3.1 Study Selection and Data Extraction

A detailed overview of the study selection is presented in the PRISMA flow diagram in Fig. 1. Twenty-nine studies were included in this systematic literature review, providing data for 8 of the 11 originally selected antimicrobial drug classes. The PK and exposure of the antimicrobial drugs are presented in alphabetical order of antimicrobial class and drugs within this class. Subsequently, the antimicrobial drugs are presented in the result section according to the ADME (absorption [if applicable], distribution, metabolism, elimination) sequence, followed by the obtained target, PTA, and evidence-based dosages if provided.

Fig. 13.2 Aminoglycosides

No PK or exposure studies could be found for amikacin, framycetin, neomycin, paromomycin, and streptomycin in pregnant women.

3.2.1 Gentamicin

One prospective cohort study of 18 third trimester pregnant women and four non-pregnant women reported on gentamicin PK and exposure [10]. All women were scheduled for a caesarean section or a gynecological surgery under general anesthesia and received gentamicin 4 mg/kg intravenously over 2–3 minutes, 10 minutes prior to surgical incision [10]. The study characteristics including the PK parameters of pregnant women (if possible, in comparison with non-pregnant women) from the included studies are reported in Table 2. When focusing on the distribution, a 39% higher Cmax was reached in pregnant compared with non-pregnant women. Furthermore, Vd was decreased by 24% in pregnant women. The CL was minimally increased by 5% during pregnancy. No p values were reported, except for the change in the elimination constant. This parameter was significantly increased in pregnant women compared with non-pregnant women (0.4127 ± 0.0736/h vs 0.3198 ± 0.0943/h; p < 0.05) [10].

Table 2 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of aminoglycosides, in alphabetical order by antimicrobial drug followed by author

In summary, it is plausible that the PK and exposure of gentamicin changed during pregnancy based on the limited data; however, more robust studies are needed. Regardless of the change in PK and exposure parameters during pregnancy, no statements on target attainment or suggestions for the starting dose were reported.

3.2.2 Tobramycin

Two papers investigated the PK and exposure of tobramycin during pregnancy, one being a prospective cohort study and one a case report with 18 pregnant women in their second or third trimester. All pregnant women were admitted to the hospital for an underlying disease demanding tobramycin treatment. In the cohort study, the women received tobramycin 2.5 mg/kg once daily intravenously over 15 minutes for 7 ± 1 days, while in the case report tobramycin 2 mg/kg was administered intravenously once over 10 minutes, 5.6 hours before caesarean (Table 2) [11, 12]. PK parameters were reported in the cohort study, in contrast with the case report. Maximum concentrations (Cmax) were slightly higher (7%) in third-trimester pregnant women than in second-trimester pregnant women. In addition, it was observed that Vd was comparable between second-and third-trimester pregnant women [11]. This result was also supported by the case report [12]. As for the elimination, AUC was increased by 22% during the third trimester compared with the second trimester. CL was significantly higher with 21% (no p-value reported) in the second trimester compared with the third trimester [11, 12], explaining the difference in AUC.

In summary, the PK and exposure of tobramycin seem to change throughout pregnancy. No PTA was reported. The authors recommended accurate therapeutic drug monitoring during pregnancy [11, 12], but did not provide evidence-based starting dose advice.

3.3 Carbapenems

No studies were found that investigated the PK or exposure for ertapenem and meropenem in pregnant women.

3.3.1 Imipenem

Only one paper investigated the PK and exposure of imipenem during pregnancy. This prospective cohort study included a total of 20 subjects, of whom seven were in their first trimester, seven in their third trimester and six were not pregnant. Imipenem was given in a single intravenous dose of 500 mg (imipenem-cilastatin 1:1) as infusion over 20 minutes (Table 3) [13]. When focusing on the distribution, Cmax, measured immediately after infusion, and plasma concentrations 2 hours after administration, were significantly decreased by 65% (p < 0.05) in first and third trimester pregnant women in comparison with non-pregnant women. Vd was significantly increased by 60% and 65% for first (p < 0.005) and third trimester (p < 0.05) compared with non-pregnant women, respectively. Furthermore, the AUC was also significantly decreased (p < 0.05) during pregnancy by 44% and 58% for first and third trimester compared with non-pregnant women, respectively. The total CL was significantly increased (p < 0.05) in the pregnant patients (52% and 65% during first and third trimester compared with non-pregnant women) [13].

Table 3 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of carbapenems

In summary, although only one study has been performed, there are indications that the PK or exposure of imipenem significantly changes during pregnancy. PTA was not reported and no recommendation for evidence-based dosing was provided.

3.4 Quinolones

No studies were found that investigated the PK or exposure for norfloxacin in pregnant women.

3.4.1 Ciprofloxacin, Levofloxacin, and Ofloxacin

One prospective cohort study reported on the PK and exposure of ciprofloxacin and one on the PK and exposure of ofloxacin during the second trimester of pregnancy [14]. In each study, 20 pregnant women were included with fetuses affected by beta-thalassemia major undergoing termination of gestation. Both ciprofloxacin (200 mg) and ofloxacin (400 mg) were administered every 12 hours intravenously (Table 4). In addition, only one prospective cohort study studied the PK and exposure during pregnancy for levofloxacin [15]. Levofloxacin 500 mg was given intravenously over 60 minutes to 12 pregnant women scheduled to undergo caesarean section for obstetric indications. Only maternal concentrations were reported in the above-mentioned studies (Table 4).

Table 4 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of quinolones, in alphabetical order by antimicrobial drug followed by author

In summary, no conclusion can be made about PK or exposure changes for ciprofloxacin, ofloxacin, and levofloxacin in pregnant women.

3.4.2 Moxifloxacin

Three studies, two prospective cohort studies and one case report, reported on the PK and exposure of moxifloxacin during pregnancy [15,16,17]. The prospective cohort study by Nemutlu et al. [17] included nine non-pregnant women and six pregnant women scheduled for caesarean section. Both groups received moxifloxacin 400 mg in a single dose intravenously over 20 minutes, with completion of infusion 30 minutes prior to surgical incision. Ten pregnant women scheduled for caesarean section were included in the prospective study by Ozyuncu et al. [15] receiving moxifloxacin 400 mg in a single dose intravenously over 60 minutes, with completion of infusion 20–25 minutes before surgical incision. The case report by van Kampenhout et al. [16] followed a pregnant woman with tuberculosis from the second trimester to 18 weeks postpartum. She received moxifloxacin 400 mg orally once a day (Table 4). The study of Ozyuncu et al. [15] only reported maternal concentrations and the case report by van Kampenhout et al. [16] only reported the AUC. As for the distribution-related parameters, Nemutlu et al. [17] reported a 65% decrease in Cmax during pregnancy. The Vd seemed to be increased during pregnancy by 70%. Furthermore, the AUC was decreased at delivery by 80% compared with non-pregnant women. No p-values were reported by Nemutlu et al. [17]. Contradictory results on AUC were reported in the case report [16], in which overall AUC did not change throughout pregnancy. The t½ seemed to be decreased by 37% at delivery compared with non-pregnant women (p-value not reported) [17].

In summary, based on the limited results, it seems that the PK and exposure of moxifloxacin changed during pregnancy compared with non-pregnant women. However, PTA and dose adjustments were not reported.

3.5 Glycopeptides

No PK or exposure studies could be found for dalbavancin, oritavancin, or teicoplanin throughout pregnancy.

3.5.1 Vancomycin

Four papers were found on PK and exposure of vancomycin during pregnancy [18,19,20,21]. Three were prospective cohort studies and one study was a case report (Table 5) [18]. In total, 86 pregnant women in labor were included [18,19,20,21]. Dosages and dosing intervals varied for these studies. Bourget et al. [18] administered vancomycin 15 mg/kg intravenously every 12 hours for 13 days. Laiprasert et al. [19] used a single dose of 1 g intravenously 6 hours before delivery. The study by Onwuchuruba et al. [20] included three dosing regimens; 1 g intravenously every 12 hours, 15 mg/kg intravenously every 12 hours, and 20 mg/kg intravenously every 8 hours. Towers and Weit [21] also administered vancomycin 20 mg/kg intravenously every 8 hours. Only the case report by Bourget et al. reported PK parameters [18]. No comparison with non-pregnant women was made. The other studies [19,20,21] only reported maternal serum levels.

Table 5 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of glycopeptides, in alphabetical order by antimicrobial drug followed by author

In summary, based on these papers, the changes in PK or exposure of vancomycin during pregnancy cannot be determined. However, the studies from Onwuchuruba et al. [20] and Towers and Weit [21] both showed that a dosing regimen of 20 mg/kg intravenously every 8 hours (with a maximum individual dose not exceeding 2 g) before delivery resulted in therapeutic serum vancomycin levels in more than 80% of the mothers.

3.6 Macrolides

No studies were found that investigated the PK or exposure of the macrolides (azithromycin, clarithromycin, erythromycin) in pregnant women.

3.7 Polypeptides

No studies were found that investigated the PK or exposure of the polypeptides (bacitracin, colistin, gramicidin, polymyxin B) throughout pregnancy.

3.8 Rifamycines

No studies were found that investigated the PK or exposure of rifabutin and rifaximin in pregnancy.

3.8.1 Rifampicin

For the PK and exposure of rifampicin during pregnancy, one prospective cohort study with 33 HIV-infected pregnant women was conducted. Rifampin was given once daily orally in a fixed-dose combination tablet (Rifafour® or Rifinah®) at a dose of ~10 mg/kg. Most participants received 600 mg daily. Twenty samples were collected during the third trimester, four during delivery and 24 postpartum (Table 6) [22]. As for the distribution, Vd was used for weight-based allometric scaling of the PK model. No differences between pregnant and non-pregnant women were reported. The elimination of rifampicin seemed to be affected by pregnancy. CL/F was significantly decreased by 14% during pregnancy compared with postpartum (p = 0.026). However, the model-estimated Cmax was similar during pregnancy and postpartum. Furthermore, the observed proportion of women achieving the target Cmax (≥ 8 mg/L) was very similar during pregnancy (54%) versus postpartum (58%). The model-estimated AUC increased slightly in pregnant women [22].

Table 6 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of rifamycines, in alphabetical order by antimicrobial drug

In summary, this study suggests that although CL/F of rifampicin is decreased in pregnant HIV-infected women, this appears to only modestly increase the rifampicin concentration and thus the rifampicin exposure. Therefore, no dose adjustment of rifampicin for HIV-infected women seems necessary during pregnancy.

3.8.2 Rifapentine

One study reported on the PK and exposure of rifapentine during pregnancy. This was a phase I/II trial including 50 pregnant women with indications for tuberculosis prophylaxis. Twenty-five women received rifapentine in the second trimester, of which ten were HIV positive and 25 women received the drug in the third trimester, of which ten were also HIV positive. In this paper, isoniazid was also administered and studied for PK (see tuberculostatic drugs). Rifapentine was given at a dose of 900 mg/week orally in combination with isoniazid in a combination preparation named 3HP for 12 weeks (Table 6) [23]. The AUC for HIV-positive pregnant women was increased by 14% compared with postpartum women and this was 21–50% higher than for HIV-positive pregnant women. No p-value was reported for this increase in AUC. As for the CL/F of rifapentine, no significant difference was observed between second and third trimester. However, a 30% increase (p < 0.001) in CL/F of rifapentine was seen for HIV-positive women compared with HIV-negative women. Additionally, it was found that HIV-negative women had a 28% decrease in CL during pregnancy compared with postpartum (P < 0.001). Based solely on these results, it cannot be concluded whether the change in AUC and CL in HIV-positive pregnant women was caused by the effect of HIV or by the efavirenz-based antiretroviral regimen [23].

In summary, although CL/F is decreased in HIV-negative pregnant women compared with postpartum women, no dose adjustments are needed for pregnant women as all women achieved the same rifapentine exposure as postpartum women.

3.9 Sulfonamides

No studies were found that investigated the PK or exposure of sulfadiazines, sulfametrole, and sulfapyridine throughout pregnancy.

3.9.1 Sulfamethoxazole (With and Without Trimethoprim)

One prospective study was found that investigated PK and exposure of sulfamethoxazole, including 20 pregnant women in total, of which 13 received sulfamethoxazole and seven received sulfamethoxazole in combination with trimethoprim. Both drugs were administered orally; sulfamethoxazole 480 mg every 12 hours for 13 women in combination with trimethoprim 960 mg every 12 hours. All women were in the first or second trimester of pregnancy and were admitted for abortion or tubal ligation. Maternal serum levels of sulfamethoxazole and trimethoprim were measured (Table 7) [24].

Table 7 Study, patient characteristics, PK and exposure parameters, probability of target attainment and dose advice of the included studies of sulfonamides

In summary, it is not known if the PK or exposure of sulfamethoxazole and trimethoprim changed during pregnancy as there was no comparison for PK and exposure during different trimesters of pregnancy or with non-pregnant women. PTA and dose adjustments were not reported.

3.10 Tetracyclines

No studies were found that investigated the PK or exposure of tetracyclines (demeclocycline, doxycycline, eravacycline minocycline, oxytetracycline, tetracycline, and tigecycline) in pregnancy.

3.11 Tuberculostatic Drugs

No PK or exposure studies have been found for bedaquiline, cycloserine, delamanid, para-aminosalicylic acid, and prothionamide in pregnant women. It must be noted that other drugs like moxifloxacin, ofloxacin, and linezolid also belong to the tuberculostatic drugs. These are described in Sects. 3.4 and 3.12, respectively.

3.11.1 Ethambutol

One prospective cohort study reported on the PK and exposure during pregnancy. This study included 18 samples from pregnant women with HIV infection treated for tuberculosis, which were studied both in third trimester and/or at delivery and postpartum. Women received a calculated number of 275-mg tablets orally daily (Rifafour® and Rifinah® combination preparation), with the dose adjusted for weight to 15–25 mg/kg (Table 8) [25]. Both the Cmax and AUC of ethambutol were slightly, but not significantly, increased by 13% during pregnancy. As for Vd/F and CL/F, no significant differences were observed between pregnant and postpartum women. No p-values were reported in this study [25].

Table 8 Study, patient characteristics PK and exposure parameters, probability of target attainment and dose advice of the included studies of tuberculostatic drugs, in alphabetical order by antimicrobial drug followed by author

In summary, it is very likely that the PK or exposure of ethambutol does not change during pregnancy. This also suggests that pregnant women could be treated with the same dose of ethambutol as postpartum women.

3.11.2 Isoniazid

Three studies reported on the PK and exposure of isoniazid during pregnancy [25]. Two studies were prospective cohort studies and one was a phase I/II trial. The first prospective study by Abdelwahab et al. [25] included a total of 29 samples, 18 during third trimester, 3 during delivery, and 8 postpartum. All women were pregnant and HIV positive, treated for tuberculosis by administering a calculated number of 75-mg tablets orally daily (Rifafour® and Rifinah® combination preparation), with the dose adjusted for weight to 4–6 mg/kg. The other prospective study of Gausi et al. [26] included 847 HIV-positive pregnant women. They received 300 mg orally daily for 28 weeks (immediately during pregnancy or starting at 12 weeks postpartum). A total of 420 levels were measured during second or third trimester and 637 levels were measured postpartum. In 210 patients, levels were measured both during pregnancy and postpartum. In the phase I/II trial by Mathad et al. [23], 50 pregnant women treated for tuberculosis were included. The women received isoniazid 900 mg weekly orally in combination with rifapentine in a combination preparation named 3HP for 12 weeks. Twenty-five women were in the second trimester, of whom 10 were HIV positive. Twenty-five women were in the third trimester, of whom ten were also HIV positive (Table 8).

The study by Mathad et al. reported no significant differences in model-estimated Cmax and AUC between second- and third-trimester pregnant and postpartum women [23]. The model-estimated Cmax was slightly, but non-significant (p-value was not reported), higher (2–14%) in two studies comparing postpartum with second/third trimester [25, 26]. Abdelwahab et al. [25] reported a model-estimated non-significant increase of 27% in AUC (no p-value reported) during the third trimester compared with the postpartum phase. On the contrary, Gausi et al. [26] found a decrease in AUC of 23% (no p-value reported) when comparing the second/third trimester with postpartum. However, both studies also showed a wide range of AUC values. The studies of Abdelwahab et al. [25] and Mathad et al. [23] reported no differences in Vd/F and CL/F between pregnant and postpartum women. Contradictory results were reported by Gausi et al. [26], who reported a 26% increase (p < 0.001) in CL/F during pregnancy.

In summary, there are conflicting results concerning PK and exposure changes of isoniazid during pregnancy. Abdelwahab et al. [25] concluded that the PK and exposure of isoniazid were, overall, not affected by pregnancy. However, the largest study by Gausi et al. [26] did conclude a reduction in isoniazid exposure during pregnancy and postpartum. The effect of PK and exposure on dosing of isoniazid is not stated and should be studied further.

3.11.3 Pyrazinamide

One prospective cohort study reported on the PK and exposure of pyrazinamide during pregnancy. This study included a total of 18 samples, all from pregnant women with HIV infection treated for tuberculosis. Pyrazinamide was administered as 400-mg tablets orally daily (Rifafour® and Rifinah® combination preparation), with the dose adjusted for weight to 20–30 mg/kg. Thirteen samples were taken during the third trimester, two while the patient was in labor, and three samples were collected postpartum (Table 8) [25]. The PK parameters for pyrazinamide showed that AUC and Cmax could be slightly decreased during pregnancy, by 2.8% and 3.9%, respectively. The Vd and CL was not different between pregnant and postpartum women. No p-values were reported [25].

In summary, it seems that the PK and exposure of pyrazinamide do not change during pregnancy and that therefore the dose can remain the same as for non-pregnant women.

3.12 Other Antimicrobial Drugs

No PK or exposure studies have been found that were performed in pregnant women for dapsone, clofazimine, aztreonam, daptomycin, fidaxomicin, fosfomycin, fusidic acid, methenamine, mupirocin, and tedizolid.

3.12.1 Chloramphenicol

One paper reported on the PK and exposure of chloramphenicol in which chloramphenicol 100 mg was vaginally administered daily in tablet form for 7 days, indicated for bacterial vaginosis in 37 pregnant women [27] (Table 9). This study reported maternal plasma levels that ranged from 0.043 × 10-3 to 0.0731 mg/L. This remained under the therapeutic concentration of 5.0–20.0 mg/L [27]. Due to these limited findings, no conclusions can be drawn regarding whether the PK or exposure of chloramphenicol changes during pregnancy.

3.12.2 Clindamycin

Three prospective cohort studies with a total of 44 subjects investigated the PK and exposure of clindamycin [28,29,30]. Fourteen subjects received clindamycin 450 mg orally after 8 or more hours of fasting as prophylaxis right before undergoing abortion [29]. The other 30 subjects received clindamycin intravenously as prevention for diagnosed Group B Streptococcus (GBS) (900 mg/kg every 8 h) or for prevention of endocarditis (600 mg every 6 h). The studies were all performed during different stages of pregnancy ranging from the first trimester to delivery (Table 9) [