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Antibiotic selection in head and neck infections
Thomas R. Flynn, DMDa,b,*, Leslie R. Halpern, DDS, MD, MPH, PhDa,b
aDepartment of Oral and Maxillofacial Surgery, Harvard School of Dental Medicine,
188 Longwood Avenue, Boston, MA 02115, USAbDepartment of Oral and Maxillofacial Surgery, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA
Oral and maxillofacial surgeons see patients with
infections as part of their everyday practice. It is
imperative to understand the mechanisms of antimi-
crobial 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.
Molecular biology of antibiotic resistance
Generally speaking, bacteria acquire antibiotic
resistance in one of four ways:
1. Alteration of a drug’s target site
2. Inability of a drug to reach its target
3. Inactivation of an antimicrobial agent
4. Active elimination of an antibiotic from the cell
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 anti-
biotics of other species. For example, the
DNA encoding of b-lactamases and penicillin-
binding proteins have several homologous
sequences [1].
2. Gene transfer. Bacteria can undergo conjuga-
tion 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 them-
selves into the genome of the recipient cell. An
example of a plasmid-mediated genetic event is
acquisition of the ability to produce b-lacta-mase by some species.
3. Bacteriophages. Viruses infect bacteria and
can insert genetic material and take control
of the host’s genetic and metabolic machin-
ery, which may encode for antibiotic re-
sistance 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 pen-
icillin resistance in Streptococcus pneumoniae
and meningococci and ampicillin resistance in
Haemophilus influenzae and gonococci [1].
1042-3699/03/$ – see front matter D 2003, Elsevier Science (USA). All rights reserved.
PII: S1042 -3699 (02 )00082 -1
* 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).
Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38
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 destruc-
tion or inactivation of the antimicrobial agent is
accomplished by the induction of specific drug-inac-
tivating enzymes, such as those that inhibit b-lactams
or aminoglycosides. Numerous gram-positive and
gram-negative bacteria, such as Staphylococcus au-
reus, Enterococcus faecium, Escherichia coli, Pseu-
domonas aeruginosa, H. influenzae, Bacteroides, and
many strains of Prevotella have this capability.
Another method used by bacteria to withstand anti-
microbial attack is the ability to synthesize neutral-
izing enzymes. The best examples are penicillinase
and the methylation of erythromycin and clindamy-
cin. Other antibiotics that are neutralized include
vancomycin, sulfonamides, aminoglycosides and
rifampin. Bacterial organisms with this capability
include S. pneumoniae, S. aureus, Clostridium per-
fringens, Bacteroides fragilis, Campylobacter spe-
cies, 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, tetracy-
clines, erythromycin, and the aminoglycosides. The
gram-negative rods E. coli, P. aeruginosa, and Sal-
monella 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 exam-
ple, 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 tetracy-
clines, 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 spe-
cies) have the ability to alter the number of drug
receptors that bind antibiotics. The sulfonamide fam-
ily 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 sub-
populations 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 ampi-
cillin 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 adminis-
tration 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 infec-
tions, however.
The question of whether antibiotic resistance in
patients with odontogenic infections who need hos-
pitalization 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 com-
pared 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 no-
menclature [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
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3818
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-lacta-mase 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 Clos-
tridium 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.
Host factors in antibiotic selection
Usual pathogens
The type of infection that presents can be char-
acterized by cause and location, and each has its
own characteristic flora. Odontogenic infections are
generally characterized by a combination of faculta-
tive streptococci and oral anaerobes. Within the
viridans group of facultative streptococci, the Strep-
tococcus milleri group, which consists of S. angino-
sus, S. intermedius, and S. constellatus, is most
frequently associated with orofacial cellulitis and
abscess. This is fortunate because only approxi-
mately 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 sal-
ivarius, are more frequently found in endocarditis,
and they can be highly penicillin resistant—up to
58% in one study [10].
Among the anaerobes, anaerobic peptostreptococci
and members of the genera Prevotella and Porphyro-
monas 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
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 anti-
biotic of choice. In odontogenic infections and dog
and cat bites, Eikenella corrodens is fairly resistant to
the penicillins and completely resistant to clindamy-
cin. 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 hypersen-
sitivity reactions. Between 1% and 10% of patients
who initially take penicillin develop an allergic reac-
tion, 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 pa-
tients 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, hyper-
sensitivity 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 mem-
bers 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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 19
The newer b-lactam antibiotics, the monobactams
(aztreonam) and the carbapenems (imipenem and
meropenem), have much less frequent cross-sensitiv-
ity with the penicillin group. A history of adverse
reaction or intolerance of an antibiotic, such as
phototoxicity with the tetracyclines or antibiotic-
associated 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 inter-
fere 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 mul-
tiplication. Some antibiotics, such as clindamycin,
seem to be bacteriostatic at lower doses and bacte-
ricidal at higher doses.
HIV-infected individuals seem to be able to han-
dle oral bacterial infections almost as well as non-
infected persons. This ability is probably caused by
the antibody-mediated immunity provided by the
B-lymphocytes, which is largely responsible for com-
bating the extracellular bacterial pathogens of most
head and neck infections. Resistance to these com-
mon 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.
Table 1
Major pathogens of head and neck infections
Type of infection Microorganisms
Odontogenic cellulitis/abscess Streptococcus milleri group
Peptostreptococci
Prevotella and Porphyromonas
Fusobacteria
Rhinosinusitis Acute Streptococcus pneumoniae
Haemophilus influenzae
Head and neck anaerobes (peptostreptococci, Prevotella,
Porphyromonas, fusobacteria)
Group A b-hemolytic streptococci
Staphylococcus aureus
Moraxella catarrhalis
Viruses
Chronic Head and neck anaerobes
Fungal Aspergillus
Rhizopus sp. (mucor)
Nosocomial
(especially if intubated)
Enterobacteriaceae (especially Pseudomonas,
Acinetobacter, Escherichia coli)
S. aureus
Yeasts (Candida species)
Osteomyelitis of the jaws Acute Odontogenic flora
S. aureus and skin flora in trauma
Salmonella in sickle cell disease
Chronic Actinomyces species
Necrotizing fasciitis Group A b-hemolytic streptococci
Regional flora (oral and sinus pathogens
in head and neck)
Fungal Mucosal or disseminated Candida species
Soft tissue Histoplasma species
Blastomyces species
Sinus Aspergillus
Rhizopus (mucor)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3820
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 re-
sistant organisms. Studies of patients who are cur-
rently 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 consid-
erable 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 endocarditis-
associated viridans streptococci (S. mitis, S. sanguis,
and S. salivarius) is high—up 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 amox-
icillin for endocarditis prophylaxis before oral proce-
dures. 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.
They are discussed in the section on adverse anti-
biotic 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 organ-
isms 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 clinda-
mycin 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, itracona-
zole, ethambutol, and saquinavir.
Penicillin G in high doses reaches 5% to 10% of
the serum concentration in the cerebrospinal fluid
Table 2
Bactericidal and bacteriostatic antibiotics
Bactericidal Bacteriostatic
b-lactams Macrolides
penicillins erythromycin
cephalosporins clarithromycin
carbapenems azithromycin
monobactams Clindamycin
Aminoglycosides Tetracyclines
Vancomycin Sulfa antibiotics
Metronidazole
Fluoroquinolones
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 21
Table 3
Spectrum of selected antibiotics
Antibiotic category Antibiotic Susceptible organisms
Natural penicillins Penicillin G and V Viridans streptococci
Oral anaerobes
Actinomyces sp. (penicillin G only)
Pasteurella multocida
Semisynthetic penicillins Ampicillin As with natural penicillins, plus enterococci
Amoxicillin Actinomyces
b-lactam/b-lactamase inhibitors Amoxicillin/clavulanate As with amoxicillin, plus
Ampicillin/sulbactam S. aureus, not MRSA
S. epidermidis, not MRSE
H. influenzae
M. catarrhalis
Klebsiella species
E. coli
Bacteroides fragilis
Penicillinase-resistant penicillins Oxacillin S. aureus, not MRSA
Dicloxacillin S. epidermidis, not MRSE
Antipseudomonal penicillins Ticarcillin/clavulanate As with natural penicillins, plus
Piperacillin/tazobactam S. aureus, not MRSA
S. epidermidis, not MRSE
H. influenzae
M. catarrhalis
Klebsiella species
E. coli
Bacteroides fragilis
Enterobacteriaceae (most)
Pseudomonas aeruginosa
Carbapenems Imipenem As with antipseudomonal penicillins, plus
Meropenem Actinomyces (imipenem)
Ertapenem
Monobactam Aztreonam Enterobacteriaceae, except Salmonella
(no data) and Acinetobacter (resistant)
Cephalosporins First generation Streptococci
Cephalexin S. aureus, not MRSA
Cefazolin H. influenzae
Klebsiella
E. coli
Second generation As with first generation, plus
Cefaclor M. catarrhalis (cefuroxime)
Cefuroxime Oral anaerobes
Cefoxitin B. fragilis (cefoxitin)
Third generation As with first generation, plus
Cefotaxime M. catarrhalis
Ceftriaxone Oral anaerobes
Actinomyces (ceftriaxone)
Macrolides Erythromycin Streptococci
Clarithromycin Actinomyces
Azithromycin Peptostreptococci (azithromycin)
Clindamycin Clindamycin Streptococci
Oral anaerobes
Actinomyces
S. aureus, not MRSA
Metronidazole Obligate anaerobes
Fluoroquinolones Ciprofloxacin S. aureus, not MRSA
Enterobacteriaceae (most)
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3822
when the meninges are inflamed. In odontogenic
infections that threaten the central nervous system,
the addition of metronidazole (30%–100% penetra-
tion) 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 concentra-
tion dependent, whereas with other antibiotics, such
as the b-lactams and vancomycin, it is time depen-
dent. In concentration-dependent antibiotics, efficacy
is determined by the ratio of the serum concentration
of the antibiotic to the minimum inhibitory concen-
tration (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 penicil-
lin 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 approx-
imately 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
achievedwith amoxicillin, 500mgorally, 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 concen-
tration 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
Table 3 (continued )
Antibiotic category Antibiotic Susceptible organisms
Moxifloxacin Streptococci
Oral anaerobes
S. aureus, not MRSA
Actinomyces
B. fragilis
Enterobacteriaceae (most)
Aminoglycosides Gentamicin S. aureus, not MRSA
Tobramycin Enterococci (gentamicin synergistic with ampicillin)
Enterobacteriaceae (many)
Pseudomonas
Glycopeptides Vancomycin Streptococci
Teicoplanin S. aureus, including MRSA
S. epidermidis, including MRSE (vancomycin)
Oxazolidinones Linezolid Streptococci
Staphylococci, including VISA, VRSE, MRSA, MRSE
Peptostreptococci
Enterococci, including VRE
Pristinamycins Quinupristin/dalfopristin Streptococci
Staphylococci, including VISA, VRSE, MRSA, MRSE
Legionella
Ketolides Telithromycin Streptococci
S. aureus (not MRSA?)
H. influenzae
M. catarrhalis
Legionella
Abbreviations: MRSA, methicillin-resistant S. aureus; MRSE, methicillin-resistant S. epidermidis; VISA, vancomycin-inter-
mediate S. aureus; VRSE, vancomycin-resistant S. epidermidis.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 23
Table 4
Antibiotics of choice for head and neck pathogens
Pathogen Type First choice antibiotics Alternative antibiotics
Actinomyces +, R, A Penicillin G or ampicillin Doxycycline
Clindamycin
Erythromycin
Bacteroides fragilis � , R, AN Metronidazole Clindamycin
Cefoxitin, not cefotetan (DOT)
Ampicillin/sulbactam
Clostridium species
(except C. difficile)
+, R, AN Penicillin G F clindamycin Metronidazole
Doxycycline
Cephalosporin (1st)a
Clostridium difficile +, R, AN Metronidazole p.o. Vancomycin p.o.
Bacitracin p.o.
Eikenella corrodens � , R, A Penicillin G or V Fluoroquinolones
Amoxicillin
Amoxicillin/clavulanate
TMP/SMX (avoid
clindamycin)
Enterococcus faecalis
(group D streptococcus)
+, C, F Ampicillin F gentamicin
(for endocarditis or meningitis
Vancomycin
Ampicillin/sulbactam
Linezolid
Enterococcus faecium (group D
streptococcus: b-lactamase +,
aminoglycoside and
vancomycin resistant)
+, C, F Linezolid + quinupristin/dalfopristin Fchoramphenicol F doxycycline
Teicoplanin + aminoglycoside
(van B)
For some strains: no effective
regimen (I.D. consultation)
Escherichia coli � , R, A Ticarcillin/clavulanate
Cephalosporins
Imipenem
Fluoroquinolones
Meropenem for central nervous system
Aztreonam
TMP/SMX
Tobramycin
Fusobacterium species � , R, AN Penicillin G or V Metronidazole
Clindamycin
Haemophilus influenzae
(b-lactamase positive)
� , R, F Amoxicillin/clavulanate
Cefaclor
Azithro/clarithromycin
Cefotaxime (if life threatening)
Ciprofloxacin
TMP/SMX
Klebsiella pneumoniae � , R, A Cephalosporin (3rd)* Tobramycin
Fluoroquinolones Ticarcillin/clavulanate
Imipenem/cilastatin
Klebsiella pneumoniae
(producing extended spectrum
b-lactamases: ESBLs)
� , R, A Imipenem/cilastatin
Fluoroquinolones
Meropenem
Pasteurella multocida
(eg, dog and cat bites)
� , R, A Penicillin G
Amoxicillin/Clavulanate
Doxycline
Cephalosporin (2nd)a
TMP/SMX
Peptostreptococcus
(and former Peptococcus)
+, C, AN Penicillin G or V Clindamycin
Doxycline
Vancomycin
Black pigmented oral
anaerobes (Prevotella and
Porphyromonas)
� , R, AN Clindamycin PCN + metronidazole
Amoxicillin
Cefotetan
Proteus vulgaris (indole +) � , R, A Cephalosporin (3rd) Tobramycin
Fluoroquinolones Imipenem
Ticarcillin/clavulanate
Pseudomonas aeruginosa � , R, A Ciprofloxacin Aztreonam + ceftazidime
Tobramycin Piperacillin + tobramycin
Cefepime + tobramycin
Salmonella typhi � , R, A Fluoroquinolones Chloramphenicol
Ceftriaxone Amoxicillin
TMP/SMX
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3824
Table 4 (continued )
Pathogen Type First choice antibiotics Alternative antibiotics
Serratia marcescens � , R, A Cephalosporin (3rd) Gentamicin
Imipenem Aztreonam
Meropenem
Fluoroquinolones
Shigella � , R, A Fluoroquinolones TMP/SMX + ampicillin
Azithromycin
Staphylococcus aureus
(methicillin sensitive)
+, C, A Penicillinase-resistant
penicillin
Cephalosporin (1st)a
Vancomycin
Clindamycin
Staphylococcus aureus
(methicillin resistant)
+, C, A Vancomycin Teicoplanin
Quinupristin-dalfopristin
TMP/SMX (some strains)
Linezolid
Staphylococcus aureus
(methicillin and
vanco mycin resistant)
+, C, A No effective regimen
Try vancomycin F rifampin
Quinupristin/dalfopristin
Linezolid
Staphylococcus epidermidis
(methicillin resistant)
+, C, A Vancomycin (+ rifampin
+ gentamicin
for prosthetic valve endocarditis)
Quinupristin/dalfopristin
Staphylococcus epidermidis
(methicillin and
glycopeptide resistant)
+, C, A Quinupristin/dalfopristin
Linezolid
Vancomycin (high dose)
New fluoroquinolones?b
(rapid resistance a problem)
Streptococcus pneumoniae
(Pneumococcus)
(penicillin sensitive)
+, C, A Penicillin G or V
Ceftriaxone
Amoxicillin
Cefuroxime, cefipime
Imipenem
New fluoroquinolonesb
Streptococcus pneumoniae
(Pneumococcus) (multiantibiotic
resistant, including high-level
penicillin, erythromycin,
tetracycline, chloramphenicol,
and TMP/SMX)
+, C, A Vancomycin + Rifampin Clindamycin
New fluoroquinolones (in vitro)
Streptococcus pyogenes
(b-hemolytic streptococcus)
+, C, A Penicillin G or V (+ gentamicin
if serious group B infection)
Cephalosporin (1st)a
Erythromycin
Streptococcus viridans
(a-hemolytic streptococcus)
+, C, A Penicillin G or V Cephalosporin (1st)a
Macrolides
Fungal organisms
Blastomyces Fungus Amphotericin B
(for systemic cases)
Itraconazole (if surface)
Fluconazole (if surface)
Candida Fungus Fluconazole Nystatin (if surface)
Amphotericin B
(for systemic cases)
Clotrimazole (if surface)
Ketoconazole (if surface)
Itraconazole (if surface)
Coccidioides immitis Fungus Itraconazole Fluconazole
Amphotericin B
Histoplasma Fungus Amphotericin B (for systemic
or immunocompromised cases)
Itraconazole (immunocompetent)
Itraconazole (immunocompromised)
Mucormyces Fungus Amphotericin B Control underlying systemic disease
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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 25
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 endocarditis-
associated strains are less so.
The pharmacokinetics of the clinically available
antibiotics have been determined during drug devel-
opment. 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 nephrotox-
icity 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 anti-
biotics 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 cephalospo-
rins, gastrointestinal intolerance of the erythromycins,
nephrotoxicity and ototoxicity of the amino-
glycosides, and antibiotic-associated colitis with the
b-lactam/b-lactamase inhibitor combinations (eg,
Augmentin, Unasyn), antipseudomonal penicillins
(eg, ticarcillin, piperacillin), cephalosporins, and clin-
damycin, 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 fluo-
roquinolones, because of chondrotoxicity in growing
cartilage. Among the carbapenems, imipenem is not
recommended because of the risk of seizures. Mer-
openem 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.
Table 5
Highly resistant organisms and the antibiotics to which they
are resistant
Organism Resistant to
Acinetobacter baumanii Penicillins
Third generation
cephalosporins
Antipseudomonal
aminoglycosides
Fluoroquinolones
Imipenem
Enterococcus faecalis
b-lactamase negative
Glycopeptides
Streptomycin
Gentamicin
Enterococcus faecalis
b-lactamase positive
All b-lactams
Glycopeptides
Aminoglycosides
Enterococcus faecium
b-lactamase negative
Glycopeptides
Streptomycin
Gentamicin
Enterococcus faecium
b-lactamase positive
all b-lactams
Glycopeptides
Aminoglycosides
Klebsiella pneumoniae
ESBL positive
Penicillins
Third generation
cephalosporins
Aztreonam
Pseudomonas
aeruginosa
Penicillins
Cephalosporins
Carbapenems
Staphylococcus
aureus MRSA
Methicillin
S. aureus VISA or GISA Methicillin
Vancomycin only
Vancomycin and
teicoplanin (both
available glycopeptides)
Staphylococcus
epidermidis MRSE
Methicillin
S. epidermidis VRMRSE Methicillin
Glycopeptides
Streptococcus pneumoniae
penicillin intermediate
or resistant
Penicillin G
S. pneumoniae
multi-antibiotic resistant
Penicillins
Cephalosporins
Aztreonam
Abbreviations: ESBL, extended-spectrum b-lactamase;
GISA, glycopeptide-intermediate S. aureus; MRSE, methi-
cillin-resistant S. epidermidis; VRMRSE, vancomycin-
resistant 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) 17–3826
Antibiotic drug interactions
Two important categories of antibiotic drug inter-
action are interference with the effectiveness of oral
contraceptives and interference with the metabolism
of drugs, which involves the cytochrome P450 sys-
tem. These and other selected antibiotic drug inter-
actions 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, dap-
sone, trimethoprim/sulfamethoxazole, and the antivi-
ral 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 contracep-
tive 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 enter-
ohepatic 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 estrogen-
glucuronide bond, which allows the pure estrogen
molecule to be reabsorbed by the gut, thus support-
ing 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-threat-
ening or fatal cardiac dysrhythmias, such as ven-
tricular fibrillation and torsade des pointes, have
occurred. The most significant interactions invol-
ving the cytochrome P450 system are included in
Table 9.
Table 6
Selected antibiotics and the blood-brain barrier
Cerebrospinal fluid Antibiotic
Therapeutic
levels achieved
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
Therapeutic levels
not achieved
Cephalosporins
cefazolin
cephalexin
Aminoglycosides
Macrolides
erythromycin
clarithromycin
azithromycin
Clindamycin
Antifungal drugs
amphotericin
itraconazole
Antiviral drugs
saquinavir
zidovudine
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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 27
Table 7
Major adverse reactions of selected antibiotics
Adverse reactions
Penicillin G
and V
Ampicillin,
amoxicillin Fclavulanate
Ticarcillin Fclavulanate Impenem Meropenem
Gentamicin,
tobramycin
Cephalexin,
cefazolin Cefuroxime Cefoxitin Cefotaxime Cefaclor
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.Flyn
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/OralMaxillo
facia
lSurg
Clin
NAm
15(2003)17–38
28
Table 7 (continued )
Erythromycin
Clarithromycin,
azithromycin Clindamycin Metronidazole Ciprofloxacin Moxifloxacin Vancomycin
Tetracycline,
doxycycline Linezolid Telithromycin
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 + + + + +
T.R.Flyn
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/OralMaxillo
facia
lSurg
Clin
NAm
15(2003)17–38
29
Cost
Although clinical effectiveness and reduction of
the morbidity of infection and treatment are of para-
mount 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 admin-
istration, 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 pre-
scription for the given antibiotic by that of penicillin V.
Table 11 compares the cost of intravenous anti-
biotics. The cost of administration assumes great
importance. Each dose requires sterile intravenous ad-
ministration supplies, professional labor, and hospital
sterile processing and drug error prevention systems.In
Table 11, these costs are conservatively estimated at
Table 8
Pregnancy risk categories of selected antibiotics
Antibiotic Pregnancy risk category Pregnancy risk
Penicillins
penicillin G and V B
ampicillin B
amoxicillin B
amoxicillin/clavulanate B
ticarcillin/clavulanate B
Cephalosporins
cephalexin B
cefazolin B
cefaclor B
cefuroxime B
cefoxitin B
cefotaxime B
Carbapenems
imipenem C Spontaneous abortions in monkeys
meropenem B
Macrolides
erythromycin B
clarithromycin C Fetal defects in mice and monkeys
azithromycin B
Antianaerobic
clindamycin B
metronidazole B
Fluoroquinolones
ciprofloxacin C Spontaneous abortions in rabbits
moxifloxacin C Fetal toxicity in rodents and monkeys
Aminoglycosides
gentamicin D Ototoxicity in human fetuses
tobramycin D Ototoxicity in human fetuses
Other
vancomycin C Potential ototoxicity in human fetuses
tetracyclines D Intrinsic dental staining
doxycycline D Intrinsic dental staining
linezolid C Fetal toxicity in rodents
telithromycin 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.
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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3830
Table 9
Selected antibiotic interactions with other drugsa,b
Antibiotic Second drug Adverse effects Mechanism
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Theophylline Seizures, dysrhythmias Antibiotic inhibits
cytochrome P450
metabolism of second
drug; ketoconazole
not implicated
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Cisapride Dysrythmias (torsades) Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Alfentanil z Respiratory depression Antibiotic inhibits
cytochrome P450
metabolism of second
drug; ketoconazole
not implicated
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Bromocriptine z CNS effects, hypotension Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Carbamazepine Ataxia, vertigo, drowsiness Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Cyclosporine z Immunosuppression
and nephrotoxicity
Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Felodipine, possibly other
calcium channel blockers
Hypotension, tachycardia,
edema
Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Methylprednisolone,
prednisone
z Immunosuppression Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Lovastatin, possibly
other -statins
Muscle pain, rhabdomyolysis Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Triazolam, oral midazolam z Sedative depth and duration Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin, clarithromycin,
ketoconazole, itraconazole
Disopyramide Dysrhythmias Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Erythromycin Clindamycin # Antibiotic effect Mutual antagonism
Erythromycin, tetracyclines Digoxin Digitalis toxicity,
dysrhythmias, visual
disturbances,
hypersalivation
Antibiotic kills
Eubacterium lentum,
which metabolizes
digoxin in the gut
Erythromycin, clarithromycin,
metronidazole
Warfarin
Anisindione
z Anticoagulation Antibiotic interferes
with metabolism of
the second drug
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 31
Table 9 (continued )
Antibiotic Second drug Adverse effects Mechanism
Tetracycline, cefamandole,
cefotetan, cefoperazone,
sulfonamides, aminoglycosides
Warfarin, anisindione z Anticoagulation Antibiotic kills gut
flora that synthesize
vitamin K, which
antagonizes the second
drug; poor vitamin K
intake a factor
Metronidazole, cephalosporins Alcohol, ritonavir Flushing, headache,
palpitations, nausea
Antibiotic inhibits
acetaldehyde
dehydrogenase,
causing accumulation
of acetaldehyde;
ritonavir preparations
contain alcohol
Metronidazole Disulfiram Acute toxic psychosis
Metronidazole, tetracyclines Lithium Lithium toxicity: confusion,
ataxia, kidney damage
Antibiotic inhibits
lithium excretion by
kidney; tetracycline
interaction not well
established
Tetracyclines, fluoroquinolones Divalent and trivalent cations
(dairy, antacids, vitamins)
didanosine
# Absorption of antibiotic Second drug interferes
with absorption of
antibiotic; didanosine
is formulated with
calcium carbonate and
magnesium hydroxide
buffers
Clindamycin, aminoglycosides,
tetracyclines, bacitracin
Neuromuscular blocking
agents
z Depth and duration
of paralysis
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
Clindamycin Erythromycin # Antibiotic effect Mutual antagonism
Penicillins, cephalosporins,
metronidazole, erythromycin,
clarithromycin, tetracyclines,
rifampin
Estrogen- and progestin-
containing oral contraceptives
Contraceptive failure Interference with
enterohepatic
recirculation of
estrogen caused by
killing of gut flora;
rifampin is the only
antibiotic in which
this has been
clinically proven
Ampicillin, amoxicillin Allopurinol Rash Unknown, possibly
caused by hyperuricemia
in patients taking
allopurinol
Cephalosporins Aminoglycosides z Nephrotoxicity Additive or
potentiating effect
Trimethoprim/sulfamethoxazole Thiazide diuretics Purpura, bleeding in
elderly patients
Thrombocytopenia
Vancomycin Aminoglycosides z Renal toxicity Additive effect
(continued on next page)
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3832
$4.00 per dose. Even this small additional cost can
make an infrequently administered butmore expensive
antibiotic more economical than a cheaper, more fre-
quently dosed antibiotic. An example of this effect can
be found by comparing the cost ratio of penicillin G
(analogous to the penicillinVcost ratio)with cefazolin.
Table 11 also illustrates the markedly increased
cost of combined antibiotic therapy as compared to
monotherapy. For example, 1 week’s intravenous
therapy of penicillin G plus metronidazole costs
$690, whereas 1 week’s 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
Table 9 (continued )
Antibiotic Second drug Adverse effects Mechanism
Fluoroquinolones, sulfonamides,
chloramphenicol, fluconazole,
itraconazole
Oral hypoglycemic agents Hypoglycemia Antibiotic displaces
second drug from
plasma proteins
Ciprofloxacin, sulfonamides,
chloramphenicol, fluconazole,
ketoconazole, itraconazole
Phenytoin z Serum level of phenytoin,
confusion, delirium
Interference with
phenytoin metabolism
Sulfonamides Methotrexate z Methotrexate concentration Antibiotic displaces
methotrexate
from plasma proteins
Protease inhibitors (ritonavir,
amprenavir, saquinavir,
nelfinavir, indinavir,
and others)
Hydrocodone, fentanyl,
alfentanil, amiodarone,
lidocaine, anticonvulsants,
loratidine,
Benzodiazepines
b-blockersCalcium channel blockers
Cisapride
Corticosteroids
-statin type
antihyperlipidemics
Warfarin
z Levels of second drug,
with possible toxic effects
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
Protease inhibitors Codeine, morphine,
contraceptives
# Levels of second drug Antibiotic enhances
cytochrome P450
metabolism of
second drug
Delavirdine (Rescriptor) Cisapride, clarithromycin,
protease inhibitors, warfarin
z Levels of second drug,
with possible toxic effects
Antibiotic inhibits
cytochrome P450
metabolism of
second drug
Didanosine (ddl, Videx) Metronidazole z Risk of peripheral
neuropathy
Additive effect
Foscarnet (Foscavir) Ciprofloxacin z Risk of seizures 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-HIVantibiotics 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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 33
the viridans streptococci, oral anaerobes, and acti-
nomyces. They are also effective against sinus
pathogens, staphylococci, Enterobacteriaceae, and
B. fragilis. Their broad spectrum is a relative dis-
advantage 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 gram-
negative 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-
Table 10
Oral antibiotic costs
Antibiotic
Usual dose
(mg)
Usual interval
(h)
Pharmacy
Cost ’01 * *
Cost for
24 hours
Retail cost for
1 weekdPenicillin
cost ratioc
Penicillins
Penicillin V 500 6 $0.14 $0.56 $9.99 1.00
Amoxicillin 500 8 $0.31 $0.93 $13.89 1.39
Augmentina 500 8 $3.65 $10.95 $104.99 10.51
Augmentin 875 12 $4.76 $9.52 $97.59 9.77
Dicloxacillin 500 6 $0.66 $2.64 $26.69 2.67
Cephalosporins (generation)
Cephalexin caps (1st) 500 6 $1.07 $4.28 $24.89 2.49
Keftabs (1st)b 500 6 $3.11 $12.44 $104.99 10.51
Cephradine (1st) 500 6 $0.52 $2.08 $70.59 7.07
Cefuroxime (2nd) 500 8 $7.43 $22.29 $199.99 20.02
Cefaclor (2nd) 500 8 $4.00 $12.00 $77.59 7.77
Erythromycins
Erythromycin base 500 6 $0.36 $1.44 $13.89 1.39
Erythromycin stearate 333 6 $0.36 $1.44 $16.29 1.63
Erythromycin estolate 250 6 $0.31 $1.24 $13.49 1.35
Dirythromycin (Dynabec) 500 24 $12.39 $12.39 $63.99 6.41
Clarithromycin (Biaxin) 500 12 $3.57 $7.14 $71.99 7.21
Azithromycin (Zithromax) 250 24 $6.75 $6.75 $60.59 6.07
Anti-anaerobic
Clindamycin (generic) 150 6 $0.98 $3.92 $31.29 3.13
Clindamycin (2 T generic) 300 6 $1.96 $7.84 $54.86 5.49
Clindamycin (Cleocin) 300 6 $4.22 $16.88 $118.27 11.84
Metronidazole (250 mg = $0.08) 500 6 $0.72 $2.88 $10.02 1.00
Other
Trimethoprim/sulfamethoprim 160/800 12 $0.15 $0.30 $11.69 1.17
Ciprofloxacin 500 12 $4.15 $8.30 $80.59 8.07
Doxycycline 100 12 $0.08 $0.16 $9.99 1.00
Vancomycin 125 6 $5.38 $21.52 $187.99 18.82
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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3834
dia pneumoniae, and Legionella pneumophila. Its
most frequent use probably is in respiratory tract
infections, especially pneumonia [26,27].
Pristinamycins
Quinupristin/dalfopristin (Synercid), a combina-
tion 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 cul-
ture and sensitivity test results are available; specific
antibiotic therapy is selected based on culture and
sensitivity results. Table 12 lists the empiric anti-
biotics of choice for selected types of head and neck
infections, including odontogenic infections.
Table 11
Intravenous antibiotic costs
Antibiotic
Usual
dosebUsual interval
(hour)bPharmacy
cost ’00
Pharmacy
cost ’01
Total cost
24 hours
Total cost
for 7 days
Penicillin G
cost ratioa
Penicillins
Penicillin G 2 mu 6 $1.33 $1.32 $21.28 $148.96 1.00
Ampicillin 1 g 6 $1.64 $1.31 $21.24 $148.68 1.00
Unasyn 2 g 6 $10.18 $14.45 $73.80 $516.60 3.47
Oxacillin 1 g 6 $2.68 $5.14 $36.56 $255.92 1.72
Ticarcillin 3 g 4 $12.92 $13.43 $104.58 $732.06 4.91
Timentin 3.1 g 4 $15.40 $15.20 $115.20 $806.40 5.41
Cephalosporins (generation)
Cefazolin (1st) 1 g 8 $1.74 $1.90 $17.70 $123.90 0.83
Cefotetan (2nd) 1 g 12 $11.58 $11.60 $31.20 $218.40 1.47
Cefuroxime (2nd) 1.5 g 8 $13.93 $13.80 $53.40 $373.80 2.51
Cefotaxime (3rd) 2 g 8 $21.16 $26.38 $91.14 $637.98 4.28
Ceftazidime (3rd) 2 g 8 $28.45 $28.45 $97.35 $681.45 4.57
Ceftriaxone (3rd) 1 g 24 $42.00 $40.18 $44.18 $309.26 2.08
Monobactam
Aztreonam 1 g 8 $16.97 $16.97 $62.91 $440.37 2.96
Carbapenem
Imipenem-cilastatin 0.5 g 6 $30.32 $30.32 $137.28 $960.96 6.45
Penicillin allergy
Erythromycinc 1 g 6 $22.16 $23.00 $108.00 $756.00 5.08
Azithromycin 0.5 g 24 $23.70 $24.44 $28.44 $199.08 1.34
Vancomycin 0.5 g 6 $7.80 $8.28 $49.12 $343.84 2.31
Vancomycin 1.0 g 12 $15.60 $16.56 $41.12 $287.84 1.93
Anti-anaerobic
Clindamycin 0.9 g 8 $13.88 $13.88 $53.64 $375.48 2.52
Metronidazole 0.5 g 6 $19.03 $15.34 $77.36 $541.52 3.64
Other
Doxycycline 0.1 g 12 $21.07 $4.16 $16.32 $114.24 0.77
Trimethoprim-sulfa 800 mg 6 $16.42 $16.42 $81.68 $571.76 3.84
Ciprofloxacind 400 mg 12 $30.00 $30.00 $68.00 $476.00 3.20
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 whole-
sale price.d Cipro IV is for NPO patients only because of excellent oral absorption.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 35
In a prospective case series of 34 cases of odonto-
genic 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 in-
adequate 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 sen-
sitivity 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 anti-
biotic 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 odon-
togenic 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 resist-
ant to most cephalosporins, especially those in the
first generation, the cephalosporins remain second-
line choices.
Sinus infections
Acute rhinosinusitis of odontogenic origin is char-
acterized by the same flora as other odontogenic
infections, except that not all of the species found
in the periapical infection survive in the sinus loca-
tion [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 second-
or third-generation cephalosporin is prescribed for
two weeks [15]. On the other hand, a recent system-
atic 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 peptostrep-
tococci, 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 sus-
pected and treated urgently with antibiotics and
surgery in patients with acute rhinosinusitis who have
diabetes mellitus with acute ketoacidosis, neutro-
penia, or previous treatment with deferoxamine.
Amphotericin B and surgery are indicated, along with
discontinuation of deferoxamine, if applicable. Defer-
oxamine (Desferal) is an iron-chelating agent used in
Alzheimer’s disease. Mucormycosis has been found
in patients who are undergoing simultaneous defero-
xamine 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 ulti-
mately may become the most rapid and reliable
method for identifying Actinomyces [30]. Long
courses of the antibiotics effective against the Actino-
myces 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) 17–3836
and may cause disseminated and invasive disease in
immunocompromised persons. Histoplasmosis, blas-
tomycosis, and mucormycosis are diagnosed by sur-
gical 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 candidia-
sis in a patient with a healthy immune system,
clotrimazole is a better-tasting yet economical alter-
native to nystatin.
Table 12
Empiric antibiotics of choice for head and neck infections
Type of infection Empiric antibiotic of choice
Odontogenic infections
Outpatient Penicillin
Clindamycin
Cephalexin (or other first-generation cephalosporin)
Penicillin allergy Clindamycin
Cephalexin (only if nonanaphylactoid penicillin reaction)
Inpatient Clindamycin
Ampicillin + metronidazole
Ampicillin + sulbactam
Penicillin allergy Clindamycin
Moxifloxacin
Cefotaxime (only if nonanaphylactoid penicillin reaction)
Rhinosinusitis
Acute Amoxicillin
Amoxicillin/clavulanate
Cefuroxime
Moxifloxacin (over 18 years of age)
Penicillin allergy Clarithromycin or azithromycin
Telithromycin
Moxifloxacin (over 18 years of age)
Chronic Antibiotics not effective:
otolaryngologic consultation
Intubated Imipenem or meropenem
Ticarcillin or piperacillin
Ceftazidime + vancomycin
Cefepime
Fungal Amphotericin B
Osteomyelitis of
the jaw
Clindamycin
Ampicillin + metronidazole
Ampicillin + sulbactam
Penicillin allergy Clindamycin
Moxifloxacin
Histoplasmosis and
blastomycosis
Itraconazole
Fluconazole
Amphotericin B
(systemic or disseminated)
Candidiasis
Oral, non-AIDS Fluconazole or itraconazole
Nystatin or clotrimazole
Oral, AIDS 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.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–38 37
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 geo-
graphic. Much more research is necessary in this field
to solve the current problems with the need for more
timely culture and sensitivity results, increasing anti-
biotic resistance, and best practices in antibiotic usage.
References
[1] 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. p. 23–50.
[2] Molinari JA. Antibiotic resistance and maxillofacial
pathogens: emerging treatment issues. J California
Dental Assoc 1999;27:386–92.
[3] Neu HC. Emerging trends in antimicrobial resistance
in surgical infections: a review. Eur J Surg Suppl 1994;
573:7–18.
[4] Kulekei G, Inane D, Kocak H, et al. Bacteriology of
dentoalveolar abscesses in patients who have received
empirical antibiotic therapy. Clin Infect Dis Suppl
1996;1:S51–3.
[5] Kuriyama T, Nakagawa K, Karasawa T, et al. Past
administration of b-lactam antibiotics and increase in
the emergence of b-lactamase-producing bacteria in
patients with orofacial odontogenic infections. Oral
Surg Oral Med Oral Pathol Oral Radiol Endod
2000;89:186–92.
[6] Haug RH, Hoffman MJ, Indresano AT. An epidemio-
logic and anatomic survey of odontogenic infections.
J Oral Maxillofac Surg 1991;49:976–80.
[7] Storoe W, Haug RH, Lillich TT. The changing face of
odontogenic infections. J Oral Maxillofac Surg 2001;
59:739–48.
[8] Flynn TR, Wiltz M, Adamo AK, et al. Predicting
length of hospital stay and penicillin failure in severe
odontogenic infections. Int J Oral Maxillofac Surg
1999;28(Suppl 1):48.
[9] Brook I. Microbiology of common infections in the
upper respiratory tract. Prim Care 1998;25:637–47.
[10] Doern GV, Ferraro MJ, Brueggemann AB, Ruoff
KL. Emergence of high rates of antimicrobial resist-
ance among viridans group streptococci in the
United States. Antimicrob Agents Chemother 1996;
40:891–4.
[11] Fazakerley MW, McGowan P, Hardy P, Martin MV.
A comparative study of cephradine, amoxycillin
and phenoxymethylpenicillin in the treatment of acute
dentoalveolar infection. Br Dent J 1993;174:359–63.
[12] Gilmore WC, Jacobus NV, Gorbach SL, et al. A pro-
spective double-blind evaluation of penicillin versus
clindamycin in the treatment of odontogenic infections.
J Oral Maxillofac Surg 1988;46:1065–70.
[13] Lewis MA, Carmichael F, MacFarlane TW, Milligan
SG. A randomised trial of co-amoxiclav (Augmentin)
versus penicillin V in the treatment of acute dentoal-
veolar abscess. Br Dent J 1993;175:169–74.
[14] Paterson SA, Curzon ME. The effect of amoxycillin
versus penicillin V in the treatment of acutely ab-
scessed primary teeth. Br Dent J 1993;174:443–9.
[15] Gilbert DN, Moellering Jr RC, Sande MA. The San-
ford guide to antimicrobial therapy, 32nd edition. Hyde
Park (VT): Antimicrobial Therapy Inc.; 2000.
[16] Craig TJ, Mende C. Common allergic and allergic-like
reactions to mediations: when the cure becomes the
curse. Postgrad Med 1999;105:173–81.
[17] Bowrey DJ, Morris-Stiff GJ. Drug allergy: fact or fic-
tion? Int J Clin Pract 1998;52:20–1.
[18] Warrington RJ, Lee KR, McPhillips S. The value of
testing for penicillin allergy in an inpatient population:
analysis of the subsequent patient management. Al-
lergy Asthma Proc 2000;21:297–9.
[19] DeFonseca MA. Adverse reaction to amoxicillin:
a case report. Pediatr Dent 2000;22:401–4.
[20] Ebersole JL, Cappelli D. Acute-phase reactants in in-
fections and inflammatory diseases. Periodontology
2000;23:19–49.
[21] 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.
[22] Kasten MJ. Clindamycin, metronidazole, and chloram-
phenicol. Mayo Clin Proc 1999;74:825–33.
[23] Fisman DN, Kaye KM. Once-daily dosing of amino-
glycoside antibiotics. Infect Dis Clin North Am
2001;14:475–87.
[24] Hersh EV. Adverse drug interactions in dental practice:
interactions involving antibiotics. Part II. J Am Dent
Assoc 1999;130:236–51.
[25] Marchese A, Schito GC. The oxazolidinones as a new
family of antimicrobial agent. Clin Microbiol Infect
2001;7(Suppl 4):66–74.
[26] Felmingham D. Microbiological profile of telithromy-
cin, the first ketolide antimicrobial. Clin Microbiol In-
fect 2001;7(Suppl 3):2–10.
[27] Linden PK. Treatment options for vancomycin-resist-
ant enterococcal infections. Drugs 2002;62:425–41.
[28] Brook I, Frazier EH, Gher Jr ME. Microbiology of
periapical abscesses and associated maxillary sinusitis.
J Periodontol 1996;67:608–10.
[29] Williams Jr JW, Aguilar C, Makela M, et al. Antibi-
otics for acute maxillary sinusitis. Cochrane Library
2000;3:1–51.
[30] Bergman SA. Fungal, viral, and protozoal infections
of the maxillofacial region. In: Topazian RG, Goldberg
MH, Hupp JR, editors. Oral and maxillofacial infec-
tions. 4th edition. Philadelphia: W.B. Saunders Co.;
2002. p. 243–78.
T.R. Flynn, L.R. Halpern / Oral Maxillofacial Surg Clin N Am 15 (2003) 17–3838