2003 Antibiotic Selection in Head and Neck Infections

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)


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


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


(continued on next page)


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


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.


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




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


(methicillin sensitive)

+, C, A Penicillinase-resistant

penicillin


Vancomycin

Clindamycin


(methicillin resistant)

+, C, A Vancomycin Teicoplanin

Quinupristin-dalfopristin

TMP/SMX (some strains)

Linezolid


(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


(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)


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.


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


b-lactamase negative

Glycopeptides

Streptomycin

Gentamicin


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


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.


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.


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

n,L.R.Halpern

/OralMaxillo

facia

lSurg

Clin

NAm

15(2003)17–38

28


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

n,L.R.Halpern

/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.


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



Cisapride Dysrythmias (torsades) Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Alfentanil z Respiratory depression Antibiotic inhibits

cytochrome P450

metabolism of second

drug; ketoconazole

not implicated



Bromocriptine z CNS effects, hypotension Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Carbamazepine Ataxia, vertigo, drowsiness Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Cyclosporine z Immunosuppression

and nephrotoxicity

Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Felodipine, possibly other

calcium channel blockers

Hypotension, tachycardia,

edema

Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Methylprednisolone,

prednisone

z Immunosuppression Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Lovastatin, possibly

other -statins

Muscle pain, rhabdomyolysis Antibiotic inhibits

cytochrome P450

metabolism of

second drug



Triazolam, oral midazolam z Sedative depth and duration Antibiotic inhibits

cytochrome P450

metabolism of

second drug



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


metronidazole

Warfarin

Anisindione

z Anticoagulation Antibiotic interferes

with metabolism of

the second drug





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



$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



Fluoroquinolones, sulfonamides,

chloramphenicol, fluconazole,

itraconazole

Oral hypoglycemic agents Hypoglycemia Antibiotic displaces

second drug from

plasma proteins

Ciprofloxacin, sulfonamides,

chloramphenicol, fluconazole,


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.


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.


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.


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


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


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


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.


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.

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