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Clin Pharmacokinet 2005; 44 (3): 305-316ORIGINAL RESEARCH ARTICLE 0312-5963/05/0003-0305/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Pharmacokinetic/PharmacodynamicEvaluation of AntimicrobialTreatments of OrofacialOdontogenic Infections

Arantxa Isla,1 Andr´ es Canut,2 Alicia R. Gasc´ on,1 Alicia Labora,2 Bruno Ardanza-Trevijano,3 Maria ´ Angel´ es Solin´ is1 and Jose Luis Pedraz1

1 Laboratory of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of

the Basque Country, Vitoria-Gasteiz, Spain

2 Microbiology Unit, Santiago Apostol Hospital, Vitoria-Gasteiz, Spain

3 Maxillofacial Unit, Santiago Apostol Hospital, Vitoria-Gasteiz, Spain

Objective: To evaluate the efficacy of antimicrobial therapy in oral odontogenicAbstractinfections using estimated pharmacokinetic/pharmacodynamic parameters or effi-

cacy indices, and to compare pharmacokinetic/pharmacodynamic breakpoints

with National Committee for Clinical Laboratory Standards’ (NCCLS)

breakpoints.

Study design: Retrospective literature search to obtain minimum inhibitory

concentration (MIC) values, pharmacokinetic parameters of antimicrobials and

NCCLS breakpoints. Pharmacokinetic simulations were carried out using Win-

Nonlin software (Pharsight Corporation, Mountain View, CA, USA).

Methods: For antimicrobials with time-dependent activity, the time that the

plasma drug concentration exceeds the MIC as the percentage of dose interval at

steady state was calculated. For antimicrobials with concentration-dependent

activity, the total area under the plasma concentration-time curve over 24 hours at

steady state divided by the MIC was calculated. Pharmacokinetic/pharmacody-

namic breakpoints were calculated according to these parameters.

Results: Only amoxicillin/clavulanic acid and clindamycin showed adequate

efficacy indices against the most commonly isolated bacteria in odontogenic

infections. Metronidazole reached good indices against anaerobes only.

Pharmacokinetic/pharmacodynamic susceptibility breakpoints do not coincide

exactly with NCCLS breakpoints.

Conclusion: Owing to the scarcity of double-blind, clinical trials on the use of

antimicrobials in endodontics, this study may be useful in determining the best

antimicrobial treatment in these infections. However, as we have not used



306 Isla et al.

concentration data in infected tissue to determine pharmacokinetic/pharmacody-

namic indices, it would be necessary to design clinical trials in order to confirm

these results.

Systemic antimicrobial treatment can be a power- double-blinded clinical trials on the use of an-

ful tool for the therapeutic management of timicrobials in endodontics that provide conclusive

dentoalveolar infections, gingivitis and periodontal evidence of therapeutic benefit.[1] As a result, anti-

diseases.[1] Many dentists prescribe antimicrobials microbial usage in endodontics is almost totally

to minimise the risk of infection, ensure the efficacy empirical.[2]

of the treatment, shorten infection periods or mini- Empirical therapy should be based on the most

mise associated risks; however, there is clear evi- common microorganisms isolated and on the effica-dence that these drugs have been overused by den- cy of the treatments. There is a lot of information in

tists for a variety of conditions.[2] Recent studies the literature about the bacteria isolated from pa-

have shown that general dental practitioners in dif- tients with orofacial odontogenic infections, but not

ferent countries prescribe antimicrobials inappropri- many clinical analyses comparing the efficacy of

ately, both therapeutically and prophylactically (e.g. different antimicrobial treatments for these infec-

some odontogenic infections can be managed with- tions have been carried out. Owing to the serious-

out the use of antimicrobials – by tooth extraction, ness of the problems associated with the inappropri-

surgical treatment, endodontic therapy, etc.).[3] They ate use of antimicrobials, especially bacterial resis-

have also demonstrated lack of knowledge about the tance, it is very important to know the efficacy of thedevelopment of multi-resistant bacterial strains.[4-11] antimicrobial treatments in order to select the most

adequate agent for each situation.The rational use of antimicrobials must be based

upon three variables: a defined indication, the ap- Interest in the pharmacokinetic/pharmacodynam-

propriateness of the antimicrobial, and the adverse ic relationships used to describe the antimicrobial

effects associated with the drug. The first factor is activity of antimicrobial agents has recently in-

important because the practitioner needs to be aware creased. It is well known that the final response to

that antimicrobials are not an alternative to dental antimicrobial treatment depends not only on the

intervention, but rather an adjunct to it. Each patient susceptibility of the infecting bacteria, but also on

should be assessed and antimicrobials prescribed other factors that should be taken into account, such

only when necessary because indiscriminate pre- as the pharmacokinetic profile of the chosen anti-

scription can cause drug resistance, which is an infective agent.

emerging and significant problem with oral micro- Schentag et al.[12] defined the clinical practice

organisms.[2] that considers the antimicrobial activity and

In order to select the most effective antimicrobial pharmacokinetic profile of the drug to optimise the

therapy for a patient, isolation and identification of dosage as ‘dual individualisation’. This practice

the involved microorganism should be made. How- uses different mixed parameters (named efficacy

ever, the microflora associated with odontogenic indices) to provide information about the potential

infections is complex, and culture and sensitivity efficacy of the treatment. These indices are based on

testing are not routinely recommended for endodon- both microbiological (pharmacodynamic) andtic procedures. Moreover, there are few controlled, pharmacokinetic parameters. The time that the plas-

© 2005 Adis Data Information BV. All rights reserved. Clin Pharmacokinet 2005; 44 (3)



PK/PD of Antimicrobials in Odontogenic Infections 307

ma drug concentration exceeds the minimum inhibi- Methods

tory concentration (MIC) as a percentage of the dose

interval at steady state (tss(%)>MIC) has been report- Data Acquisitioned as the best predictor of efficacy for antimicrobials

with time-dependent antimicrobial activity. On the The bibliographical search was made using theother hand, for drugs with concentration-dependent WINSPIRS computer system. Information about thebactericidal activity, the total area under the plasma 90% MIC (MIC90) values of the most commonlyconcentration-time curve (AUC) over 24 hours at prescribed antimicrobials for the pathogens moststeady state divided by the MIC (AUC24,ss /MIC) has frequently isolated in odontogenic infections werebeen reported as the best parameter.[13-19]

collected (table I). These antimicrobials were amox-

Dual dosage individualisation has become an im- icillin (alone and with clavulanic acid), azithro-

portant instrument in deciding the treatment to be mycin, cefuroxime axetil, clindamycin, erythromy-used for patients with different disease states.[12] cin, spiramycin, levofloxacin, metronidazole, mino-

Therefore, the aim of this work was the application cycline and phenoxymethylpenicillin (penicillin V).

of pharmacokinetic/pharmacodynamic parameters The strains of viridans group streptococci, Peptos-

in the prediction of the effectiveness of antimicrobi- treptococcus spp., Prevotella intermedia and

al therapy in oral odontogenic infections. We also Fusobacterium nucleatum were divided into two

estimated the pharmacokinetic/pharmacodynamic groups, as done by Kuriyama et al.:[3] benzylpenicil-

susceptibility breakpoints, which allowed us to pre- lin (penicillin G)-susceptible strains and

dict the efficacy of an antimicrobial treatment benzylpenicillin-resistant strains. A different MIC

against a pathogen if its MIC value is known. We value for each group was considered. All

have also compared these breakpoints with the Na- Porphyromonas gingivalis were judged as ben-

tional Committee for Clinical Laboratory Standards’ zylpenicillin susceptible because they do not pro-

(NCCLS) breakpoints that are normally used in duce β-lactamase. The pharmacokinetic parameters

microbiology laboratories. of these antimicrobials in healthy Caucasian volun-

Table I. Ninety percent minimum inhibitory concentration (MIC90) values (mg/L) of antimicrobials for pathogens responsible for odontogenic

infectionsa

Antimicrobial Viridans group Peptostreptococcus Prevotella Porphyromonas Fusobacterium

streptococci[3,20,21] spp.[3,21-24] intermedia [3,21,25-27] gingivalis [3,21,25-27] nucleatum [3,21,25-27]

PS PR PS PR PS PR PS PS PR

Amoxicillin 1 0.25 16 16 8

Amoxicillin/clavulanic acid 1 0.25 2 2 2

Azithromycin 0.12 16 2 1 1 4

Cefuroxime axetil 4 16

Clindamycin 0.5 0.5 2 0.01 0.06 0.03 0.12

Erythromycin 0.06 2 8 64 1 32 0.25 64

Levofloxacin 8 1 8 4 1 4

Metronidazole >128 2 2 2 8

Minocycline 0.5 2 2 4 0.12 8 2 1 2

Phenoxymethylpenicillin 0.25 2 32 0.12 1

(penicillin V)

Spiramycin 0.5 2 0.1 0.2 16

a When more than one MIC90 value was available, the highest one was selected.PR = benzylpenicillin-resistant strains; PS = benzylpenicillin (penicillin G)-susceptible strains.




308 Isla et al.

ised by a time-dependent bactericidal activity, the

tss(%)>MIC was calculated. These data were ob-

tained using the Derive computer system (Derive4.11 for Windows, Soft Warehouse, Inc., HI, USA).

This software allowed us to calculate, from the

corresponding concentration-time equation, a time

interval above a certain drug concentration (MIC)

that is expressed as a percentage of the dose interval.

Treatment with the penicillins was considered effec-

tive when tss(%)>MIC was higher than 40%, and for

the other time-dependent bactericidal drugs, when

this efficacy index was higher than 50%.[60] Al-

though these values had been defined in the litera-

ture for aerobes, in this evaluation they have been

used for both aerobes and anaerobes.

For concentration-dependent bactericidal drugs

such as azithromycin, levofloxacin, metronidazole

and minocycline, the AUC24,ss /MIC was calculated.

For nonsevere infections or infections in immu-

Table II. Pharmacokinetic parameters of the antimicrobials most

commonly prescribed in odontogenic infections[28-59]

Antimicrobial Vd/F ka kel

(L) (h–1) (h–1)β-Lactams

Amoxicillin 29.3 1.68 0.693

Cefuroxime axetil 50.0 1.60 0.495

Phenoxymethylpenicillin 60.0 2.68 0.693

(penicillin V)

Macrolides

Azithromycin 1890.0 0.69 0.034

Erythromycin 100.0 0.70 0.404

Spiramycin 1000.0 0.87 0.088

Lincosamides

Clindamycin 68.9 1.51 0.244

Fluoroquinolones

Levofloxacin 105.95 2.10 0.100

Nitroimidazoles

Metronidazole 49.5 4.07 0.083

Tetracyclines

Minocycline 84.4 2.30 0.040

k a = absorption rate constant; k el = elimination rate constant; Vd/F

= apparent volume of distribution/bioavailability.

nocompetent hosts, in order for treatment to be

successful with these kinds of antimicrobials it is

teers defining a one-compartment model were also necessary to reach an AUC24,ss /MIC ratio highertaken from the literature (table II). Simulations of than 25.[60] In other cases (in more severe infections

the plasma concentration-time curves for the mostor those in immunocompromised hosts) the

common regimens used with each antimicrobial (ta-AUC24,ss /MIC ratio should be higher than 100.[60]

ble III) were carried out with the WinNonlinThese values had been obtained studying aerobic

pharmacokinetic computer system (WinNonlinbacteria, but in this study they have also been used

Standard 1.1, Pharsight Corporation, Mountainfor anaerobes.

View, CA, USA) using the pharmacokinetic param-

eter values given in table II. A one-compartment

Pharmacokinetic/Pharmacodynamicopen model for oral administration with first-order

Breakpoints and National Committee forabsorption and first-order elimination was fitted. At

Clinical Laboratory Standards’ Breakpointsleast eight doses were introduced to simulate steady-

state conditions. AUC was calculated using the trap-

ezoidal rule. If the MIC90 of a strain or group of strains of

bacteria is at or below the breakpoint, or antimicro-

bial concentration, the bacteria will be susceptible toEstimation of Efficacy Indices and

the antimicrobial, and if the MIC90 is above thisEfficacy Criteria

breakpoint the pathogen will be resistant to it.

For amoxicillin (alone and with clavulanic acid), For antimicrobials with time-dependent activity,

cefuroxime axetil, clindamycin, erythromycin, the breakpoint was established by calculating thespiramycin and phenoxymethylpenicillin, character- concentration for which plasma concentrations re-





mained above that value during 40–50% of the The NCCLS breakpoints were taken from the

dosage interval. literature.[61,62]

For antimicrobials with concentration-dependentResultsactivity, the breakpoint was calculated using the

following equation 1:Tables IV and V show the values of tss(%)>MIC

PK/PDbreakpoint = AUC24,ss /25calculated for antimicrobials with time-dependent

activity, and AUC24,ss /MIC values for drugs with

concentration-dependent activity, respectively,

against viridans group streptococci, Peptostrepto-

coccus spp., P. intermedia, P. gingivalis and F.

nucleatum.

As can be seen in table IV, the usual regimens of

phenoxymethylpenicillin, amoxicillin, cefuroxime

axetil, erythromycin and spiramycin were not able

to reach plasma concentrations above the MIC val-

ues for all pathogens included in this study for

40–50% of the dosage interval. Amoxicillin only

reached the needed value (40%) against Gram-posi-

tive bacteria (viridans group streptococci and

Peptostreptococcus spp.). Phenoxymethylpenicillin

did not reach a tss(%)>MIC value higher than 40%for P. intermedia. Cefuroxime axetil did not exceed

the MIC during 50% of the dose interval against

Gram-positive bacteria. For Gram-negative patho-

gens, there were no MIC data available in the litera-

ture. Erythromycin and spiramycin did not exceed

the value of 50% against Peptostreptococcus spp. or

F. nucleatum with either of the regimens.

Plasma concentrations of amoxicillin/clavulanic

acid were above the MIC of all bacteria during the

necessary time when administering at least 500mg

three times daily or 1000mg twice daily. In the case

of clindamycin, it was necessary to administer at

least 300mg three times daily in order to reach

adequate concentrations.

None of the regimens of the antimicrobials with

concentration-dependent activity had AUC24,ss /

MIC values that were higher than 25 for all bacteria.

Metronidazole reached good efficacy indices

against all anaerobes (Peptostreptococcus spp., P.intermedia, P. gingivalis and F. nucleatum), but

Table III. Oral dosage regimens considered for the evaluation of

the antimicrobial efficacy against pathogens most commonly isolat-

ed in odontogenic infections

Antimicrobial Dosage

(mg)β-Lactams

Amoxicillin 500 bid/tid

875 bid/tid

1000 bid/tid

Amoxicillin/clavulanic acid 500 bid/tid

875 bid/tid

1000 bid/tid

Cefuroxime axetil 250 bid

500 bid

1000 bid

Phenoxymethylpenicillin (penicillin V) 500 tid/qid

1000 tid/qid

Macrolides

Azithromycin 500 od

Erythromycin 250 bid

500 od/bid/tid

Spiramycin 500 bid/tid

1000 bid

2000 bid

Lincosamides

Clindamycin 150 qid

300 tid/qid600 tid

Fluoroquinolones

Levofloxacin 500 od/bid

Nitroimidazoles

Metronidazole 250 bid/tid

400 bid/tid

500 bid/tid

750 bid/tid

Tetracyclines

Minocycline 100 od/bid

bid = twice daily; od = once daily; qid = four times daily; tid = threetimes daily.




310 Isla et al.

failed for the viridans group streptococci. Azithro- and penicillin-resistant P. intermedia when adminis-

mycin only reached an adequate AUC24,ss /MIC tering minocycline 100mg twice daily.

value against penicillin-susceptible viridans group Table VI shows the calculated pharmacokinetic/ streptococci; levofloxacin only against penicillin-

pharmacodynamic breakpoints of oral pathogens tosusceptible Peptostreptococcus spp. and P.

time-dependent and concentration-dependent bacte-gingivalis. Adequate values were not reached

against penicillin-resistant Peptostreptococcus spp. ricidals. This table also summarises differences be-

Table IV. Time that the plasma drug concentration exceeds the 90% minimum inhibitory concentration as the percentage of dose interval at

steady state (tss(%)>MIC90) for the antimicrobials with time-dependent activity

Antimicrobial Dosage Viridans group Peptostreptococcus Prevotella Porphyromonas Fusobacterium

streptococci spp. intermedia gingivalis nucleatum

(mg) PS PR PS PR PS PR PS PS PR

Phenoxymethylpenicillin 500 qid 91.8 40.1 0.0a 100 57.9

(penicillin V) 1000 qid 100 57.9 0.0a 100 75.0

500 tid 68.6 29.8a 0.0a 81.9 43.1

1000 tid 81.2 43.1 0.0a 94.5 56.0

Amoxicillin 500 tid 60.3 85.8 0.0a 0.0a 12.5a

875 tid 70.7 95.9 0.0a 0.0a 29.5a

1000 tid 73.1 98.3 12.5a 12.5a 32.6a

500 bid 40.1 57.1 0.0a 0.0a 8.2a

875 bid 47.0 63.9 0.0a 0.0a 19.5a

1000 bid 48.7 65.5 8.2a 8.2a 21.6a

Amoxicillin/clavulanic acid 500 tid 60.3 85.8 47.0 47.0 47.0

875 tid 70.7 95.9 58.7 58.7 58.71000 tid 73.1 98.3 60.3 60.3 60.3

500 bid 40.1 57.1 31.3a 31.3a 31.3a

875 bid 47.0 63.9 38.4a 38.4a 38.4a

1000 bid 48.7 65.5 40.1 40.1 40.1

Cefuroxime axetil 250 bid 0.0a 0.0a ND ND ND

500 bid 17.6a 0.0a ND ND ND

1000 bid 32.0a 0.0a ND ND ND

Erythromycin 500 qid 100 55.8 0.0a 0.0a 98.3 0.0a 100 0.0a

500 tid 100 34.3a 0.0a 0.0a 69.3 0.0a 100 0.0a

500 bid 100 19.3a 0.0a 0.0a 44.2a 0.0a 78.0 0.0a

500 od 54.2 9.1a 0.0a 0.0a 21.8a 0.0a 38.8a 0.0a

250 bid 94.0 0.0a 0.0a 0.0a 19.3a 0.0a 62.0 0.0a

Spiramycin 500 tid 100 0.0a 100 100 0.0a

500 bid 44.5a 0.0a 100 100 0.0a

1000 bid 100 0.0a 100 100 0.0a

2000 bid 100 44.5a 100 100 0.0a

Clindamycin 150 qid 100 100 16.9a 100 100 100 100

300 qid 100 100 100 100 100 100 100

300 tid 100 100 100 100 100 100 100

600 tid 100 100 100 100 100 100 100

a tss(%)>MIC value <40% for penicillins and <50% for other antimicrobials.

bid = twice daily; ND = not determined; od = once daily; PR = benzylpenicillin-resistant strains; PS = benzylpenicillin (penicillin G)-

susceptible strains; qid = four times daily; tid = three times daily.





Table V. Area under the plasma concentration-time curve over 24 hours at steady state divided by the 90% minimum inhibitory

concentration (AUC24,ss /MIC90) for the antimicrobials with concentration-dependent activity

Antimicrobial Dosage (mg) Viridans group Peptostreptococcus Prevotella Porphyromonas Fusobacterium

streptococci spp. intermedia gingivalis nucleatum PS PR PS PR PS PR PS PS PR

Azithromycin 500 od 64.8 0.5a 3.9a 7.8a 7.8a 2.0a

Levofloxacin 500 bid 11.8a 94.4 11.8a 23.6a 94.4 23.6a

500 od 5.8a 46.7 5.8a 11.7a 46.7 11.7a

Metronidazole 250 tid 1.4a 91.3 91.3 91.3 22.8a

400 tid 2.3a 146 146 146 36.5

500 tid 2.9a 183 183 183 45.6

750 tid 4.3a 274 274 274 65.8

250 bid 1.0a 60.9 60.9 60.9 15.2a

400 bid 1.5a 97.4 97.4 97.4 24.3a

500 bid 1.9a 122 122 122 30.4

750 bid 2.9a 183 183 183 45.6

Minocycline 100 bid 117 29.3 29.3 14.7a 488 7.3a 29.3 58.7 29.3

100 od 58.7 14.7a 14.7a 7.3a 244 3.7a 14.7a 29.3 14.7a

a An AUC24,ss /MIC <25 is required for treatment to be successful in nonsevere infections or infections in immunocompetent hosts.

bid = twice daily; od = once daily; PR = benzylpenicillin-resistant strains; PS = benzylpenicillin (penicillin G)-susceptible strains; tid = three

times daily.

tween NCCLS and pharmacokinetic/pharmacody- upsets. The best dosage option with clindamycin is

namic breakpoints. 300mg three times daily, which is the smallest ade-

quate dosage of this drug. The use of higher dosages

Discussion is not necessary because the risk of adverse effects

would be increased. None of the antimicrobials withAs mentioned in the introductory section, culture

concentration-dependent activity reached adequateand sensitivity testing are not routinely performed

efficacy indices against the five bacteria, althoughfor endodontic procedures; therefore, the spectrum

metronidazole obtained good indices against all an-of the selected antimicrobial should cover the most

aerobes.common microorganisms associated with these

Breakpoints indicate whether or not a microorga-kinds of infections. Amoxicillin/clavulanic acid andnism is susceptible or resistant to an antimicrobialclindamycin are the antimicrobials that provide thetreatment. If the MIC has the same value or isbetter efficacy indices for orofacial infectionssmaller than the pharmacokinetic/pharmacodynam-caused by the most common pathogens isolated inic breakpoint, the microorganism will be suscepti-this localisation, as shown in tables IV and V. Al-

ble, otherwise the treatment will be ineffective. Forthough there are different amoxicillin/clavulanic ac-

example, when amoxicillin 500mg three times dailyid regimens that could be used (500mg three times

is administered, plasma concentrations are above 2daily, 875mg three times daily, 1000mg three times

mg/L during the 40% of the dosage interval (3.2daily and 1000mg twice daily), we consider that

hours), therefore that regimen will be useful against1000mg twice daily would be the best option be-

microorganisms with an MIC value of ≤2 mg/L.cause it is more convenient for the patient owing to

When the concentration-dependent antimicrobialits 12-hour dosage interval (versus an 8-hour dosage

metronidazole is administered at a dosage of 250mginterval), and because it minimises the clavulanicacid dose, thus decreasing the risk of gastrointestinal three times daily, the AUC24,ss is 182.5 mg • h/L. In




312 Isla et al.

Table VI. Comparison of pharmacokinetic/pharmacodynamic (PK/PD) and National Committee for Clinical Laboratory Standards’ (NCCLS)

breakpoints for oral pathogens to time-dependent and concentration-dependent bactericidals

Antimicrobial Dosage (mg) PK/PD breakpoint (mg/L) NCCLS breakpoint (mg/L)a

[all organisms] Streptococcus spp.b (S/R) anaerobesc (S/R)

Amoxicillin 500 tid 2 0.25/8 4/16

875 tid 4

1000 tid 4

500 bid 1

875 bid 1

1000 bid 2

Amoxicillin/clavulanic acid 500 tid 2 2/8

875 tid 4

1000 tid 4

500 bid 1

875 bid 11000 bid 2

Cefuroxime axetil 250 bid 0.25

500 bid 0.5

1000 bid 1

Clindamycin 150 qid 1 0.25/1 2/8

300 qid 2

300 tid 2

600 tid 4

Erythromycin 250 bid 0.25

500 bid 0.5

500 qid 2500 tid 1

500 od 0.06

Spiramycin 500 tid 0.5

500 bid 0.25

1000 bid 0.5

2000 bid 1

Phenoxymethylpenicillin (penicillin V) 500 qid 2 0.12/4 0.5/2

1000 qid 4

500 tid 1

1000 tid 2

Azithromycin 500 od 0.25 0.5/2

Levofloxacin 500 bid 2 2/8

500 od 1

Metronidazole 250 tid 4 8/32

400 tid 8

500 tid 8

750 tid 16

250 bid 4

400 bid 4

500 bid 8

Continued next page





Table VI. Contd

Antimicrobial Dosage (mg) PK/PD breakpoint (mg/L) NCCLS breakpoint (mg/L)a

[all organisms] Streptococcus spp.b (S/R) anaerobesc (S/R)

750 bid 8

Minocycline 100 bid 2

100 od 1

a NCCLS breakpoints are applicable for all dosages of the particular drug.

b NCCLS does not have a specific breakpoint for viridans group streptococci.

c NCCLS does not have a specific breakpoint for Peptostreptococcus spp., Prevotella intermedia, Porphyromonas gingivalis and

Fusobacterium nucleatum . These bacteria are anaerobes; therefore, we have considered the breakpoint for anaerobes.

bid = twice daily; od = once daily; qid = four times daily; S/R = sensitive/resistant; tid = three times daily.

order to obtain an AUC24,ss /MIC ratio of 25, the spiramycin[66] and minocycline[67] reach higher con-

MIC value must be 4 mg/L, therefore 4 mg/L will be centrations in gingiva than in plasma. For thesethe pharmacokinetic/pharmacodynamic breakpoint. antimicrobials, if we consider the concentration in

When the MIC value of the pathogen is ≤4 mg/L, the gingival fluid, efficacy indices would be better

this regimen will be adequate. than those calculated by using plasma concentra-

tions. This means that we cannot totally reject theseOur pharmacokinetic/pharmacodynamic break-

antimicrobials when considering the results ob-points do not coincide exactly with NCCLS suscep-

tained in our study. In the case of metronidazole,tibility breakpoints. This may be attributable to dif-

there are some investigators that have found higherferent causes:

concentrations in gingiva than in plasma,[68] but in• NCCLS has not established specific data for eachother studies gingival concentrations were equal tobacterium. Values have been taken from thethose in blood.[69] Macrolides are preferentially tak-breakpoint data given to Streptococcus other thanen up by phagocytes and fibroblasts; therefore, theseS. pneumoniae and also to anaerobes.cells could act as a reservoir and release drugs

• NCCLS values are established without takingslowly in infected tissues,[64,70] resulting in a longerchanges in dosage regimen into account.exposure time to the antimicrobial.

In our study we have used plasma drug concen-

When the pathological process progresses, treat-tration data. We have not taken into account the

ment must be established in a different way. Pulpalantimicrobial concentration in the gingival tissue

infection is an acute process that may cause invasionand this must be considered in order to carry out a

of the periapical area (periapical abscess) or themore appropriate evaluation of this study. The

alveolar bone (acute alveolar abscess) and, in theclinical efficacy of an antimicrobial treatment is

worst cases, it can evolve to osteomyelitis. In otherdetermined by its pharmacokinetic and pharmaco-

cases, the chronic irritation from the necrotic pulpdynamic profile at the infection site. There are no

may result in periapical granuloma or cyst forma-data in the literature about pharmacokinetic profiles

tion, which may be relatively asymptomatic. antimi-of antimicrobials in the gingival tissue and, there-

crobial therapy is indicated when infection has per-fore, it is not possible to establish pharmacokinetic/

forated the cortex and has spread into the surround-pharmacodynamic parameters using concentration

ing soft tissue. When the bone is affected,data from infected tissues. However, there are some

amoxicillin/clavulanic acid, clindamycin, me-data about drug penetration onto the gingival tissue

tronidazole or fluoroquinolones (levofloxacin) areand the periodontal pocket, which may be useful.recommended. As metronidazole and fluoroqui-For example, azithromycin,[63,64] clindamycin,[65]




314 Isla et al.

nolones have shown good bone penetration,[71,72] a formance of clinical trials is necessary to confirm

combined therapy is recommended in these cases; the usefulness of this methodology.

amoxicillin/clavulanic acid will be a good option forpathogens sited in soft tissues, as we have deter- Acknowledgementsmined in our study, and metronidazole and levoflox-

We would like to thank the Basque Government for theacin will be good options for anaerobes sited in thepre-doctoral research grant to Arantxa Isla. This study wasbone.supported by the Microbiology Unit of Santiago Apostol

Additional studies to establish in vivo efficacy of Hospital and the Laboratory of Pharmacy and Pharmaceutical

different antimicrobials against different pathogens Technology, University of the Basque Country, Vitoria-Gas-

teiz, Spain.in odontogenic infections would be of great interest

to corroborate these results; otherwise, it would be

necessary to modify the pharmacokinetic/pharmaco-Referencesdynamic breakpoints that allow us to predict effica- 1. Ellen RP, McCulloch CA. Evidence versus empiricism: rational

use of systemic antimicrobial agents for treatment of periodon-cy in this kind of pathological process (especiallytitis. Periodontol 2000 1996; 10: 29-44

for antimicrobials that reach different concentra-2. Longman LP, Preston AJ, Martin MV, et al. Endodontics in the

adult patient: the role of antibiotics. J Dent 2000; 28 (8): 539-tions in orofacial tissues than in plasma). Once those48new breakpoints have been established (if necessa-

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