Difference in pharmacokinetics of antibiotics during pregnancy in normal, overweight and obese women.

Antibiotic use in the general population has increased over the last decades,
{Adriaenssens, 2011 #6} which has also resulted in an increased antibiotic use
during pregnancy.{Broe, 2014 #7} Nowadays 21% of pregnancies are complicated by
an infection for which antibiotics are required, such as urinary tract
infection, upper respiratory infection but also wound infections.{de Jonge,
2014 #8} Pregnant women with overweight (BMI>25-30) and obesity (BMI >30) are
at increased risk for infection due to the effects obesity has on the immune
responses {Bearden, 2000 #15} and thus antibiotic use.{Broe, 2014 #7} In the
Netherlands, 30-50% of all pregnant women have a BMI > 25, which accounts for
25.000-35.000 pregnancies per year.{Gaillard, 2013 #9}{Gaillard, 2013 #9}
Health care-associated infections contribute to the increasing cost of health
care as well as patient morbidity and mortality. Pregnant women with an
increased BMI, defined as BMI> 25, are also more likely to have maternal
complications, such as a caesarean section and an increased risk for operative
morbidity such as wound complications.{Marchi, 2015 #10} Of all hospital-based
surgeries performed in the United States, cesarean deliveries were the most
frequently performed surgery.{Valent, 2017 #11} Approximately, 3% to 12% of all
caesarean sections are complicated by surgical site infection (SSI) and with
increasing maternal weight, the risk of SSI increases. {Alanis, 2010 #12;Leth,
2011 #13;Wloch, 2012 #14}
Obese, non-pregnant patients have higher percentage of adipose tissue, lower
percentage of total body water and lean body mass. {Tucker, 2014 #16} In
addition, during pregnancy, most maternal organ systems are affected by both
anatomical and physiological changes, which include increased total body water
and plasma volume, decreased concentrations of drug-binding proteins and
altered activity of drug-metabolizing enzymes in the liver. Enzymes affected by
pregnancy include the cytochrome P450 isoenzymes CYP3A4, CYP2D6, CYP2C9,
CYP1A2, and CYP2C19. (reviewed in {Pariente, 2016 #17}) Obesity and pregnancy
combined cause several alterations in cardiac output, blood volume, volume of
distribution (Vd), renal function, and hepatic function.{Pai, 2007 #18;Pai,
2000 #19}
Pharmacokinetic changes caused by aforementioned variations must be taken into
account when prescribing antibiotics, as they will undoubtedly influence
clinical outcomes and the potential for antimicrobial resistance and drug
toxicity.{Pai, 2007 #18} Despite weight differences in pregnant women, there
are no differences in the dosing regimens of most antibiotics. Neither has been
investigated, re-evaluated or refined to determine the optimal doses or
treatment interval for different BMI-classes. With the current health care
approach of personalized medicine in mind, the same universal approach for
everybody, independent of gestational age, maternal weight or comorbidity one
dose does not fit all since it often has not the desired effect. Due to the
lack of optimization of the above mentioned antibiotic drug regimens,
significant gaps in knowledge exist. An important aspect to set up, investigate
and understand dosing and also dosing interval experiments, is knowledge of the
maternal individual pharmacokinetics and pharmacogenetics of the drug of
interest during pregnancy. As an example, most antibiotics are eliminated by
the liver by action of the above mentioned cytochrome P450 isoenzymes and
variations of Single Nucleotide Polymorphisms (SNPs) in these genes will result
in different drug effects and even potential adverse effects.

Primary
To examine the pharmacokinetics of standard antibiotic regimen used at the
department of Obstetrics at the Erasmus MC for postsurgical prophylaxis after
caesarean section.

Secondary
- To examine the relation between the weight category (1. BMI <25, 2. BMI
25-<30, 3. BMI 30-40, 4. BMI >40) before conception and the pharmacokinetics of
the antibiotic regimen (primary objective).
- To examine the relation between the gestational age (weeks) and the
pharmacokinetics of the antibiotic regimen (primary objective).
- To examine the relation between maternal age (years) and the pharmacokinetics
of the antibiotic regimen (primary objective).
- To examine the relation between fetal sex and the pharmacokinetics of the
antibiotic regimen (primary objective).
- To examine the relation between maternal SNPs in cytochrome P450 isoenzyme
genes and the pharmacokinetics of the antibiotic regimen (primary objective).

A clinical observational pilot study.

For all participants the burden will be the insertion of an intravenous canule
that will solely be used for blood sample collection. After the administration
of antibiotics, blood samples (approximately 5 ml, 1 EDTA tube) will be
collected in sampling time windows according to the following schedule: t0
(administration), t0-30 min, t1-3 hrs, t5-8 hrs, t10-12hrs. Insight into
individual pharmacodynamics of antibiotics and its association with SNPs of the
cytochrome P450 isoenzymes as well as patient characteristics will allow for
future trials with individualized regimens to maximize benefits and minimize
side effects which could lead to personalized and patient-tailored medicine for
infection or postsurgical prophylaxis.