ESTUDO DIRIGIDO FARMACOLOGIA

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FARMACOLOGIA – Estudo Dirigido PK/PD – 12/03/2019
Nome do grupo :_____________________________________________________________________________________________________
Considere as informações abaixo e responda as questões:
 
1 – Explique o significado do conceito farmacocinético descrito acima?
Os beta-lactâmicos são drogas tempo-dependentes, assim necessitam estar uma certa porcentagem do tempo entre as administrações acima da MIC (a concentração mínima necessária para inibir o desenvolvimento visível do antimicrobiano).
A porcentagem do tempo com concentração acima da MIC necessária para o medicamento fazer o efeito desejado é aproximadamente 35-40%. 
O máximo efeito desse medicamento ocorre quando fica acima de 60-70% do tempo acima da MIC, mas as vezes não é necessário atingirmos o efeito máximo, pois o problema já pode ser resolvido com uma concentração mais baixa (o corpo consegue desenvolver defesa para destruir essa quantidade já diminuída de microrganimos).
Essas concentrações são atingidas conforme o medicamento é mais uniformemente distribuído na corrente sanguínea, o que depende da absorção, distribuição, metabolização, excreção e da biodisponibilidade (farmacocinética).
2 – Explique a afirmação: “...maximal effects are reached with%T>MIC above 60-70%.
Acima de 60-70% do tempo entre as doses acima da MIC, o medicamento pode alcançar a maior quantidade de receptores para a sua ação, o que resulta em efeito máximo, ou seja, a resposta do medicamento que desejamos será maior.
Os B lactâmicos são antibióticos tempo dependentes, isto é, precisam ficar maior parte do tempo acima da MIC. Os melhores efeitos do antibiótico são alcançados quando ficam 60 a 70% do tempo sobre a MIC, por isso devem ser dados com menores intervalos de doses e não pode atrasar as doses, pois isso diminui eficácia. 
Ainda do mesmo artigo...
3 – Explique a figura 3 quando o MIC da amoxicilina/clavulanato é 1.
Todos os pacientes alcançaram a concentração inibitória mínima quando ela era 1mg/L, pois é uma concentração mais baixa.
Todos pacientes atingiram a meta de ficar 40% do tempo acima da MIC. 
4 – Explique a figura 3 quando o MIC da amoxicilina/clavulanato é 4.
Todos os pacientes maiores de 70 anos alcançaram a meta de ficar 40% acima da MIC quando a MIC 4. 80% dos pacientes com menos de 70 anos alcançaram a MIC 4.
5 – Explique a figura 3 quando o MIC da amoxicilina/clavulanato é 16.
5% dos pacientes com menos de 70 anos alcançaram a meta de ficar 40% do tempo acima da MIC 16, pois eles estão em maior número, aproximadamente 30% dos pacientes com mais de 70 anos alcançaram a MIC.
3 – Explique a figura 4 quando o MIC da amoxicilina/clavulanato é 8 nas três doses analisadas.
Na dose de 1g, somente 70% dos pacientes alcançaram a porcentagem acima da MIC. Na dose de 2g, 100% dos pacientes alcançaram. Assim, quanto maior a dose, mais chance de alcançar a MIC.
100% dos pacientes com 6dd 2000 mg atingiram a meta de ficar 40% do tempo acima da MIC 8. 
70% dos pacientes com 4dd 1000 mg atingiram a meta. 
95% dos pacientes com 6dd 1000 mg atingiram a meta. 
4 – Ainda considerando a figura 4 considere a possibilidade da utilização de amoxicilina quando o MIC=64.
Essa MIC não é vantajosa, pois nenhum dos pacientes a alcançou nas três diferentes doses analisadas.
5 – Ainda considerando a figura 4 considere a possibilidade da utilização de amoxicilina quando o MIC=128.
Essa MIC não é vantajosa, pois nenhum dos pacientes a alcançou nas três diferentes doses analisadas.
6 – Qual a idéia principal do texto acima?
No quadro de sepse, as propriedades farmacocinéticas dos medicamentos mudam, o que acontece na obesidade também. Dessa forma, se administrarmos medicamentos pelo regime padrão (de não-obesos), pode ocorrer falha no tratamento, toxicidade e/ou resistência bacteriana.
	Os obesos possuem:
· Maior porcentagem de gordura e menor porcentagem de tecido magro e água;
· Fluxo de sangue/grama de tecido adiposo menor;
· DC e volume sanguíneo total aumentados;
· Atividade pulmonar diminuída;
· Perfusão tecidual diminuída;
· Comum: alterações histológicas hepáticas; hiperaminotransferasemia; taxa de filtração glomerular aumentada;
· Absorção de medicamentos não-alterada;
· Volume de distribuição muito aumentado, com aumento do tempo de meia-vida de eliminação (gordura!); - mas isso pode estar diminuído, depende do caráter lipofílico da molécula.
“Drogas com distribuição restrita a tecidos magros deveriam ter sua dose baseada no peso corporal ideal dos pacientes, enquanto drogas com distribuição notável em tecido adiposo deveriam ter a dosagem ajustada e baseada no peso corporal total (Mancini, 2001)”. 
7 – Considerando a figura 2 do mesmo artigo da página anterior explique o comportamento das curvas de meropenem (MEM) em pacientes obesos e não obesos para MIC 0,5; MIC 4 e MIC 16.
Os pacientes obesos precisam de uma concentração desse medicamento maior do que os não-obesos, pois tanto na MIC 0,5 quanto na MIC 4 os obesos tiveram menor probabilidade de atingir os efeitos desejados. Na MIC 16, a concentração necessária se iguala aos não-obesos.
8 – Considerando a figura 2 do mesmo artigo da página anterior explique o comportamento das curvas de CEFEPIME (CEF) em pacientes obesos e não obesos para MIC 0,5; MIC 4 e MIC 16.
Na MIC 0,5 e MIC 4, os não obesos atingiram em maior porcentagem a meta de ficar acima da MIC. Logo, os obesos precisariam de uma dose maior para atingir a MIC.
Para esse medicamento, é necessária uma concentração menor do medicamento nos obesos na MIC 16, se comparado aos não-obesos. Nas MICs abaixo de 8 ocorre o contrário, necessitando de concentrações maiores.
9 – Comente o texto acima com 4 breves afirmações.
1. Os testes de eficácia de tratamentos baseados em altas dosagens somente levam em consideração a resposta clínica do paciente, ainda não existindo maiores estudos sobre;
2. Não é possível saber dos efeitos dessas terapias sobre os pacientes a longo prazo.
10 – Encontre um artigo sobre uso de Sulfametoxazol/trimetropim em infecções por S. aureus resistente a meticilina e discuta sobre a eficácia.
__________________________________________________________________________________________________________________________________________
__________________________________________________________________________________________________________________________________________
Case-Control Study of Drug Monitoring of !-Lactams in Obese
Critically Ill Patients
Maya Hites,a Fabio Silvio Taccone,b Fleur Wolff,c Frédéric Cotton,c Marjorie Beumier,b Daniel De Backer,b Sandrine Roisin,d
Sophie Lorent,e Rudy Surin,a Lucie Seyler,a Jean-Louis Vincent,b Frédérique Jacobsa
Departments of Infectious Diseases,a Intensive Care,b Clinical Chemistry,c Microbiology,d and Pharmacy,e Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum !-lactams (meropenem, ceftazidime/cefepime,
and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinet-
ics of these agents. We reviewed our data on critically ill obese patients (body mass index of >30 kg/m2) treated with a broad-
spectrum !-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically
nonobese patients (body mass index of <25 kg/m2) to assess whether there were differences in reaching optimal drug concentra-
tions for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was con-
siderable variability in !-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard
drug regimens of !-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations
in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a pro-
tective factor for insufficient !-lactamserum concentrations. The serum drug levels from the obese cohort were well matched
for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 non-
obese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem
and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No
differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of !-lac-
tams should be continued in obese critically ill patients.
The first antibiotic choice in the treatment of severe hospital-related infections is a broad-spectrum !-lactam. !-Lactam
dosage regimens are based on pharmacokinetic (PK) data ob-
tained in healthy, nonobese volunteers or patients who are not
severely ill. However, PK variables can be altered by sepsis. Vol-
ume of distribution (Vd) may increase due to capillary leak syn-
drome, increased cardiac output, fluid resuscitation, and/or use of
vasopressors. Antibiotic clearance (CL) may also either increase
due to increased glomerular filtration or decrease due to organ
failure (1–3). Obesity could further alter these PK variables: Vd
could be further increased due to increased lean body mass and
increased adipose tissue, and CL could be increased due to in-
creased kidney mass and global filtration or decreased due to
chronic hypertensive or diabetic nephropathy. Administration of
standard drug regimens (SDRs) to obese critically ill patients may
thus potentially result in more frequent inadequate serum drug
concentrations than in nonobese individuals, which may be re-
sponsible for increased treatment failure, toxicity, and/or emer-
gence of bacterial resistance.
Despite increasing numbers of obese patients worldwide, there
is little information on when and how doses of !-lactams should
be adjusted in these patients. A correction formula for weight has
been proposed but never validated (4). In our intensive care unit
(ICU), therapeutic drug monitoring (TDM) of broad-spectrum
!-lactams (ceftazidime or cefepime [CEF], piperacillin-tazobac-
tam [TZP], or meropenem [MEM]) is now routinely performed.
We thus reviewed the serum drug concentrations obtained in crit-
ically ill obese patients and compared them to those obtained in
critically nonobese patients to determine whether there were dif-
ferences in reaching optimal drug concentrations for the treat-
ment of nosocomial infections. We also evaluated whether !-lac-
tam dose adjustment, using a correction formula for weight,
would have optimized serum drug levels in this cohort of obese
patients.
MATERIALS AND METHODS
Study design and data sources. We reviewed data on obese, critically ill
patients who had received broad-spectrum !-lactams (CEF, TZP, or
MEM) in the 35-bed ICU at Erasme Hospital, an 858-bed university hos-
pital, between 1 October 2009 and 31 December 2011. Routine TDM of
broad-spectrum !-lactams was initiated in our ICU in October 2009.
Patients were included if they had sepsis diagnosed according to standard
criteria (5), had a body mass index (BMI) greater than or equal to 30
kg/m2, and had been treated with a broad-spectrum !-lactam (CEF, TZP,
or MEM) and if TDM had been performed during antimicrobial therapy.
Patients could be included more than once if a TDM was performed for a
different antibiotic. When multiple TDMs were performed for the same
antibiotic, they were all noted for evaluation.
Antibiotic treatment. The clinician’s choice of antibiotic therapy was
based on local guidelines. Most patients received an SDR, consisting of a
first dose of 2 g for CEF, 4 g for TZP, or 1 g for MEM, followed by doses
adapted to creatinine clearance (CrCl), calculated using the Cockroft-
Gault formula (6). Doses were also adjusted for continuous renal replace-
ment therapy (CRRT) (see Table S1 in the supplemental material). Occa-
Received 29 May 2012 Returned for modification 7 July 2012
Accepted 7 November 2012
Published ahead of print 12 November 2012
Address correspondence to Maya Hites, Maya.Hites@erasme.ulb.ac.be.
Supplemental material for this article may be found at http://dx.doi.org/10.1128
/AAC.01083-12.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.01083-12
The authors have paid a fee to allow immediate free access to this article.
708 aac.asm.org Antimicrobial Agents and Chemotherapy p. 708–715 February 2013 Volume 57 Number 2
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://aac.asm.org
Case-Control Study of Drug Monitoring of !-Lactams in Obese
Critically Ill Patients
Maya Hites,a Fabio Silvio Taccone,b Fleur Wolff,c Frédéric Cotton,c Marjorie Beumier,b Daniel De Backer,b Sandrine Roisin,d
Sophie Lorent,e Rudy Surin,a Lucie Seyler,a Jean-Louis Vincent,b Frédérique Jacobsa
Departments of Infectious Diseases,a Intensive Care,b Clinical Chemistry,c Microbiology,d and Pharmacy,e Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum !-lactams (meropenem, ceftazidime/cefepime,
and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinet-
ics of these agents. We reviewed our data on critically ill obese patients (body mass index of >30 kg/m2) treated with a broad-
spectrum !-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically
nonobese patients (body mass index of <25 kg/m2) to assess whether there were differences in reaching optimal drug concentra-
tions for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was con-
siderable variability in !-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard
drug regimens of !-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations
in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a pro-
tective factor for insufficient !-lactam serum concentrations. The serum drug levels from the obese cohort were well matched
for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 non-
obese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem
and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No
differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of !-lac-
tams should be continued in obese critically ill patients.
The first antibiotic choice in the treatment of severe hospital-related infections is a broad-spectrum !-lactam. !-Lactam
dosage regimens are based on pharmacokinetic (PK) data ob-
tained in healthy, nonobese volunteers or patients who are not
severely ill. However, PK variables can be altered by sepsis. Vol-
ume of distribution (Vd) may increase due to capillary leak syn-
drome, increased cardiac output, fluid resuscitation, and/or use of
vasopressors. Antibiotic clearance (CL) may also either increase
due to increased glomerular filtration or decrease due to organ
failure (1–3). Obesity could further alter these PK variables: Vd
could be further increased due to increased lean body mass and
increased adipose tissue, and CL could be increased due to in-
creased kidney mass and global filtration or decreased due to
chronic hypertensive or diabetic nephropathy. Administration of
standard drug regimens (SDRs) to obese critically ill patients may
thus potentially result in more frequent inadequate serum drug
concentrations than innonobese individuals, which may be re-
sponsible for increased treatment failure, toxicity, and/or emer-
gence of bacterial resistance.
Despite increasing numbers of obese patients worldwide, there
is little information on when and how doses of !-lactams should
be adjusted in these patients. A correction formula for weight has
been proposed but never validated (4). In our intensive care unit
(ICU), therapeutic drug monitoring (TDM) of broad-spectrum
!-lactams (ceftazidime or cefepime [CEF], piperacillin-tazobac-
tam [TZP], or meropenem [MEM]) is now routinely performed.
We thus reviewed the serum drug concentrations obtained in crit-
ically ill obese patients and compared them to those obtained in
critically nonobese patients to determine whether there were dif-
ferences in reaching optimal drug concentrations for the treat-
ment of nosocomial infections. We also evaluated whether !-lac-
tam dose adjustment, using a correction formula for weight,
would have optimized serum drug levels in this cohort of obese
patients.
MATERIALS AND METHODS
Study design and data sources. We reviewed data on obese, critically ill
patients who had received broad-spectrum !-lactams (CEF, TZP, or
MEM) in the 35-bed ICU at Erasme Hospital, an 858-bed university hos-
pital, between 1 October 2009 and 31 December 2011. Routine TDM of
broad-spectrum !-lactams was initiated in our ICU in October 2009.
Patients were included if they had sepsis diagnosed according to standard
criteria (5), had a body mass index (BMI) greater than or equal to 30
kg/m2, and had been treated with a broad-spectrum !-lactam (CEF, TZP,
or MEM) and if TDM had been performed during antimicrobial therapy.
Patients could be included more than once if a TDM was performed for a
different antibiotic. When multiple TDMs were performed for the same
antibiotic, they were all noted for evaluation.
Antibiotic treatment. The clinician’s choice of antibiotic therapy was
based on local guidelines. Most patients received an SDR, consisting of a
first dose of 2 g for CEF, 4 g for TZP, or 1 g for MEM, followed by doses
adapted to creatinine clearance (CrCl), calculated using the Cockroft-
Gault formula (6). Doses were also adjusted for continuous renal replace-
ment therapy (CRRT) (see Table S1 in the supplemental material). Occa-
Received 29 May 2012 Returned for modification 7 July 2012
Accepted 7 November 2012
Published ahead of print 12 November 2012
Address correspondence to Maya Hites, Maya.Hites@erasme.ulb.ac.be.
Supplemental material for this article may be found at http://dx.doi.org/10.1128
/AAC.01083-12.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.01083-12
The authors have paid a fee to allow immediate free access to this article.
708 aac.asm.org Antimicrobial Agents and Chemotherapy p. 708–715 February 2013 Volume 57 Number 2
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://aac.asm.org
Case-Control Study of Drug Monitoring of !-Lactams in Obese
Critically Ill Patients
Maya Hites,a Fabio Silvio Taccone,b Fleur Wolff,c Frédéric Cotton,c Marjorie Beumier,b Daniel De Backer,b Sandrine Roisin,d
Sophie Lorent,e Rudy Surin,a Lucie Seyler,a Jean-Louis Vincent,b Frédérique Jacobsa
Departments of Infectious Diseases,a Intensive Care,b Clinical Chemistry,c Microbiology,d and Pharmacy,e Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium
Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum !-lactams (meropenem, ceftazidime/cefepime,
and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinet-
ics of these agents. We reviewed our data on critically ill obese patients (body mass index of >30 kg/m2) treated with a broad-
spectrum !-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically
nonobese patients (body mass index of <25 kg/m2) to assess whether there were differences in reaching optimal drug concentra-
tions for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was con-
siderable variability in !-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard
drug regimens of !-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations
in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a pro-
tective factor for insufficient !-lactam serum concentrations. The serum drug levels from the obese cohort were well matched
for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 non-
obese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem
and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No
differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of !-lac-
tams should be continued in obese critically ill patients.
The first antibiotic choice in the treatment of severe hospital-related infections is a broad-spectrum !-lactam. !-Lactam
dosage regimens are based on pharmacokinetic (PK) data ob-
tained in healthy, nonobese volunteers or patients who are not
severely ill. However, PK variables can be altered by sepsis. Vol-
ume of distribution (Vd) may increase due to capillary leak syn-
drome, increased cardiac output, fluid resuscitation, and/or use of
vasopressors. Antibiotic clearance (CL) may also either increase
due to increased glomerular filtration or decrease due to organ
failure (1–3). Obesity could further alter these PK variables: Vd
could be further increased due to increased lean body mass and
increased adipose tissue, and CL could be increased due to in-
creased kidney mass and global filtration or decreased due to
chronic hypertensive or diabetic nephropathy. Administration of
standard drug regimens (SDRs) to obese critically ill patients may
thus potentially result in more frequent inadequate serum drug
concentrations than in nonobese individuals, which may be re-
sponsible for increased treatment failure, toxicity, and/or emer-
gence of bacterial resistance.
Despite increasing numbers of obese patients worldwide, there
is little information on when and how doses of !-lactams should
be adjusted in these patients. A correction formula for weight has
been proposed but never validated (4). In our intensive care unit
(ICU), therapeutic drug monitoring (TDM) of broad-spectrum
!-lactams (ceftazidime or cefepime [CEF], piperacillin-tazobac-
tam [TZP], or meropenem [MEM]) is now routinely performed.
We thus reviewed the serum drug concentrations obtained in crit-
ically ill obese patients and compared them to those obtained in
critically nonobese patients to determine whether there were dif-
ferences in reaching optimal drug concentrations for the treat-
ment of nosocomial infections. We also evaluated whether !-lac-
tam dose adjustment, using a correction formula for weight,
would have optimized serum drug levels in this cohort of obese
patients.
MATERIALS AND METHODS
Study design and data sources. We reviewed data on obese, critically ill
patients who had received broad-spectrum !-lactams (CEF, TZP, or
MEM) in the 35-bed ICU at Erasme Hospital, an 858-bed university hos-
pital, between 1 October 2009 and 31 December 2011. Routine TDM of
broad-spectrum !-lactams was initiated in our ICU in October 2009.
Patients were included if they had sepsis diagnosed according to standard
criteria (5), had a body mass index (BMI) greater than or equal to 30
kg/m2, and had been treated with a broad-spectrum !-lactam (CEF, TZP,
or MEM) and if TDM had been performed during antimicrobial therapy.Patients could be included more than once if a TDM was performed for a
different antibiotic. When multiple TDMs were performed for the same
antibiotic, they were all noted for evaluation.
Antibiotic treatment. The clinician’s choice of antibiotic therapy was
based on local guidelines. Most patients received an SDR, consisting of a
first dose of 2 g for CEF, 4 g for TZP, or 1 g for MEM, followed by doses
adapted to creatinine clearance (CrCl), calculated using the Cockroft-
Gault formula (6). Doses were also adjusted for continuous renal replace-
ment therapy (CRRT) (see Table S1 in the supplemental material). Occa-
Received 29 May 2012 Returned for modification 7 July 2012
Accepted 7 November 2012
Published ahead of print 12 November 2012
Address correspondence to Maya Hites, Maya.Hites@erasme.ulb.ac.be.
Supplemental material for this article may be found at http://dx.doi.org/10.1128
/AAC.01083-12.
Copyright © 2013, American Society for Microbiology. All Rights Reserved.
doi:10.1128/AAC.01083-12
The authors have paid a fee to allow immediate free access to this article.
708 aac.asm.org Antimicrobial Agents and Chemotherapy p. 708–715 February 2013 Volume 57 Number 2
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://dx.doi.org/10.1128/AAC.01083-12
http://aac.asm.org
nonobese patients concerning treatment with vasopressors and me-
chanical ventilation on the day of TDM (data not shown). Therefore,
these factors do not explain the lower serum concentrations observed
in this subgroup of patients.
There are no reports on !-lactams in critically ill obese patients
and very few series on !-lactams in noncritically ill obese patients.
Studies on prophylaxis with narrow-spectrum cephalosporins
showed that dosages needed to be doubled to reach target concen-
trations in obese patients (15, 16, 26). A dose of 2 g twice daily of
cefepime was insufficient to reach PD targets (17). Serum concen-
trations of ertapenem were lower in obese patients than in non-
obese patients (18). Finally, the average steady-state serum con-
centration of TZP in a very obese septic patient was less than the
concentration obtained in a healthy, nonobese population (19).
Previous studies on general populations of critically ill patients
have already shown that SDRs of !-lactams are inadequate in
general populations of critically ill patients (3, 12). Therefore, obe-
sity alone is unlikely to explain the insufficient drug levels mea-
sured in our critically ill patients but may have aggravated the
inadequacy of !-lactam serum concentrations, particularly in the
case of MEM.
A correction dosage formula for weight has been proposed for
use in obese patients, based on a correction factor of 0.30 to take
into account the lower distribution of !-lactams in adipose tissue
(4). This correction formula induced small increases of daily doses
(33%, 25%, and 33% for TZP, CEF, and MEM, respectively) and
only minor modifications in serum concentrations without im-
pact on the adequacy of treatment.
There are several limitations to our study. First of all, the study
is retrospective: serum concentrations were performed only in
selected patients and not in all patients. Second, results are more
robust for MEM than for TZP and CEF because of larger groups of
patients. More patients are needed in the TZP and CEF groups
before any conclusions can be made. Finally, because CRRT was a
risk factor for higher serum concentrations in the obese patient
cohort, probably because of lower efficacy of dialysis, there is rea-
son to believe that there are two populations of obese critically ill
patients: those who receive CRRT and those who do not receive
CRRT. Because of the great variability of serum concentrations
observed in critically ill patients and the impact of CRRT on these
concentrations, it is challenging to show differences between the
two groups of patients.
Finally, our definitions of adequate, insufficient, and over-
dosed serum concentrations are not based on a consensus. How-
ever, the target of 4" the MIC of a drug for the given pathogen for
the specified time periods has been extensively discussed (11, 12).
We defined the upper limit target as 8" the MIC for the specified
time periods (40% of the time for MEM, 50% of the time for TZP,
and 70% of the time for CEF) based on in vitro data showing the
absence of better efficacy with concentrations greater than 4" to
5" the MIC for the pathogen (20, 21) and reported toxicity,
TABLE 5 Total daily doses necessary to reach pharmacodynamic targets for all patients
Drug
Minimum median dose (range) by cohort and/or treatment (g)a
Total population With CRRT Without CRRT
Obese Nonobese P value Obese Nonobese P value Obese Nonobese P valueb
MEM 2 (1–9) 2 (1–7) 0.433 1 (1–2) 1 (1–7) 0.272 3 (1–5) 2 (1–3) 0.011
TZP 12 (6–76) 12 (4–76) 0.422 8 (4–76) 12 (4–16) 0.921 24 (8–40) 20 (4–76) 0.674
CEF 4 (2–18) 10 (2–30) 0.419 2 (2–4) 6 (2–12) 0.127 12 (2–24) 12 (2–30) 0.757
a CRRT, continuous renal replacement therapy.
b Boldface indicates a significant P value.
FIG 2 Probability of attaining the target CT of #4" MIC for various MICs when standard dosage regimens of CEF, TZP, and MEM were administered in obese
and nonobese patient cohorts.
Hites et al.
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Serum concentration of co-trimoxazole during a high-dosage regimen
Sirwan Muhammed Ameen, Jean-Marc Rolain, Marie-Noelle Le Poullain, Véronique Roux,
Didier Raoult and Michel Drancourt*
Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), UMR CNRS 7278,
IRD 198, INSERM 1095, Faculté de Médecine, Marseille, France
*Corresponding author. Tel: +33-4-91-38-55-17; Fax: +33-4-91-38-77-72; E-mail: michel.drancourt@univmed.fr
Received 28 December 2012; returned 2 April 2013; revised 2 August 2013; accepted 12 September 2013
Objectives: Sulfamethoxazole and trimethoprim have been used for decades, yet high dosages are rarely reported.
We aimed to measure blood concentrations of both molecules in this situation.
Methods: Between 2002 and 2010, 22 patients received two tablets of co-trimoxazole three times a day, equiva-
lent to a daily dosage of 2400 mg of sulfamethoxazole and 480 mg of trimethoprim. The trimethoprim and sulfa-
methoxazole concentrations were determined 3 h after administration using ion-paired HPLC.
Results: In the presence of a negative control, which yielded no peaks at the retention times for trimethoprim and
sulfamethoxazole, the mean+SD value for sulfamethoxazole concentration was 161.01+69.154 mg/L and the
mean+SD value for trimethoprim was 5.788+2.74 mg/L.
Conclusions: These concentrations are largely above the trimethoprim and sulfamethoxazole MIC distributions as
well as the trimethoprim resistance clinical breakpoint (4 mg/L) reported by EUCAST in 2012 for most bacterial
pathogens, including Gram-positive species such as Staphylococcus aureus. Our results support proposing a
high-dosage regimen of co-trimoxazole as a suitable alternative for methicillin-resistant S. aureus infections.
Keywords: sulfamethoxazole, trimethoprim, MRSA
Introduction
Sulphonamide compounds have been used as antibiotics since the
1930s and trimethoprim was first used 30 years later.1 Sulfameth-
oxazole and trimethoprim both interfere with folate metabolism
and the 1:5 trimethoprim/sulfamethoxazole combination known
as co-trimoxazole is a broad-spectrum antimicrobial agent used
to treat infections due to aerobic Gram-positive and Gram-
negative bacteria, fungi and protozoa.2 Co-trimoxazole is available
in oral and intravenous preparations with the standard single-
strength tablet containing 80 mg of trimethoprim combined with
400 mg of sulfamethoxazole.
Trimethoprim/sulfamethoxazole concentrations have been mea-
sured in the serum of patients receiving oral co-trimoxazole equiva-
lent to 160 mg of trimethoprim and 800mg of sulfamethoxazole
daily (Figure 1).3–5 However, a clinical benefit of higher dosage co-
trimoxazole regimens has been demonstrated in patients suffering
opportunistic infections during human HIV coinfection, including
patients diagnosed with Pneumocystis jirovecii infection.6 We
previously showed the efficacy of a high-dosage co-trimoxazole
regimen for treating patients diagnosed with Staphylococcus
aureus osteitis.7 However, the actual co-trimoxazole serum con-
centration has not been reported in patients receiving a high-
dosage regimen of co-trimoxazole for several days.
Methods
Between 2002 and 2010, 22 patients received two tablets of co-
trimoxazole three times a day, equivalent to a daily dosage of 2400 mg
of sulfamethoxazole and 480 mg of trimethoprim, as previously described.7
In these patients, serum specimens were routinelycollected forco-trimoxazole
concentration determination after ≥4 weeks of treatment. Venous blood
samples were collected 3 h after administration of drugs and the serum
was immediately separated from blood cells by centrifugation at 1500 g
for 10 min and frozen at 2208C until analysis. Previously, plasma samples
containing co-trimoxazole were found to be stable ≥24 h when the
samples were kept at room temperature (percentage difference ,15%).
The concentrations of co-trimoxazole in plasma that underwent three
freeze–thaw cycles or storage at 2208C for 30 days were found to be
stable, with percentage difference ,15%.8
A negative control serum was obtained from a voluntary healthy person
who had not received medication for .4 weeks. All patients gave written
informed consent for the study and the study was approved by the local in-
stitute Fédératif de Recherche IFR48 Ethics Committee. HPLC-grade analyt-
ical reagents were obtained from Sigma–Aldrich (Saint-Quentin, France).
The trimethoprim and sulfamethoxazole concentrations were determined
using ion-paired HPLC. The HPLC equipment consisted of a Merck L6200
pump and Merck UV detector L4000 (Merck, Darmstadt, Germany). The
analytical column was a Merck Lichrospher RP18 (5 mm, 125×4 mm). The
mobile phase consisted of phosphate buffer (0.1 M, pH 4.5) mixed at an
86:14 (v/v) ratio with acetonitrile. The flow rate was 1.3 mL/min and
# The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother 2014; 69: 757–760
doi:10.1093/jac/dkt400 Advance Access publication 11 October 2013
757
 by guest on N
ovem
ber 10, 2015
http://jac.oxfordjournals.org/
D
ow
nloaded from
 
http://jac.oxfordjournals.org/
Serum concentration of co-trimoxazole during a high-dosage regimen
Sirwan Muhammed Ameen, Jean-Marc Rolain, Marie-Noelle Le Poullain, Véronique Roux,
Didier Raoult and Michel Drancourt*
Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), UMR CNRS 7278,
IRD 198, INSERM 1095, Faculté de Médecine, Marseille, France
*Corresponding author. Tel: +33-4-91-38-55-17; Fax: +33-4-91-38-77-72; E-mail: michel.drancourt@univmed.fr
Received 28 December 2012; returned 2 April 2013; revised 2 August 2013; accepted 12 September 2013
Objectives: Sulfamethoxazole and trimethoprim have been used for decades, yet high dosages are rarely reported.
We aimed to measure blood concentrations of both molecules in this situation.
Methods: Between 2002 and 2010, 22 patients received two tablets of co-trimoxazole three times a day, equiva-
lent to a daily dosage of 2400 mg of sulfamethoxazole and 480 mg of trimethoprim. The trimethoprim and sulfa-
methoxazole concentrations were determined 3 h after administration using ion-paired HPLC.
Results: In the presence of a negative control, which yielded no peaks at the retention times for trimethoprim and
sulfamethoxazole, the mean+SD value for sulfamethoxazole concentration was 161.01+69.154 mg/L and the
mean+SD value for trimethoprim was 5.788+2.74 mg/L.
Conclusions: These concentrations are largely above the trimethoprim and sulfamethoxazole MIC distributions as
well as the trimethoprim resistance clinical breakpoint (4 mg/L) reported by EUCAST in 2012 for most bacterial
pathogens, including Gram-positive species such as Staphylococcus aureus. Our results support proposing a
high-dosage regimen of co-trimoxazole as a suitable alternative for methicillin-resistant S. aureus infections.
Keywords: sulfamethoxazole, trimethoprim, MRSA
Introduction
Sulphonamide compounds have been used as antibiotics since the
1930s and trimethoprim was first used 30 years later.1 Sulfameth-
oxazole and trimethoprim both interfere with folate metabolism
and the 1:5 trimethoprim/sulfamethoxazole combination known
as co-trimoxazole is a broad-spectrum antimicrobial agent used
to treat infections due to aerobic Gram-positive and Gram-
negative bacteria, fungi and protozoa.2 Co-trimoxazole is available
in oral and intravenous preparations with the standard single-
strength tablet containing 80 mg of trimethoprim combined with
400 mg of sulfamethoxazole.
Trimethoprim/sulfamethoxazole concentrations have been mea-
sured in the serum of patients receiving oral co-trimoxazole equiva-
lent to 160 mg of trimethoprim and 800 mg of sulfamethoxazole
daily (Figure 1).3–5 However, a clinical benefit of higher dosage co-
trimoxazole regimens has been demonstrated in patients suffering
opportunistic infections during human HIV coinfection, including
patients diagnosed with Pneumocystis jirovecii infection.6 We
previously showed the efficacy of a high-dosage co-trimoxazole
regimen for treating patients diagnosed with Staphylococcus
aureus osteitis.7 However, the actual co-trimoxazole serum con-
centration has not been reported in patients receiving a high-
dosage regimen of co-trimoxazole for several days.
Methods
Between 2002 and 2010, 22 patients received two tablets of co-
trimoxazole three times a day, equivalent to a daily dosage of 2400 mg
of sulfamethoxazole and 480 mg of trimethoprim, as previously described.7
In these patients, serum specimens were routinelycollected forco-trimoxazole
concentration determination after ≥4 weeks of treatment. Venous blood
samples were collected 3 h after administration of drugs and the serum
was immediately separated from blood cells by centrifugation at 1500 g
for 10 min and frozen at 2208C until analysis. Previously, plasma samples
containing co-trimoxazole were found to be stable ≥24 h when the
samples were kept at room temperature (percentage difference ,15%).
The concentrations of co-trimoxazole in plasma that underwent three
freeze–thaw cycles or storage at 2208C for 30 days were found to be
stable, with percentage difference ,15%.8
A negative control serum was obtained from a voluntary healthy person
who had not received medication for .4 weeks. All patients gave written
informed consent for the study and the study was approved by the local in-
stitute Fédératif de Recherche IFR48 Ethics Committee. HPLC-grade analyt-
ical reagents were obtained from Sigma–Aldrich (Saint-Quentin, France).
The trimethoprim and sulfamethoxazole concentrations were determined
using ion-paired HPLC. The HPLC equipment consisted of a Merck L6200
pump and Merck UV detector L4000 (Merck, Darmstadt, Germany). The
analytical column was a Merck Lichrospher RP18 (5 mm, 125×4 mm). The
mobile phase consisted of phosphate buffer (0.1 M, pH 4.5) mixed at an
86:14 (v/v) ratio with acetonitrile. The flow rate was 1.3 mL/min and
# The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother 2014; 69: 757–760
doi:10.1093/jac/dkt400 Advance Access publication 11 October 2013
757
 by guest on N
ovem
ber 10, 2015
http://jac.oxfordjournals.org/
D
ow
nloaded from
 
http://jac.oxfordjournals.org/Serum concentration of co-trimoxazole during a high-dosage regimen
Sirwan Muhammed Ameen, Jean-Marc Rolain, Marie-Noelle Le Poullain, Véronique Roux,
Didier Raoult and Michel Drancourt*
Aix-Marseille Université, Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), UMR CNRS 7278,
IRD 198, INSERM 1095, Faculté de Médecine, Marseille, France
*Corresponding author. Tel: +33-4-91-38-55-17; Fax: +33-4-91-38-77-72; E-mail: michel.drancourt@univmed.fr
Received 28 December 2012; returned 2 April 2013; revised 2 August 2013; accepted 12 September 2013
Objectives: Sulfamethoxazole and trimethoprim have been used for decades, yet high dosages are rarely reported.
We aimed to measure blood concentrations of both molecules in this situation.
Methods: Between 2002 and 2010, 22 patients received two tablets of co-trimoxazole three times a day, equiva-
lent to a daily dosage of 2400 mg of sulfamethoxazole and 480 mg of trimethoprim. The trimethoprim and sulfa-
methoxazole concentrations were determined 3 h after administration using ion-paired HPLC.
Results: In the presence of a negative control, which yielded no peaks at the retention times for trimethoprim and
sulfamethoxazole, the mean+SD value for sulfamethoxazole concentration was 161.01+69.154 mg/L and the
mean+SD value for trimethoprim was 5.788+2.74 mg/L.
Conclusions: These concentrations are largely above the trimethoprim and sulfamethoxazole MIC distributions as
well as the trimethoprim resistance clinical breakpoint (4 mg/L) reported by EUCAST in 2012 for most bacterial
pathogens, including Gram-positive species such as Staphylococcus aureus. Our results support proposing a
high-dosage regimen of co-trimoxazole as a suitable alternative for methicillin-resistant S. aureus infections.
Keywords: sulfamethoxazole, trimethoprim, MRSA
Introduction
Sulphonamide compounds have been used as antibiotics since the
1930s and trimethoprim was first used 30 years later.1 Sulfameth-
oxazole and trimethoprim both interfere with folate metabolism
and the 1:5 trimethoprim/sulfamethoxazole combination known
as co-trimoxazole is a broad-spectrum antimicrobial agent used
to treat infections due to aerobic Gram-positive and Gram-
negative bacteria, fungi and protozoa.2 Co-trimoxazole is available
in oral and intravenous preparations with the standard single-
strength tablet containing 80 mg of trimethoprim combined with
400 mg of sulfamethoxazole.
Trimethoprim/sulfamethoxazole concentrations have been mea-
sured in the serum of patients receiving oral co-trimoxazole equiva-
lent to 160 mg of trimethoprim and 800 mg of sulfamethoxazole
daily (Figure 1).3–5 However, a clinical benefit of higher dosage co-
trimoxazole regimens has been demonstrated in patients suffering
opportunistic infections during human HIV coinfection, including
patients diagnosed with Pneumocystis jirovecii infection.6 We
previously showed the efficacy of a high-dosage co-trimoxazole
regimen for treating patients diagnosed with Staphylococcus
aureus osteitis.7 However, the actual co-trimoxazole serum con-
centration has not been reported in patients receiving a high-
dosage regimen of co-trimoxazole for several days.
Methods
Between 2002 and 2010, 22 patients received two tablets of co-
trimoxazole three times a day, equivalent to a daily dosage of 2400 mg
of sulfamethoxazole and 480 mg of trimethoprim, as previously described.7
In these patients, serum specimens were routinelycollected forco-trimoxazole
concentration determination after ≥4 weeks of treatment. Venous blood
samples were collected 3 h after administration of drugs and the serum
was immediately separated from blood cells by centrifugation at 1500 g
for 10 min and frozen at 2208C until analysis. Previously, plasma samples
containing co-trimoxazole were found to be stable ≥24 h when the
samples were kept at room temperature (percentage difference ,15%).
The concentrations of co-trimoxazole in plasma that underwent three
freeze–thaw cycles or storage at 2208C for 30 days were found to be
stable, with percentage difference ,15%.8
A negative control serum was obtained from a voluntary healthy person
who had not received medication for .4 weeks. All patients gave written
informed consent for the study and the study was approved by the local in-
stitute Fédératif de Recherche IFR48 Ethics Committee. HPLC-grade analyt-
ical reagents were obtained from Sigma–Aldrich (Saint-Quentin, France).
The trimethoprim and sulfamethoxazole concentrations were determined
using ion-paired HPLC. The HPLC equipment consisted of a Merck L6200
pump and Merck UV detector L4000 (Merck, Darmstadt, Germany). The
analytical column was a Merck Lichrospher RP18 (5 mm, 125×4 mm). The
mobile phase consisted of phosphate buffer (0.1 M, pH 4.5) mixed at an
86:14 (v/v) ratio with acetonitrile. The flow rate was 1.3 mL/min and
# The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail: journals.permissions@oup.com
J Antimicrob Chemother 2014; 69: 757–760
doi:10.1093/jac/dkt400 Advance Access publication 11 October 2013
757
 by guest on N
ovem
ber 10, 2015
http://jac.oxfordjournals.org/
D
ow
nloaded from
 
http://jac.oxfordjournals.org/
RESEARCH ARTICLE Open Access
Is the standard dose of amoxicillin-clavulanic acid
sufficient?
Michiel Haeseker1,3,5*, Thomas Havenith2, Leo Stolk2, Cees Neef2, Cathrien Bruggeman1,3 and Annelies Verbon4
Abstract
Background: The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition
concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always
reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic
acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T >MIC. Additionally, the association of
demographic anthropomorphic and clinical parameters with the pharmacokinetics and pharmacodynamics of
amoxicillin were determined.
Methods: In serum of 57 hospitalised patients amoxicillin concentrations were measured using high performance
liquid chromatography. Patients were older than 18 years and most patients had an abdominal infection. The
standard amoxicillin/clavulanic acid dose was 4 times a day 1000/200 mg iv. Pharmacokinetic parameters were
calculated with maximum a posteriori Bayesian estimation (MW\Pharm 3.60). A one-compartment open model was
used. Individual dosing simulations were performed with MW\Pharm.
Results: In our study population, the mean (±SD) age was 67 (±16) years and the mean clearance corrected for
bodyweight was 0.17 (±0.07) L/h/kg. Only, 65% of the patients reached the proposed amoxicillin 40%T > MIC with
amoxicillin/clavulanic acid for bacterial MICs of 8 mg/L. A computer simulated increase of the standard dose to 6
times daily, increased this percentage to 95%. In this small study group 40%T >MIC was not associated with clinical
or microbiological cure.
Conclusion: A substantial proportion of the hospitalised patients did not reach the 40%T > MIC with the standard
dose amoxicillin/clavulanic acid for a bacterial MIC of 8 mg/L. Therefore, we suggest increasing the standard dose
of amoxicillin/clavulanic acid to 6 times a day in patients with severe Enterobacteriaceae infections.
Trial registration: Trial registration number: NTR1725 16th march 2009.
Keywords: Amoxicillin, Clavulanic acid, Pharmacokinetics, Age
Background
In vitro and animal studies have shown that β-lactam anti-
biotics for Gram-positive bacteria and Gram-negative bac-
teria are effective when the percentage time above the
minimal inhibition concentration (%T >MIC) of the un-
bound serum concentration is more than 35-40%. Max-
imal effects are reached with %T >MIC above 60-70%
[1-3]. Only sparse pharmacokinetic/pharmacodynamic
(PK/PD) data are estimated in human clinical studies.Pharmacokinetic analysis of amoxicillin/clavulanic acid has
mostly been done in healthy individuals [4,5]. In human
clinical studies amoxicillin/clavulanic acid has been found
to cure Streptococcus pneumoniae and Haemophilus influ-
enza infections clinically and microbiologically when %T >
MIC was ≥40% [1]. To our knowledge, there are no human
pharmacodynamic efficacy studies for Enterobacteriaceae.
Amoxicillin/clavulanic acid is a commonly used broad
spectrum antibiotic. Clavulanic acid extends the spectrum
of amoxicillin to β-lactamase producing strains, such as E.
coli, K. pneumoniae, H. influenzae and S. aureus. Clavula-
nic acid has very little intrinsic antibacterial effect. Clavu-
lanic acid irreversibly inhibits β-lactamase, protecting
amoxicillin [6]. Therefore, amoxicillin is measured for
* Correspondence: m.haeseker@mumc.nl
1Department of Medical Microbiology, Maastricht University Medical Centre,
Maastricht, the Netherlands
3Care and Public Health Research Institute (CAPHRI), Maastricht, the
Netherlands
Full list of author information is available at the end of the article
© 2014 Haeseker et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Haeseker et al. BMC Pharmacology and Toxicology 2014, 15:38
http://www.biomedcentral.com/2050-6511/15/38
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1725
mailto:m.haeseker@mumc.nl
http://creativecommons.org/licenses/by/4.0
http://creativecommons.org/publicdomain/zero/1.0/
RESEARCH ARTICLE Open Access
Is the standard dose of amoxicillin-clavulanic acid
sufficient?
Michiel Haeseker1,3,5*, Thomas Havenith2, Leo Stolk2, Cees Neef2, Cathrien Bruggeman1,3 and Annelies Verbon4
Abstract
Background: The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition
concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always
reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic
acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T >MIC. Additionally, the association of
demographic anthropomorphic and clinical parameters with the pharmacokinetics and pharmacodynamics of
amoxicillin were determined.
Methods: In serum of 57 hospitalised patients amoxicillin concentrations were measured using high performance
liquid chromatography. Patients were older than 18 years and most patients had an abdominal infection. The
standard amoxicillin/clavulanic acid dose was 4 times a day 1000/200 mg iv. Pharmacokinetic parameters were
calculated with maximum a posteriori Bayesian estimation (MW\Pharm 3.60). A one-compartment open model was
used. Individual dosing simulations were performed with MW\Pharm.
Results: In our study population, the mean (±SD) age was 67 (±16) years and the mean clearance corrected for
bodyweight was 0.17 (±0.07) L/h/kg. Only, 65% of the patients reached the proposed amoxicillin 40%T > MIC with
amoxicillin/clavulanic acid for bacterial MICs of 8 mg/L. A computer simulated increase of the standard dose to 6
times daily, increased this percentage to 95%. In this small study group 40%T >MIC was not associated with clinical
or microbiological cure.
Conclusion: A substantial proportion of the hospitalised patients did not reach the 40%T > MIC with the standard
dose amoxicillin/clavulanic acid for a bacterial MIC of 8 mg/L. Therefore, we suggest increasing the standard dose
of amoxicillin/clavulanic acid to 6 times a day in patients with severe Enterobacteriaceae infections.
Trial registration: Trial registration number: NTR1725 16th march 2009.
Keywords: Amoxicillin, Clavulanic acid, Pharmacokinetics, Age
Background
In vitro and animal studies have shown that β-lactam anti-
biotics for Gram-positive bacteria and Gram-negative bac-
teria are effective when the percentage time above the
minimal inhibition concentration (%T >MIC) of the un-
bound serum concentration is more than 35-40%. Max-
imal effects are reached with %T >MIC above 60-70%
[1-3]. Only sparse pharmacokinetic/pharmacodynamic
(PK/PD) data are estimated in human clinical studies.
Pharmacokinetic analysis of amoxicillin/clavulanic acid has
mostly been done in healthy individuals [4,5]. In human
clinical studies amoxicillin/clavulanic acid has been found
to cure Streptococcus pneumoniae and Haemophilus influ-
enza infections clinically and microbiologically when %T >
MIC was ≥40% [1]. To our knowledge, there are no human
pharmacodynamic efficacy studies for Enterobacteriaceae.
Amoxicillin/clavulanic acid is a commonly used broad
spectrum antibiotic. Clavulanic acid extends the spectrum
of amoxicillin to β-lactamase producing strains, such as E.
coli, K. pneumoniae, H. influenzae and S. aureus. Clavula-
nic acid has very little intrinsic antibacterial effect. Clavu-
lanic acid irreversibly inhibits β-lactamase, protecting
amoxicillin [6]. Therefore, amoxicillin is measured for
* Correspondence: m.haeseker@mumc.nl
1Department of Medical Microbiology, Maastricht University Medical Centre,
Maastricht, the Netherlands
3Care and Public Health Research Institute (CAPHRI), Maastricht, the
Netherlands
Full list of author information is available at the end of the article
© 2014 Haeseker et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Haeseker et al. BMC Pharmacology and Toxicology 2014, 15:38
http://www.biomedcentral.com/2050-6511/15/38
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1725
mailto:m.haeseker@mumc.nl
http://creativecommons.org/licenses/by/4.0
http://creativecommons.org/publicdomain/zero/1.0/
RESEARCH ARTICLE Open Access
Is the standard dose of amoxicillin-clavulanic acid
sufficient?
Michiel Haeseker1,3,5*, Thomas Havenith2, Leo Stolk2, Cees Neef2, Cathrien Bruggeman1,3 and Annelies Verbon4
Abstract
Background: The pharmacodynamic (PD) efficacy target of amoxicillin is 40% time above the minimal inhibition
concentration (40%T > MIC). Recent studies of other antibiotics have shown that PD-efficacy targets are not always
reached. The aim of this study was to evaluate the percentage of hospitalised patients, using amoxicillin/clavulanic
acid intravenously (iv), that reach the pharmacodynamic efficacy target 40%T >MIC. Additionally, the association of
demographic anthropomorphic and clinical parameters with the pharmacokinetics and pharmacodynamics of
amoxicillin were determined.
Methods: In serum of 57 hospitalised patients amoxicillin concentrations were measured using high performance
liquid chromatography. Patients were older than 18 years and most patients had an abdominal infection. The
standard amoxicillin/clavulanic acid dose was 4 times a day 1000/200 mg iv. Pharmacokinetic parameters were
calculated with maximum a posteriori Bayesian estimation (MW\Pharm 3.60). A one-compartment open model was
used. Individual dosing simulations were performed with MW\Pharm.
Results: In our study population, the mean (±SD) age was 67 (±16) years and the mean clearance corrected for
bodyweight was 0.17 (±0.07) L/h/kg. Only, 65% of the patients reached the proposed amoxicillin40%T > MIC with
amoxicillin/clavulanic acid for bacterial MICs of 8 mg/L. A computer simulated increase of the standard dose to 6
times daily, increased this percentage to 95%. In this small study group 40%T >MIC was not associated with clinical
or microbiological cure.
Conclusion: A substantial proportion of the hospitalised patients did not reach the 40%T > MIC with the standard
dose amoxicillin/clavulanic acid for a bacterial MIC of 8 mg/L. Therefore, we suggest increasing the standard dose
of amoxicillin/clavulanic acid to 6 times a day in patients with severe Enterobacteriaceae infections.
Trial registration: Trial registration number: NTR1725 16th march 2009.
Keywords: Amoxicillin, Clavulanic acid, Pharmacokinetics, Age
Background
In vitro and animal studies have shown that β-lactam anti-
biotics for Gram-positive bacteria and Gram-negative bac-
teria are effective when the percentage time above the
minimal inhibition concentration (%T >MIC) of the un-
bound serum concentration is more than 35-40%. Max-
imal effects are reached with %T >MIC above 60-70%
[1-3]. Only sparse pharmacokinetic/pharmacodynamic
(PK/PD) data are estimated in human clinical studies.
Pharmacokinetic analysis of amoxicillin/clavulanic acid has
mostly been done in healthy individuals [4,5]. In human
clinical studies amoxicillin/clavulanic acid has been found
to cure Streptococcus pneumoniae and Haemophilus influ-
enza infections clinically and microbiologically when %T >
MIC was ≥40% [1]. To our knowledge, there are no human
pharmacodynamic efficacy studies for Enterobacteriaceae.
Amoxicillin/clavulanic acid is a commonly used broad
spectrum antibiotic. Clavulanic acid extends the spectrum
of amoxicillin to β-lactamase producing strains, such as E.
coli, K. pneumoniae, H. influenzae and S. aureus. Clavula-
nic acid has very little intrinsic antibacterial effect. Clavu-
lanic acid irreversibly inhibits β-lactamase, protecting
amoxicillin [6]. Therefore, amoxicillin is measured for
* Correspondence: m.haeseker@mumc.nl
1Department of Medical Microbiology, Maastricht University Medical Centre,
Maastricht, the Netherlands
3Care and Public Health Research Institute (CAPHRI), Maastricht, the
Netherlands
Full list of author information is available at the end of the article
© 2014 Haeseker et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,
unless otherwise stated.
Haeseker et al. BMC Pharmacology and Toxicology 2014, 15:38
http://www.biomedcentral.com/2050-6511/15/38
http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1725
mailto:m.haeseker@mumc.nl
http://creativecommons.org/licenses/by/4.0
http://creativecommons.org/publicdomain/zero/1.0/
Discussion
In this study, we demonstrate that the efficacy target of
40%T >MIC for amoxicillin/clavulanic acid was reached
in 93% of the patients tested when the MIC was 4 mg/L
and only in 65% of the patients tested when the MIC
was 8 mg/L. In the EUCAST and CLSI criteria Entero-
bacteriaceae are considered to be susceptible for amoxi-
cillin/clavulanic acid with bacterial MIC ≤ 8 mg/L [11].
High bacterial MICs for amoxicillin/clavulanic acid are
an increasing problem in the Netherlands and in Europe
[19,20]. To prevent treatment failure for individual pa-
tients and to prevent development of antibiotic resist-
ance on population level, increasing the standard dose of
amoxicillin/clavulanic acid seems warranted. Dosing
simulation showed that increasing the standard dose of
amoxicillin/clavulanic acid to 6 times a day 1000/200 mg
increased the number of patients reaching 40%T >MIC
to 100% for bacterial MIC ≤ 4 and to 95% with bacterial
MIC ≤ 8. Continuous iv dosing is an alternative for fre-
quent dosing of time dependent β-lactam antibiotics.
Figure 2 Correlation between amoxicillin actual measured concentration and estimated with maximum a posteriori Bayesian fitting
(MW/Pharm 3.60, Mediware, the Netherlands).
Figure 3 The percentage of patients that reach the 40%T >MIC for different age categories at different MICs.
Haeseker et al. BMC Pharmacology and Toxicology 2014, 15:38 Page 5 of 8
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Unfortunately, amoxicillin is not very suitable for continu-
ous iv dosing, because of the instability of amoxicillin at
room temperature. Therefore, we suggest increasing the
dose of amoxicillin/clavulanic acid to 6 times a day in pa-
tients with severe Enterobacteriaceae sepsis or intra-
abdominal infection.
In general amoxicillin/clavulanic acid is well tolerated.
The most frequent adverse drug events are diarrhoea,
nausea and vomiting. However, amoxicillin/clavulanic
acid is also associated with liver injury, which is esti-
mated to occur from 1 to 1.7 per 10.000 users [21,22].
Clavulanic acid seems to be responsible for the adverse
drug reaction, since amoxicillin alone is rarely associated
with liver injury and causes less gastrointestinal prob-
lems than the combination preparation [23-25]. In vitro
pharmacodynamic studies demonstrate that low dose of
clavulanic acid suffice and the β-lactamase inhibition of
clavulanic acid lasts for 8–12 hours [26,27]. Therefore,
increasing the standard dose of amoxicillin/clavulanic
acid of 4 times a day 1000/200 mg iv with amoxicillin
twice daily 1000 mg iv may be a safe and effective
alternative.
CLam/W is correlated with CLcr and the amoxicillin
dose is adjusted with to the CLcr. However, other covariates
also influence the CLam/W. CLam/W was significantly
correlated with age. However, age and creatinine were not
correlated to each other, meaning that elderly patients can
have both a normal creatinine and a decreased CLam/W.
Therefore, the correlation of age with CLam/W seems in-
dependent of the creatinine. Furthermore, the 4 patients
that did not reach the efficacy target with bacterial MIC = 4
were all young patients with excellent clearance. Our mea-
sured attainment results are lower than those calculated at-
tainment results in the EUCAST rationale document, in
which Monte Carlo simulations were used to calculate the
target attainment rates (40%T >MIC) of different dosing
regimens (from 500 mg 3 times a day to 2 g 4 times a day)
for different bacterial MICs (0.5-32 mg/L) [11]. The target
attainment in the EUCAST rationale document for the
standard dose (1000/200 mg 4 times a day) is 100% at bac-
terial MIC ≤ 4 and 75% with bacterial MIC ≤ 8 mg/L [11].
In our real life blood level determination study, these per-
centages were 93% and 65%, respectively. This difference
may be explained by the larger interindividual variability of
our population and in particular by a group of younger pa-
tients with normal renal clearance (CLcr > 60 mL/min).
Remarkably, in the EUCAST rationale document, the inter-
individual variation is extremely small; t½ is 1.1 (±0.1) h,
versus t½ is 1.5 (±0.6) h in our study. The higher t½ in our
study may be due to the high mean age of our population.
No significant associations have been found between the
target 40%T >MIC and clinical outcome. As expected,
our study population was too small and too heteroge-
neous. A large number of patients are needed to draw
Table 3 Univariate Pearson correlation coefficients
between amoxicillin/clavulanic acid, CLam/W and
predictors used in this study
Univariate CLam/W
R P-value
Creatinine −0.584 <0.001
Age −0.476 <0.001
Gender −0.034 0.812
V/W −0.608 <0.001
40%T >MIC −0.424 0.025
CLam/W, amoxicillin/clavulanic acid clearance corrected for bodyweight.
V/W, amoxicillin/clavulanic acid volume of distribution corrected
for bodyweight.
0
10
20
30
40
50
60
7080
90
100
0.5 1 2 4 8 16 32 64 128
MIC (mg/L)
P
er
ce
nt
ag
e 
of
 p
at
ie
nt
s 
th
at
 r
ea
ch
 
th
e 
ef
fic
ac
y 
ta
rg
et
 (%
)
4dd1000mg
6dd1000mg
6dd2000mg
Figure 4 Calculated percentage of patients with 40%T >MIC at different MICs for increasing amoxicillin dosages.
Haeseker et al. BMC Pharmacology and Toxicology 2014, 15:38 Page 6 of 8
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