing simultaneous deferoxamine treatment and hemodialysis. Osteomyelitis of the jaw The microbiology of osteomyelitis of the jaws has not been reported specifically in a large case series. It is increasingly apparent from case reports, however, that the usual odontogenic pathogens are the most frequent cause. One also may suspect skin and soil pathogens in traumatic osteomyelitis and salmonella in sickle-cell osteomyelitis. Actinomyces are another prominent pathogen in chronic osteomyelitis, and culture and microscopic examination may be required to identify this organism. Molecular methods ultimately may become the most rapid and reliable method for identifying Actinomyces [30]. Long courses of the antibiotics effective against the Actinomyces are required (see Table 4). Oral penicillins plus probenecid can be used for long-term outpatient therapy. Probenecid inhibits the renal excretion of penicillin and increases the blood level obtained by the oral route. Fungal infections Various fungi cause a wide spectrum of infectious manifestations in the head and neck. An excellent review of the topic can be found in a recent chapter by Bergman [30]. The major fungal infections of concern to oral and maxillofacial surgeons are histoplasmosis and blastomycosis, which may cause granulomatous oral lesions; aspergillosis and mucormycosis, which tend to cause sinusitis; and candidiasis, which causes surface lesions in non-immunocompromised patients

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 Table 12 Empiric antibiotics of choice for head and neck infections Type of infection Odontogenic infections Outpatient Empiric antibiotic of choice

37

Penicillin allergy Inpatient

Penicillin allergy

Penicillin Clindamycin Cephalexin (or other first-generation cephalosporin) Clindamycin Cephalexin (only if nonanaphylactoid penicillin reaction) Clindamycin Ampicillin + metronidazole Ampicillin + sulbactam Clindamycin Moxifloxacin Cefotaxime (only if nonanaphylactoid penicillin reaction) Amoxicillin Amoxicillin/clavulanate Cefuroxime Moxifloxacin (over 18 years of age) Clarithromycin or azithromycin Telithromycin Moxifloxacin (over 18 years of age) Antibiotics not effective: otolaryngologic consultation Imipenem or meropenem Ticarcillin or piperacillin Ceftazidime + vancomycin Cefepime Amphotericin B Clindamycin Ampicillin + metronidazole Ampicillin + sulbactam Clindamycin Moxifloxacin Itraconazole Fluconazole Amphotericin B (systemic or disseminated)

Rhinosinusitis Acute

Penicillin allergy

Chronic Intubated

Fungal Osteomyelitis of the jaw

Penicillin allergy Histoplasmosis and blastomycosis

Candidiasis Oral, non-AIDS Oral, AIDS

Fluconazole or itraconazole Nystatin or clotrimazole Fluconazole or itraconazole Amphotericin B

Data from Gilbert DN, Moellering RC Jr, Sande MA. The Sanford guide to antimicrobial therapy. 32nd edition. Hyde Park (VT): Antimicrobial Therapy Inc.;2002.

and may cause disseminated and invasive disease in immunocompromised persons. Histoplasmosis, blastomycosis, and mucormycosis are diagnosed by surgical sampling for culture, histologic examination with special stains, and use of molecular methods, such as polymerase chain reaction. In general, fungal

infections are treated with the azole-type antifungal agents for less severe cases and amphotericin B for disseminated and severe disease. In surface candidiasis in a patient with a healthy immune system, clotrimazole is a better-tasting yet economical alternative to nystatin.

38

T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 1738 spective double-blind evaluation of penicillin versus clindamycin in the treatment of odontogenic infections. J Oral Maxillofac Surg 1988;46:1065 70. Lewis MA, Carmichael F, MacFarlane TW, Milligan SG. A randomised trial of co-amoxiclav (Augmentin) versus penicillin V in the treatment of acute dentoalveolar abscess. Br Dent J 1993;175:169 74. Paterson SA, Curzon ME. The effect of amoxycillin versus penicillin V in the treatment of acutely abscessed primary teeth. Br Dent J 1993;174:443 9. Gilbert DN, Moellering Jr RC, Sande MA. The Sanford guide to antimicrobial therapy, 32nd edition. Hyde Park (VT): Antimicrobial Therapy Inc.; 2000. Craig TJ, Mende C. Common allergic and allergic-like reactions to mediations: when the cure becomes the curse. Postgrad Med 1999;105:173 81. Bowrey DJ, Morris-Stiff GJ. Drug allergy: fact or fiction? Int J Clin Pract 1998;52:20 1. Warrington RJ, Lee KR, McPhillips S. The value of testing for penicillin allergy in an inpatient population: analysis of the subsequent patient management. Allergy Asthma Proc 2000;21:297 9. DeFonseca MA. Adverse reaction to amoxicillin: a case report. Pediatr Dent 2000;22:401 4. Ebersole JL, Cappelli D. Acute-phase reactants in infections and inflammatory diseases. Periodontology 2000;23:19 49. Bancescu G, Skaug N, Dumitriu S, et al. Antimicrobial susceptibility of some streptococci strains of anginosus group isolated from oral and maxillofacial infections. Roum Arch Microbiol Immunol 1999;58:57 63. Kasten MJ. Clindamycin, metronidazole, and chloramphenicol. Mayo Clin Proc 1999;74:825 33. Fisman DN, Kaye KM. Once-daily dosing of aminoglycoside antibiotics. Infect Dis Clin North Am 2001;14:475 87. Hersh EV. Adverse drug interactions in dental practice: interactions involving antibiotics. Part II. J Am Dent Assoc 1999;130:236 51. Marchese A, Schito GC. The oxazolidinones as a new family of antimicrobial agent. Clin Microbiol Infect 2001;7(Suppl 4):66 74. Felmingham D. Microbiological profile of telithromycin, the first ketolide antimicrobial. Clin Microbiol Infect 2001;7(Suppl 3):2 10. Linden PK. Treatment options for vancomycin-resistant enterococcal infections. Drugs 2002;62:425 41. Brook I, Frazier EH, Gher Jr ME. Microbiology of periapical abscesses and associated maxillary sinusitis. J Periodontol 1996;67:608 10. Williams Jr JW, Aguilar C, Makela M, et al. Antibiotics for acute maxillary sinusitis. Cochrane Library 2000;3:1 51. Bergman SA. Fungal, viral, and protozoal infections of the maxillofacial region. In: Topazian RG, Goldberg MH, Hupp JR, editors. Oral and maxillofacial infections. 4th edition. Philadelphia: W.B. Saunders Co.; 2002. p. 243 78.

Summary Antibiotic selection remains as much of an art as it is a science. It requires the integration of many factors that are host specific, pharmacologic, and even geographic. Much more research is necessary in this field to solve the current problems with the need for more timely culture and sensitivity results, increasing antibiotic resistance, and best practices in antibiotic usage.
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