Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Τετάρτη 31 Μαΐου 2017
Τρίτη 30 Μαΐου 2017
Sore throat and an ache radiating from the centre of the anterior neck to the both ears and the occiput.Idiopathic Carotidynia,TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome,Vascular Neck Pain,Painful carotid artery,Inflammation of Carotid artery and neck pain,Carotidynia on ultrasound and magnetic resonance imaging,CT findings in a patient with bilateral metachronous carotidyniaContralateral recurrence of carotidynia during steroid therapy,,Carotidynia Possibly due to Localized Vasculitis,
Carotidynia
From Wikipedia, the free encyclopedia
Carotidynia is a syndrome characterized by unilateral (one-sided) tenderness of the carotid artery, near the bifurcation. It was first described in 1927 by Temple Fay.[1] The most common cause of carotidynia may be migraine, and then it is usually self-correcting. Common migraine treatments may help alleviate the carotidynia symptoms. Recent histological evidence has implicated an inflammatory component of carotidynia, but studies are limited.[2] Carotid arteritis is a much less common cause of carotidynia, but has much more serious consequences. It is a form ofgiant cell arteritis, which is a condition that usually affects arteries in the head. Due to this serious condition possibly causing carotidynia, and the possibility that neck pain is related to some other non-carotidynia and serious condition, the case should be investigated by a medical doctor.[3]Because carotidynia can be caused by numerous causes, Biousse and Bousser in 1994 recommended the term not be used in the medical literature.[4] However, recent MRI and ultrasound studies have supported the existence of a differential diagnosis of carotidynia consistent with Fay's characterization.[5][6]
References
- Hill and Hastings list this reference as: Fay, Temple (1927) "Atypical neuralgia." Arch Neurol Psychiatry.
- Upton, P.; Smith, J. G.; Charnock, D. R. (2003). "Histologic confirmation of carotidynia". Otolaryngology - Head and Neck Surgery. 129 (4): 443–444. doi:10.1016/S0194-5998(03)00611-9. PMID 14574303.
- Hill LM, Hastings G (1994). "Carotidynia: a pain syndrome.". J Fam Pract. 39 (1): 71–5. PMID 8027735.
- Biousse V, Bousser MG (1994). "The myth of carotidynia.". Neurology. 44 (6): 993–5. doi:10.1212/wnl.44.6.993. PMID 8208434.Available here
- Lee TC, Swartz R, McEvilly R, Aviv RI, Fox AJ, Perry J, Symons SP. CTA, MR and MRA imaging of carotidynia: case report. Canadian Journal of Neurological Sciences. 2009 May; 36(3):373-375.
- Kuhn, J.; Harzheim, A.; Horz, R.; Bewermeyer, H. (2006). "MRI and ultrasonographic imaging of a patient with carotidynia". Cephalalgia. 26 (4): 483–485. doi:10.1111/j.1468-2982.2006.01053.x. PMID 16556251.
External links
- Family Practice notebook.com
- Blog assessing whether carotidynia is a valid medical diagnosis.
- Carotidynia condition page on PatientsLikeMe.
Case Rep Vasc Med. doi: 10.1155/2013/585789
Carotidynia Possibly due to Localized Vasculitis in a Patient with Latent Mycobacterium tuberculosis Infection.
Cassone G1, Colaci M1, Giuggioli D1, Manfredi A1, Sebastiani M1, Ferri C1.
Author information
1Chair and Rheumatology Unit, University of Modena and Reggio Emilia, Medical School, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Via del Pozzo 71, 41100 Modena, Italy.
Abstract
Carotidynia is a syndrome characterized by tenderness of the carotid artery near the bifurcation due to numerous, heterogeneous causes. Here we reported the case of a 31-year-old Moroccan woman with right-sided neck pain and tenderness with irradiation to ipsilateral ear, eye, and occipital region. Clinical symptoms and imaging findings were suggestive of primary variant of carotidynia syndrome. In particular, color-Doppler ultrasonography revealed a concentric wall thickening of the distal common carotid artery, while thoracic magnetic resonance showed localized perivascular enhancement of the soft tissue in the right medial-distal common carotid artery in T1-weighted images, without intraluminal diameter variation. Moreover, careful clinicoserological and imaging investigations (cranial, cervical, and thoracic angiocomputed tomography and magnetic resonance) excluded well-known disorders potentially responsible for carotidynia syndrome. The patient was scarcely responsive to nonsteroidal anti-inflammatory drugs, but clinical symptoms resolved after three months. Of interest, the patient showed latent Mycobacterium tuberculosis infection (positive tuberculosis interferon-gamma release assay; QuantiFERON-TB Gold); this finding suggested a possible triggering role of mycobacterial antigens in the immune-mediated mechanism responsible for localized carotid injury.
PMID: 24363952
J Stroke Cerebrovasc Dis. doi: 10.1016/j.jstrokecerebrovasdis.2012.10.011
Contralateral recurrence of carotidynia during steroid therapy.
Inatomi Y1, Nakajima M2, Yonehara T3, Hirano T4.
Author information
1Department of Neurology, Saiseikai Kumamoto Hospital, Kumamoto, Japan. Electronic address: y.inatomix@silk.ocn.ne.jp.
2Department of Neurology, Saiseikai Kumamoto Hospital, Kumamoto, Japan; Division of Neurology, University of British Columbia, Vancouver, British Columbia, Canada.
3Department of Neurology, Saiseikai Kumamoto Hospital, Kumamoto, Japan.
4Department of Internal Medicine III, Faculty of Medicine, Oita University, Oita, Japan.
Abstract
A 44-year-old woman presented with contralateral recurrence of carotidynia during steroid therapy at 1 month after onset. Carotidynia can present with a multiphasic clinical course and can affect the neck bilaterally. Therefore, patients with carotidynia should be observed even after remission.
Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Carotidynia; arteritis; carotid artery; magnetic resonance imaging; temporal arteritis; ultrasonography
PMID: 23253536
Wien Klin Wochenschr. doi: 10.1007/s00508-014-0633-2
A pain in the throat: a 19-year history of symptoms relating to the carotid artery.
Elkins A1, Barakate M, Henderson J, Grieve S.
Author information
1School of Medicine, The University of New South Wales, Sydney, NSW, Australia.
Abstract
A 38-year-old man presented with a 19-year history of sore throat and an ache radiating from the centre of the anterior neck to the both ears and the occiput. Computed tomography angiography revealed a tortuous submucosal right internal carotid artery, which was causing tonsillar displacement. The diagnosis of carotidynia has a controversial history within the literature and is currently not accepted as a distinct pathological entity by the International Headache Society. In this patient, the clinical and imaging features, in addition to the absence of any other pathology confers support to the diagnosis of carotidynia.
PMID: 25398291
Clin Imaging. 2015 Mar-Apr;39(2):305-7. doi: 10.1016/j.clinimag.2014.12.001
CT findings in a patient with bilateral metachronous carotidynia.
Young JY1, Hijaz TA2, Karagianis AG2.
Author information
1Northwestern Memorial Hospital, Department of Radiology, Neuroradiology Section, 251 East Huron Street, Chicago, IL, 60611. Electronic address: joseph.y.young@gmail.com.
2Northwestern Memorial Hospital, Department of Radiology, Neuroradiology Section, 251 East Huron Street, Chicago, IL, 60611.
Abstract
Carotidynia is a self-limiting, idiopathic clinical syndrome characterized by acute unilateral neck pain and tenderness of the carotid artery. We describe a unique case of bilateral carotidynia that occurred metachronously, with each incident resolving without long-term sequelae. Knowledge of this entity is important to properly interpret the imaging findings and to not mistake this finding as an ill-defined tumor, thus avoiding unnecessary biopsy.
Copyright © 2015 Elsevier Inc. All rights reserved.KEYWORDS:CT; Carotidynia; inflammation; neck; pain.PMID: 25575581
J Mal Vasc. 2015 Dec;40(6):395-8. doi: 10.1016/j.jmv.2015.06.001
Comparative evolution of carotidynia on ultrasound and magnetic resonance imaging.
Behar T1, Menjot N2, Laroche JP3, Böge B3, Quéré I3, Galanaud JP3.
Author information
1Clinical investigation center and department of internal medicine, hôpital de Montpellier, university hospital, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 05, France. Electronic address: t-behar@chu-montpellier.fr.
2Department of neuroradiology, university hospital, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 05, France.
3Clinical investigation center and department of internal medicine, hôpital de Montpellier, university hospital, 80, avenue Augustin-Fliche, 34295 Montpellier cedex 05, France.
Abstract
Carotidynia is rare and associates neck pain with tenderness to palpation usually over the carotid bifurcation, the diagnosis of which is based on magnetic resonance imaging (MRI). Ultrasounds (US) are also frequently used but their accuracy in predicting the course of the disease is unknown. We are reporting the case of a 52-year-old man who presented a typical carotidynia. Clinical symptoms, ultrasound and MRI imaging evolution were closely correlated. Our case suggest that after a first MRI to set a positive diagnosis of carotidynia and exclude differential diagnoses, US which is more widely available and less expensive could constitute the imaging of reference for the follow-up.
Copyright © 2015 Elsevier Masson SAS. All rights reserved.KEYWORDS:Carotidynia; Carotidynie; Follow-up; Imagerie par résonance magnétique; Magnetic resonance imaging; Suivi; Ultrasonography; Échographie.PMID: 26163344
Vasc Endovascular Surg. 2017 Apr;51(3):149-151. doi: 10.1177/1538574417697212.
Idiopathic Carotidynia.
Policha A1, Williams D2, Adelman M1, Veith F1, Cayne NS1.
Author information
1
1 Division of Vascular and Endovascular Surgery, New York University Langone Medical Center, New York, NY, USA.
2
2 Department of General Surgery, New York University Langone Medical Center, NY, USA.
Abstract
Idiopathic carotidynia is a syndrome characterized by pain and tenderness over the carotid artery without an associated structural luminal abnormality. Controversy exists over whether this is a distinct disease entity or merely a symptom attributable to other causes of neck pain, such as carotid dissection or vasculitis. A 50-year-old woman presented with sudden-onset right neck pain. Imaging studies demonstrated transmural inflammation of the proximal internal carotid artery, without evidence of intraluminal pathology. The patient was placed on low-dose aspirin and ibuprofen. Her symptoms resolved within a week. At 3-month follow-up, her carotid artery appeared normal on duplex ultrasonography.
KEYWORDS:
carotid artery; carotidynia; ultrasound
PMID: 2833043
AJNR Am J Neuroradiol. 2017 May 11. doi: 10.3174/ajnr.A5214
TIPIC Syndrome: Beyond the Myth of Carotidynia, a New Distinct Unclassified Entity.
Lecler A1, Obadia M2, Savatovsky J2, Picard H2, Charbonneau F2, Menjot de Champfleur N2, Naggara O2, Carsin B2, Amor-Sahli M2, Cottier JP2, Bensoussan J2, Auffray-Calvier E2, Varoquaux A2, De Gaalon S2, Calazel C2, Nasr N2, Volle G2, Jianu DC2, Gout O2, Bonneville F2, Sadik JC2.
Author information
1
From the Departments of Radiology (A.L., J.S., F.C., J.C.S.), and Neurology (M.O., G.V., O.G.), and Clinical Research Unit (H.P.), Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Department of Neuroradiology (N.M.d.C.), Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier, France; Department of Radiology (B.C.), Centre Hospitalier Régional Universitaire de Rennes, Rennes, France; Department of Neuroradiology (O.N.), Centre Hospitalier Sainte-Anne, Paris, France; Department of Neuroradiology (M.A.-S.), Pitié-Salpêtrière Hospital, Paris, France; Centre D'imagerie Médicale Tourville (M.A.-S.), Paris, France; Department of Radiology (J.P.C.), Centre Hospitalier Régional Universitaire de Tours, Tours, France; Brain and Imaging Laboratory Unite Mixte de Recherche U930 (J.P.C.), Institut National de la Santé et de la Recherche Médicale, François-Rabelais University, Tours, France; Diagnostic and Interventional Neuroradiology Department (E.A.-C.) and Neurology Department (S.D.G.), Hôpital René et Guillaume-Laënnec, Centre Hospitalier Universitaire de Nantes, Saint-Herblain, France; Department of Radiology (J.B.), Hotel-Dieu Hospital, Paris, France; Department of Radiology (A.V.), Conception Hospital, Aix-Marseille University, Marseille, France; Departments of Neuroradiology (C.C., F.B.) and Neurology (N.N.), Hôpital Pierre-Paul-Riquet, Centre Hospitalier Universitaire Purpan, Toulouse, France; and Department of Neurology (D.C.J.), Victor Babes University of Medicine and Pharmacy, Timisoara, Romania. alecler@for.paris.
2
From the Departments of Radiology (A.L., J.S., F.C., J.C.S.), and Neurology (M.O., G.V., O.G.), and Clinical Research Unit (H.P.), Fondation Ophtalmologique Adolphe de Rothschild, Paris, France; Department of Neuroradiology (N.M.d.C.), Montpellier University Hospital Center, Gui de Chauliac Hospital, Montpellier, France; Department of Radiology (B.C.), Centre Hospitalier Régional Universitaire de Rennes, Rennes, France; Department of Neuroradiology (O.N.), Centre Hospitalier Sainte-Anne, Paris, France; Department of Neuroradiology (M.A.-S.), Pitié-Salpêtrière Hospital, Paris, France; Centre D'imagerie Médicale Tourville (M.A.-S.), Paris, France; Department of Radiology (J.P.C.), Centre Hospitalier Régional Universitaire de Tours, Tours, France; Brain and Imaging Laboratory Unite Mixte de Recherche U930 (J.P.C.), Institut National de la Santé et de la Recherche Médicale, François-Rabelais University, Tours, France; Diagnostic and Interventional Neuroradiology Department (E.A.-C.) and Neurology Department (S.D.G.), Hôpital René et Guillaume-Laënnec, Centre Hospitalier Universitaire de Nantes, Saint-Herblain, France; Department of Radiology (J.B.), Hotel-Dieu Hospital, Paris, France; Department of Radiology (A.V.), Conception Hospital, Aix-Marseille University, Marseille, France; Departments of Neuroradiology (C.C., F.B.) and Neurology (N.N.), Hôpital Pierre-Paul-Riquet, Centre Hospitalier Universitaire Purpan, Toulouse, France; and Department of Neurology (D.C.J.), Victor Babes University of Medicine and Pharmacy, Timisoara, Romania.
Abstract
BACKGROUND AND PURPOSE:
The differential diagnosis of acute cervical pain includes nonvascular and vascular causes such as carotid dissection, carotid occlusion, or vasculitis. However, some patients present with unclassified vascular and perivascular changes on imaging previously reported as carotidynia. The aim of our study was to improve the description of this as yet unclassified clinico-radiologic entity.
MATERIALS AND METHODS:
From January 2009 through April 2016, 47 patients from 10 centers presenting with acute neck pain or tenderness and at least 1 cervical image showing unclassified carotid abnormalities were included. We conducted a systematic, retrospective study of their medical charts and diagnostic and follow-up imaging. Two neuroradiologists independently analyzed the blinded image datasets.
RESULTS:
The median patient age was 48 years. All patients presented with acute neck pain, and 8 presented with transient neurologic symptoms. Imaging showed an eccentric pericarotidian infiltration in all patients. An intimal soft plaque was noted in 16 patients, and a mild luminal narrowing was noted in 16 patients. Interreader reproducibility was excellent. All patients had complete pain resolution within a median of 13 days. At 3-month follow-up, imaging showed complete disappearance of vascular abnormalities in 8 patients, and a marked decrease in all others.
CONCLUSIONS:
Our study improved the description of an unclassified, clinico-radiologic entity, which could be described by the proposed acronym: TransIent Perivascular Inflammation of the Carotid artery (TIPIC) syndrome.
© 2017 American Society of Neuroradiology.
PMID: 28495942 DOI: 10.3174/ajnr.A5214
Cleveland Clinic Journal of Medicine.
LEONARD L. LOVSHIN, M.D.
Department of Internal Medicine
Abstract
A YOUNG or middle-aged women reported to her physician because of a sore throat, without fever or other constitutional manifestations, which may have been present for weeks or months. The patient believes that the glands in the neck are swollen. These "swollen glands" are said to act strangely: sometimes the swelling lasts only a few hours, sometimes it persists for weeks; it disappears mysteriously and recurs frequently. During the course of the physical examination the physician finds no abnormality, but when he re-examines the neck and follows the directions given by the patient, he finds a tender swelling that could be an inflamed lymph node.
The patient then is treated with a sulfonamide or with penicillin, and, when no relief ensues, a course of one of the broad-spectrum antibiotics is administered. This therapeutic program also is unsuccessful, and the harried physician begins to think of other possibilities. Since the patient has "swollen glands," feels weak, tired, and run-down, and antimicrobial therapy has not helped, a diagnosis of infectious mononucleosis may be considered. But, results of a heterophil antibody test are negative, and the diagnosis is changed to possible viral infection.
After several weeks or months of having diagnoses changed, the nervous patient can sense that her physician is uncertain, and she begins to worry about the looming possibility of cancer. She keeps poking in the region of the soreness, and the area becomes even more tender. In desperation, further investigations are carried out and nothing definitely abnormal is found. Teeth . . .
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Δευτέρα 29 Μαΐου 2017
Giant cell tumor in the sphenoid sinus and ethmoid sinus during childhood, and it is thought that optic atrophy was caused by compressive optic neuropathy.
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Ειδοποίηση Μελετητή - [ "κλιματική αλλαγή" ]
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Ανθρακικό Αποτύπωμα Προϊόντος: η περίπτωση των παραγόμενων αζωτούχων λιπασμάτων
Α Λυκουρέζου - 2017
... Keywords: Ανθρακικό αποτύπωμα προϊόντος - product carbon footprint;υπολογισμός ανθρακικού
αποτυπώματος - calculation of carbon footprint;αζωτούχα λιπάσματα - nitrogen fertilizers;κλιματική
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προάσπιση των ανθρώπινων δικαιωµάτων , στην κλιµατική αλλαγή αλλά και στην προστασία
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Page 1. ΤΜΗΜΑ ΑΞΙΟΠΟΙΗΣΗΣ ΦΥΣΙΚΩΝ ΠΟΡΩΝ & ΓΕΩΡΓΙΚΗΣ ΜΗΧΑΝΙΚΗΣ ΜΕΤΑΠΤΥΧΙΑΚΟ
ΠΡΟΓΡΑΜΜΑ ΣΠΟΥΔΩΝ ΕΙΔΙΚΕΥΣΗ: ΔΙΑΧΕΙΡΙΣΗ ΠΕΡΙΒΑΛΛΟΝΤΟΣ ΜΕΤΑΠΤΥΧΙΑΚΗ ΔΙΑΤΡΙΒΗ
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ΠΡΟΓΡΑΜΜΑ ΣΠΟΥΔΩΝ ΕΙΔΙΚΕΥΣΗ: ΔΙΑΧΕΙΡΙΣΗ ΠΕΡΙΒΑΛΛΟΝΤΟΣ ΜΕΤΑΠΤΥΧΙΑΚΗ ΔΙΑΤΡΙΒΗ
Σχεδίαση, κατασκευή και λειτουργία πρότυπης εγκατάστασης παραγωγής ...
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... Μερικές φορές φαίνονται µικρές οι συνέπειες , αλλά στην ουσία έχει δηµιουργηθεί ... Αυτό
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Ι Δέβρελης - 2017
... Οι απαντήσεις που περνούμε στο πρόβλημα για την επίλυση περιβαλλοντικών προβλημάτων
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Page 1. ΤΕΧΝΟΛΟΓΙΚΟ ΕΚΠΑΙΔΕΥΤΙΚΟ ΙΔΡΥΜΑ ΚΡΗΤΗΣ ΣΧΟΛΗ ΔΙΟΙΚΗΣΗΣ ΚΑΙ
ΟΙΚΟΝΟΜΙΑΣ ΤΜΗΜΑ ΔΙΟΙΚΗΣΗΣ ΕΠΙΧΕΙΡΗΣΕΩΝ ΑΓΙΟΥ ΝΙΚΟΛΑΟΥ Μελέτη της
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Κυριακή 28 Μαΐου 2017
Sometimes pain originating from a non-odontogenic pathologic condition is mistaken as endodontic illness, leading to misdiagnosis.
http://otorhinolaryngology-crete.blogspot.com/2017/05/adenoid-cystic-carcinoma-of-maxillary.html
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Subclinical hypothyroidism (SCH) has been associated with atherosclerosis and increased risk of ischemic stroke.
http://otorhinolaryngology-crete.blogspot.com/2017/05/subclinical-hypothyroidism-and-risk-of.html
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
Παρασκευή 26 Μαΐου 2017
Ειδοποίηση Μελετητή - [ "Ατμοσφαιρική ρύπανση" : επιπτώσεις στην υγεία ]
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Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks
http://pubmedsfakianakis.blogspot.com/2017/05/antibiotic-use-in-pregnancy-and.html
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
leven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting prote
Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182
6948891480
alsfakia@gmail.com
Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD , CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmaco- kinetics of drugs, there is the concern of possible terato- genic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacoki- netic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breast- feeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- cluded. TABULATION, INTEGRATION, AND RESULTS: The ter- atogenic potential in humans ranged from "none" (pen- icillin G and VK) to "unlikely" (amoxicillin, chloramphen- icol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chlor- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant phar- macokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeed- ing. CONCLUSION: Health care professionals should con- sider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially impor- tant if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women. 1 More than 10 million women are either pregnant or lactating in the United States at any one time, and they are administered antibiotics for many reasons. 2 Because of the special consider- ations associated with fetal and newborn develop- ment, these women constitute a uniquely vulnerable population for which the risks of medication use must be separately assessed. In addition to the pharmacokinetic and pharma- codynamic changes that may occur during pregnancy and lactation that can alter the effectiveness of drugs, 3 there is the added concern of the possible teratogenic and toxic effects that medications may have on the developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic information regarding the use and proper dosing of Food and Drug Administration (FDA)–approved From the Department of Obstetrics and Gynecology, Uniformed Services Uni- versity of the Health Sciences, Bethesda, Maryland; Office of Women's Health, U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. The views, opinions, interpretations, and conclusions expressed in this article are those of the authors only and do not reflect either the policies or positions of the Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- tration, or the U.S. Department of Health and Human Services. Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as limited data pertaining to the teratogenic potential and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must sometimes be assembled from diverse sources to address these issues. Recently, the threat of bioterrorism has expanded the context in which the potential use of antibiotic medications may be needed. 4 Although the possibility of a large-scale bioterrorist attack in the United States is unlikely, the potential for widespread antibiotic use in this situation emphasizes the need for health care professionals to be familiar with the risks and benefits of administering antibiotics to pregnant and lactating women. This article reviews the available information concerning the risks and special circumstances to be considered in pregnant and lactating women for a group of 11 broad-spectrum antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, clindamycin, doxy- cycline, gentamicin, levofloxacin, penicillin G, peni- cillin VK, rifampin, and vancomycin). By using this information, better choices can be made for the treatment of different types of bacterial pathogens in these particularly vulnerable populations. DATA SOURCES AND METHODS OF STUDY SELECTION Information from FDA-approved product labels, the Teratogen Information Service, Shepard's Catalog of Teratogenic Agents, REPROTOX, Clinical Pharma- cology, and the peer-reviewed literature were re- viewed for information concerning the use of 11 antibiotics in pregnant and lactating women. The medical literature was queried with the PubMed search engine. Papers searched were published from January 1940 to November 2005, in any language. The search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation,", and "[antibiotic name] and breastfeeding," were used, as was standard reference tracing. A total of 124 references were accessed through these sources that contained suffi- cient information concerning the numbers of subjects, methods of investigation, and findings to be useful for the purpose of drawing conclusions concerning phar- macokinetic parameters, teratogenic potential, and toxicity assessments of these drugs. All materials were restricted to information from nonproprietary sources that were available in the public domain. Addition- ally, information concerning the potential treatment options for exposures and diseases caused by possible agents of bioterrorism were obtained from materials published by the Centers for Disease Control and Prevention in Atlanta. RESULTS A description of the 11 broad-spectrum antibiotics and their general modes of action are provided in Table 1. All 11 antibiotics cross the placenta and enter the fetal compartment. For 5 of these, human umbilical cord blood levels are of the same order of magnitude as circulating maternal blood concentrations (chlor- amphenicol, clindamycin, gentamicin, rifampin, and vancomycin). For 4, the concentrations are of the same magnitude or higher in amniotic fluid as in maternal blood (ciprofloxacin, clindamycin, levo- floxacin, and vancomycin) (Table 2). All 11 antibiotics are excreted in human breast milk. Limited information concerning the amount in breast milk was available for 8 antibiotics (ciprofloxa- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). No quantitative data concerning breast milk concentra- tions were available for 3 (amoxicillin, chloramphen- icol, and vancomycin) (Table 2). Using the Teratogen Information Service clas- sification system for teratogenic risk, 44 the terato- genic potential of the 11 antibiotics during human pregnancy ranged from "none" in 2 cases (penicil- lin G and VK) to "unlikely" in 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "undetermined" in 3 (clindamycin, gentamicin, and vancomycin). As- sessments were based on data that were "good" for 2 (penicillin G and VK) to "fair" for 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "limited" for 2 (clinda- mycin and gentamicin) to "very limited" for 1 (vancomycin). A summary of the human and ani- mal data contributing to these assessments is shown in Table 3. The Food and Drug Administration Pregnancy Category classifications for the 11 anti- biotics (as defined under 21 CFR [Code of Federal Regulations] 201.57 for the A, B, C, D, X Preg- nancy Category system) (Table 4) were "B" in 5 cases (amoxicillin, clindamycin, penicillin G, peni- cillin VK, and vancomycin), "C" in 5 cases (chlor- amphenicol, ciprofloxacin, gentamicin, levofloxa- cin, and rifampin), and "D" in 1 case (doxycycline) (Table 3). In addition to the published literature, proprietary data were used to establish the FDA pregnancy category for these drugs. Despite numerous concerns regarding the poten- tial for maternal and fetal or neonatal toxicity of these VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121 11 drugs—including idiosyncratic and dose-related bone marrow suppression with chloramphenicol, ar- thropathies and bone and cartilage damage with ciprofloxacin and levofloxacin, dental staining and hepatic necrosis with doxycycline, and ototoxicity and nephrotoxicity with gentamicin and vancomy- cin—none of these toxicities has been documented in human mothers or offspring either during preg- nancy or breastfeeding with these antibiotics (Table 3). Very limited information was available pertain- ing to maternal pharmacokinetics in pregnancy for 8 antibiotics (amoxicillin, ciprofloxacin, clindamycin, gentamicin, levofloxacin, penicillin G, penicillin VK, and vancomycin), and none was available for 3 (chloramphenicol, doxycycline, and rifampin) (Table 2). For 4 antibiotics (amoxicillin, gentamicin, penicil- lin G, and penicillin VK), lower circulating drug concentrations were measured in pregnant women than nonpregnant, suggesting that a shorter dosing interval or increased maternal dose or both may be necessary to obtain similar circulating drug concen- trations as for women in the nonpregnant state. In the case of ciprofloxacin and levofloxacin, circulating concentrations were generally reduced in pregnant women, also suggesting that an increased maternal dose or a shorter dosing interval or both may be necessary. In 3 cases (chloramphenicol, gentamicin, and vancomycin), therapeutic drug monitoring of serum peak and trough levels is recommended to assess circulating drug levels. In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). Very little pharma- Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis. 1967 Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis. 1966 Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases. 1996 Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1943 Penicillin V (phenoxymethyl penicillin) Naturally derived beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. Considered preferable to penicillin G for oral administration because of its superior gastric acid stability. 1956 Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers. 1971 Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare. 1964 FDA, U.S. Food and Drug Administration. 1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Amoxicillin Gram-positive aerobes, most gram-positive anaerobes, gram- negative aerobes including some enteric bacilli, Helicobacter, spirochetes, actinomyces* Crosses the human placenta. 5–7 Penicillins transferred to the fetus and amniotic fluid reach therapeutic levels. 5 Excreted in human breast milk in small amounts. 8 Considered "usually compatible with breastfeeding." 9† Following therapeutic doses, mean human milk concentrations were 0.1–0.6 g/mL. 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Chloramphenicol Gram positives, gram negatives, anaerobes, chlamydia, rickettsiae Crosses the human placenta readily. Umbilical cord serum concentrations 29–106% of maternal levels. 12 Excreted in human breast milk. 13–15 In 5 patients with minor obstetrical lacerations who receive d1gPOqDfor8 days, mean milk concentrations were 0.5–2.8 g/mL. In 5 patients receivin g2gPOqDfor8 days for mastitis, mean milk concentrations were 1.8–6.1 g/mL. 13 Human milk concentrations are 51–62% of blood levels. 14 Percentage of administered dose in human breast milk per day is 1.3%. 15 Effect on breastfed infants considered "unknown but may be of concern." 16 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Serum concentrations can be monitored to keep peak and trough levels in the ranges of 10–20 and 5–10 g/mL, respectively. CBC monitored to detect bone marrow depression. Ciprofloxacin Gram-negative aerobes, some staphylococci Crosses the human placenta and concentrates in amniotic fluid (Product information Cipro, 2001). 17 In 20 women at 19–25 weeks of gestation who received two 200-mg IV doses q 12 hours, the mean amniotic fluid level 2–4 hours after dosing was 0.12 0.06 g/mL (n 7; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.57), 0.13 0.07 g/mL at 6–8 hours (n 7; AF:MS ratio 1.44), and 0.10 0.04 g/mL at 10–12 hours (n 6; AF: MS ratio 10.00). 17 Excreted in human breast milk (Product information Cipro, 2001). 17 Considered usually compatible with breastfeeding." 9† In 10 women given 750 mg q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 3.79 1.26, 2.26 0.75, 0.86 0.27, 0.51 0.18, 0.20 0.05, and 0.02 0.006 g/mL at these times and the ratios of breast milk: serum concentration were 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, respectively. 17 For breastfeeding infants consuming 150 mL/kg per day, the estimated maximum dose is 0.569 mg/kg per day or 2.8% the approved dose for infants of 20 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding ciprofloxacin in pregnant women. 19 It is unknown whether dose adjustments during pregnancy are necessary. Approximately 50–70% of a dose is excreted in the urine and, if renal function is impaired, the serum half- life is slightly prolonged (Product information Cipro, 2001). ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Clindamycin Gram-positive anaerobes, gram- negative anaerobes, aerobic gram-positive cocci, streptococci, Clostridia strains Crosses the human placenta readily. 44,20–23 In 54 women undergoing cesarean delivery who received 600 mg IV 30 minutes before surgery, umbilical cord blood concentrations were 46% of maternal serum levels. 20 After multiple oral doses prior to therapeutic abortion, fetal blood concentrations were 25% and amniotic fluid levels were 30% of maternal blood levels. 21 Excreted in human breast milk (Product information Clindamycin, 1970). Considered "usually compatible with breastfeeding." 9† At maternal doses of 150 mg orally to 600 mg IV, breast milk concentrations range from 0.7 to 3.8 g/mL (Product information Clindamycin, 1970). Pharmacokinetic parameters do not change during pregnancy in women studied during the 1st, 2nd, and 3rd trimesters of gestation. 20,24 There are no studies to indicate that dosing should be modified during pregnancy. C max and T max (after a single standard dose) and C ss (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- negatives, rickettsiae, chlamydiae, mycoplasma, spirochetes, actinomyces Crosses the placenta (Product information Vibramycin, 2001). Excreted in human breast milk. 25 Use for a short period (1 week) during breastfeeding is considered probably safe. 9,16 Breast milk concentrations are 30–40% of that found in maternal blood. 25 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic rods, many streptococci, Staphylococcus aureus , mycobacteria Crosses the human placenta. 20,26–28 In 2 different studies, peak umbilical cord blood levels were 34% 26 and 42% 20 of associated maternal blood concentrations. Excreted in human breast milk. 29,30 Considered "usually compatible with breastfeeding." 9† Poorly absorbed from the GI tract. 29 Only half of nursing newborns had detectable serum levels, which were low and not likely to cause clinical effects. 29 No adverse signs or symptoms in nursing infants as a result of maternal treatment. 9 Increased dosage suggested due to decreased serum half-life in pregnancy and lower maternal serum levels. 20,31 In 54 women undergoing cesarean delivery, levels were lower than nonpregnant women. 20 Eliminated mainly by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients. 32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). ( continued ) 1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Levofloxacin Gram-positives and gram-negatives Crosses the human placenta and concentrates in amniotic fluid (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 In 20 women at 19–25 weeks of gestation receiving two IV 400-mg doses of ofloxacin q12 hours, mean amniotic fluid concentration 3–6 hours after dosing was 0.25 0.11 g/mL (n 6; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.35), 0.15 0.11 g/mL at 6–10 hours (n 8; AF:MS ratio 0.67), and 0.13 0.11 g/mL at 11–12 hours (n 6; AF:MS ratio 2.57). 17 Excreted in human breast milk in high concentrations (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 Considered "usually compatible with breastfeeding." 9† In 10 women given 400 mg of ofloxacin q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 2.41 0.80, 1.91 0.64, 1.25 0.42, 0.64 0.21, 0.29 0.10, and 0.05 0.02 g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively. 17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding levofloxacin in pregnant women. 19 There are no data to support dosing adjustments during pregnancy. Penicillin G Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, spirochetes, actinomyces, some gram negatives* Crosses the human placenta. 5,33,34 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Bicillin, 2001; product information Penicillin V, 1997). 15 Considered "usually compatible with breastfeeding." 9† In women with serum concentrations of penicillin ranging from 6 to 120 g/dL, corresponding breast milk concentrations were 1.2–3.6 g/dL, and the amount of the maternal dose appearing in breast milk per day was estimated at 0.03%. 15 Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, gram negatives Crosses the human placenta readily. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Penicillin V, 1997). 15,36 Considered "usually compatible with breastfeeding." 9† In 18 women, penicillin V milk concentration depended on presence of mastitis, with peak levels 2.6–5.4 hours after a single PO 1,320-mg dose. 35 Peak concentration was 30–72 g/dL with mean concentration 26-37 g/dL. AUC over 8 hours after dosing was 2.1–3.0 mg-h/L. 35 Estimated dose of penicillin V ingested per day by breastfed infants is 40–60 g/kg, or 0.09– 0.14% of maternal dose per kg body weight. 35 Shorter dosing interval and/or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillin V is excreted renally, primarily via tubular secretion. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Rifampin Mycobacteria, Neisseria meningitidis , S aureus , Haemophilus influenzae , Legionella pneumophila , Chlamydia Crosses the human placenta (Product information Rifampin, 1971). 37–39 Umbilical cord concentrations between 12% and 33% of maternal blood levels, with peak levels occurring concurrently after drug administration. 37–39 Excreted in human breast milk (Product information Rifampin, 1971). 15,40,41 Considered "usually compatible with breastfeeding." 9† After a single oral dose of 600 mg, a nursing infant would ingest approximately 0.05% of the maternal dose per day, or approximately 0.3 mg/day. 15,40,41 Unknown whether dosing adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Hepatically deacetylated to active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR. 38 Vancomycin Gram positives, S aureus , Staphylococcus epidermidis , streptococci, enterococci, Clostridium , Coryne- bacterium Crosses the human placenta (Product information Vancomycin, 1964). 42,43 Appears in umbilical cord blood after IV maternal treatment (Product information Vancomycin, 1964). 42,43 Amniotic fluid and umbilical cord blood concentrations during the early 3rd trimester comparable to maternal blood levels (fetal-maternal serum concentration ratio of 0.76). 43 Excreted in human breast milk when administered IV (Product information Vancomycin, 1964). 42 When administered orally, vancomycin is poorly absorbed from the GI tract (Product information Vancomycin, 1964). It is, therefore, not likely to cause adverse effects in nursing infants. There are no studies to indicate that vancomycin dosing should be modified during pregnancy. Volume of distribution and plasma clearance both increased, but half-life similar to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy. 43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate . * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some sp ecies of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics. 1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Antibiotic Human Data: Teratogenic and Toxic Effects Animal Data: Teratogenic and Toxic Fetal Effects Magnitude of Human Teratogenic Fetal Risk (Based on TERIS Assessment) 44 FDA Pregnancy Category* Amoxicillin OR for major congenital anomalies 1.4 (95% CI 0.9–2.0) for women using amoxicillin clavulanic acid during pregnancy in a case-control study of 6,935 malformed infants (no increased risk). 45 OR (adjusted) for congenital anomalies 1.16 (95% CI 0.54– 2.50) in a Danish study (1991–2000) of 401 primiparous women who filled prescriptions for amoxicillin during pregnancy (rate 4.0%) compared with 10,237 controls who did not redeem any prescription drug (rate 4.1%). 46 No increased rate of congenital malformations among 147 women who received prescriptions for amoxicillin during the 1st trimester. 46 No increased rate of congenital anomalies among 284 infants whose mothers were administered amoxicillin or ampicillin during the 1st trimester, or in 1,060 infants whose mothers were treated at any time during pregnancy. 47 No significantly increased rate of major or minor anomalies in the children of 14 women treated with amoxicillin and probenecid during the first 14 weeks of gestation or among 57 women treated after the 14th week in a controlled clinical trial on the treatment of gonorrhea during pregnancy. 48 No adverse effects in offspring exposed to amoxicillin during the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes. 49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment during the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients. 52,53 No increased congenital malformations in mice treated with 3–7 times the maximum human therapeutic dose of amoxicillin. 54 No adverse reproductive effects in rats given amoxicillin- clavulanic acid at doses of 400 and 1,200 mg/day prior to fertilization and during the first 7 days of gestation (Product information Amoxil, 2001). 55 No adverse fetal effects in pigs given amoxicillin with clavulanic acid at doses of 600 mg/kg on days 12–42. 56 Increased frequency of embryonic death in mice treated with amoxicillin at 6–7 times the maximum therapeutic human dose. 54 Increased risk of teratogenicity is "unlikely," based on "fair" data. B Chloramphenicol OR for major congenital anomalies 1.7 (95% CI 1.2–2.6) for oral administration at any time during pregnancy in a case- control study of 22,865 malformed infants (risk marginally increased). 57 RR for congenital malformations 1.19 (95% CI 0.52–2.31) in 348 offspring born to women who took chloramphenicol at any time during pregnancy (no statistically increased risk). 58 Potential for both dose-related and idiosyncratic bone marrow toxicity. Caution should be used near term, during labor, and while breastfeeding due to the possibility of inducing "gray-baby" syndrome. 59 No increased congenital anomalies in monkeys. 60 No teratogenicity in mice or rabbits at 10–40 times the recommended human dose. 61 No teratogenicity in rats at 2–4 times the usual human dose, 62 but various fetal anomalies at 10–40 times the human dose. 61,63 Increased fetal death and decreased fetal weight in mice, rats, and rabbits. 61–63 Increased risk of teratogenicity is "unlikely," based on "fair" data. "Therapeutic doses of chloramphenicol are unlikely to pose a substantial teratogenic risk." C ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127
https://pdfs.semanticscholar.org/6dc9/a1ef535442351b406ebcfce85c43f66fec03.pdf
Reviews Antibiotic Use in Pregnancy and Lactation What Is and Is Not Known About Teratogenic and Toxic Risks Gerard G. Nahum, MD , CAPT Kathleen Uhl, USPHS, and CAPT Dianne L. Kennedy, USPHS OBJECTIVE: Over ten million women are either pregnant or lactating in the United States at any time. The risks of medication use for these women are unique. In addition to normal physiologic changes that alter the pharmaco- kinetics of drugs, there is the concern of possible terato- genic and toxic effects on the developing fetus and newborn. This article reviews the risks and pharmacoki- netic considerations for 11 broad-spectrum antibiotics that can be used to treat routine and life-threatening infections during pregnancy and lactation. DATA SOURCES: Information from the U.S. Food and Drug Administration (FDA) product labels, the Teratogen Information Service, REPROTOX, Shepard's Catalog of Teratogenic Agents, Clinical Pharmacology, and the peer- reviewed medical literature was reviewed concerning the use of 11 antibiotics in pregnant and lactating women. The PubMed search engine was used with the search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation," and "[antibiotic name] and breast- feeding" from January 1940 to November 2005, as well as standard reference tracing. METHODS OF STUDY SELECTION: One hundred twen- ty-four references had sufficient information concerning numbers of subjects, methods, and findings to be in- cluded. TABULATION, INTEGRATION, AND RESULTS: The ter- atogenic potential in humans ranged from "none" (pen- icillin G and VK) to "unlikely" (amoxicillin, chloramphen- icol, ciprofloxacin, doxycycline, levofloxacin, and rifampin) to "undetermined" (clindamycin, gentamicin, and vancomycin). Assessments were based on "good data" (penicillin G and VK), "fair data" (amoxicillin, chlor- amphenicol, ciprofloxacin, doxycycline, levofloxacin, and rifampin), "limited data" (clindamycin and gentamicin), and "very limited data" (vancomycin). Significant phar- macokinetic changes occurred during pregnancy for the penicillins, fluoroquinolones and gentamicin, indicating that dosage adjustments for these drugs may be neces- sary. With the exception of chloramphenicol, all of these antibiotics are considered compatible with breastfeed- ing. CONCLUSION: Health care professionals should con- sider the teratogenic and toxic risk profiles of antibiotics to assist in making prescribing decisions for pregnant and lactating women. These may become especially impor- tant if anti-infective countermeasures are required to protect the health, safety, and survival of individuals exposed to pathogenic bacteriologic agents that may occur from bioterrorist acts. (Obstet Gynecol 2006;107:1120–38) A ntibiotics are among the most commonly pre- scribed prescription medications for pregnant and lactating women. 1 More than 10 million women are either pregnant or lactating in the United States at any one time, and they are administered antibiotics for many reasons. 2 Because of the special consider- ations associated with fetal and newborn develop- ment, these women constitute a uniquely vulnerable population for which the risks of medication use must be separately assessed. In addition to the pharmacokinetic and pharma- codynamic changes that may occur during pregnancy and lactation that can alter the effectiveness of drugs, 3 there is the added concern of the possible teratogenic and toxic effects that medications may have on the developing fetus and newborn. In general, there is a dearth of pharmacokinetic and pharmacodynamic information regarding the use and proper dosing of Food and Drug Administration (FDA)–approved From the Department of Obstetrics and Gynecology, Uniformed Services Uni- versity of the Health Sciences, Bethesda, Maryland; Office of Women's Health, U.S. Food and Drug Administration, Rockville, Maryland; FDA Center for Drug Evaluation and Research, Silver Spring, Maryland. Presented in part at the FDA Science Forum in Washington, DC, April 27–28, 2005. The views, opinions, interpretations, and conclusions expressed in this article are those of the authors only and do not reflect either the policies or positions of the Center for Drug Evaluation and Research, the U.S. Food and Drug Adminis- tration, or the U.S. Department of Health and Human Services. Corresponding author: Gerard G. Nahum, MD, FACOG, FACS, Box 2184, Rockville, MD 20847; e-mail: GNahum2003@yahoo.com. © 2006 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/06 1120 VOL. 107, NO. 5, MAY 2006 OBSTETRICS & GYNECOLOGY drugs in pregnant and lactating women, as well as limited data pertaining to the teratogenic potential and the fetal or neonatal toxicity of these marketed medications. Accordingly, sparse information must sometimes be assembled from diverse sources to address these issues. Recently, the threat of bioterrorism has expanded the context in which the potential use of antibiotic medications may be needed. 4 Although the possibility of a large-scale bioterrorist attack in the United States is unlikely, the potential for widespread antibiotic use in this situation emphasizes the need for health care professionals to be familiar with the risks and benefits of administering antibiotics to pregnant and lactating women. This article reviews the available information concerning the risks and special circumstances to be considered in pregnant and lactating women for a group of 11 broad-spectrum antibiotics (amoxicillin, chloramphenicol, ciprofloxacin, clindamycin, doxy- cycline, gentamicin, levofloxacin, penicillin G, peni- cillin VK, rifampin, and vancomycin). By using this information, better choices can be made for the treatment of different types of bacterial pathogens in these particularly vulnerable populations. DATA SOURCES AND METHODS OF STUDY SELECTION Information from FDA-approved product labels, the Teratogen Information Service, Shepard's Catalog of Teratogenic Agents, REPROTOX, Clinical Pharma- cology, and the peer-reviewed literature were re- viewed for information concerning the use of 11 antibiotics in pregnant and lactating women. The medical literature was queried with the PubMed search engine. Papers searched were published from January 1940 to November 2005, in any language. The search terms "[antibiotic name] and pregnancy," "[antibiotic name] and lactation,", and "[antibiotic name] and breastfeeding," were used, as was standard reference tracing. A total of 124 references were accessed through these sources that contained suffi- cient information concerning the numbers of subjects, methods of investigation, and findings to be useful for the purpose of drawing conclusions concerning phar- macokinetic parameters, teratogenic potential, and toxicity assessments of these drugs. All materials were restricted to information from nonproprietary sources that were available in the public domain. Addition- ally, information concerning the potential treatment options for exposures and diseases caused by possible agents of bioterrorism were obtained from materials published by the Centers for Disease Control and Prevention in Atlanta. RESULTS A description of the 11 broad-spectrum antibiotics and their general modes of action are provided in Table 1. All 11 antibiotics cross the placenta and enter the fetal compartment. For 5 of these, human umbilical cord blood levels are of the same order of magnitude as circulating maternal blood concentrations (chlor- amphenicol, clindamycin, gentamicin, rifampin, and vancomycin). For 4, the concentrations are of the same magnitude or higher in amniotic fluid as in maternal blood (ciprofloxacin, clindamycin, levo- floxacin, and vancomycin) (Table 2). All 11 antibiotics are excreted in human breast milk. Limited information concerning the amount in breast milk was available for 8 antibiotics (ciprofloxa- cin, clindamycin, doxycycline, gentamicin, levofloxa- cin, penicillin G, penicillin VK, and rifampin). No quantitative data concerning breast milk concentra- tions were available for 3 (amoxicillin, chloramphen- icol, and vancomycin) (Table 2). Using the Teratogen Information Service clas- sification system for teratogenic risk, 44 the terato- genic potential of the 11 antibiotics during human pregnancy ranged from "none" in 2 cases (penicil- lin G and VK) to "unlikely" in 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "undetermined" in 3 (clindamycin, gentamicin, and vancomycin). As- sessments were based on data that were "good" for 2 (penicillin G and VK) to "fair" for 6 (amoxicillin, chloramphenicol, ciprofloxacin, doxycycline, levo- floxacin, and rifampin) to "limited" for 2 (clinda- mycin and gentamicin) to "very limited" for 1 (vancomycin). A summary of the human and ani- mal data contributing to these assessments is shown in Table 3. The Food and Drug Administration Pregnancy Category classifications for the 11 anti- biotics (as defined under 21 CFR [Code of Federal Regulations] 201.57 for the A, B, C, D, X Preg- nancy Category system) (Table 4) were "B" in 5 cases (amoxicillin, clindamycin, penicillin G, peni- cillin VK, and vancomycin), "C" in 5 cases (chlor- amphenicol, ciprofloxacin, gentamicin, levofloxa- cin, and rifampin), and "D" in 1 case (doxycycline) (Table 3). In addition to the published literature, proprietary data were used to establish the FDA pregnancy category for these drugs. Despite numerous concerns regarding the poten- tial for maternal and fetal or neonatal toxicity of these VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1121 11 drugs—including idiosyncratic and dose-related bone marrow suppression with chloramphenicol, ar- thropathies and bone and cartilage damage with ciprofloxacin and levofloxacin, dental staining and hepatic necrosis with doxycycline, and ototoxicity and nephrotoxicity with gentamicin and vancomy- cin—none of these toxicities has been documented in human mothers or offspring either during preg- nancy or breastfeeding with these antibiotics (Table 3). Very limited information was available pertain- ing to maternal pharmacokinetics in pregnancy for 8 antibiotics (amoxicillin, ciprofloxacin, clindamycin, gentamicin, levofloxacin, penicillin G, penicillin VK, and vancomycin), and none was available for 3 (chloramphenicol, doxycycline, and rifampin) (Table 2). For 4 antibiotics (amoxicillin, gentamicin, penicil- lin G, and penicillin VK), lower circulating drug concentrations were measured in pregnant women than nonpregnant, suggesting that a shorter dosing interval or increased maternal dose or both may be necessary to obtain similar circulating drug concen- trations as for women in the nonpregnant state. In the case of ciprofloxacin and levofloxacin, circulating concentrations were generally reduced in pregnant women, also suggesting that an increased maternal dose or a shorter dosing interval or both may be necessary. In 3 cases (chloramphenicol, gentamicin, and vancomycin), therapeutic drug monitoring of serum peak and trough levels is recommended to assess circulating drug levels. In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). Very little pharma- Table 1. Description of the Eleven Broad-Spectrum Antibiotics Investigated Antibiotic Description Year of Initial FDA Approval Amoxicillin Semi-synthetic beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1974 Chloramphenicol Broad-spectrum antibiotic isolated from Streptomyces venezuela in 1947, now synthetically available. Binds to the 50S subunit of bacterial ribosomes, inhibiting peptide bond formation and protein synthesis. 1950 Ciprofloxacin Fluoroquinolone antibiotic. Exerts its bactericidal effect by disrupting DNA replication, transcription, recombination, and repair by inhibiting bacterial DNA gyrase. 1987 Clindamycin Antibiotic derived from lincomycin that has wide-ranging antimicrobial activity. Binds to the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis. 1970 Doxycycline Broad-spectrum antibiotic that binds to the 30S bacterial ribosomal subunit. Blocks the binding of transfer-RNA to messenger-RNA, thereby disrupting protein synthesis. 1967 Gentamicin Aminoglycoside antibiotic with broad-spectrum activity. Binds irreversibly to 30S bacterial ribosomal subunit, thereby inhibiting protein synthesis. 1966 Levofloxacin Fluoroquinolone antibiotic. L-isomer of ofloxacin, which provides its principal antibiotic effect. Inhibits bacterial DNA replication, transcription, recombination, and repair by inhibiting bacterial type II topoisomerases. 1996 Penicillin G Beta-lactam antibiotic that is primarily bactericidal. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. 1943 Penicillin V (phenoxymethyl penicillin) Naturally derived beta-lactam antibiotic. Inhibits the final stage of bacterial cell wall synthesis, leading to cell lysis. Considered preferable to penicillin G for oral administration because of its superior gastric acid stability. 1956 Rifampin Rifamycin B derivative that inhibits bacterial and mycobacterial DNA-dependent RNA polymerase activity. Used primarily for the treatment of tuberculosis, with additional utility for the treatment of both leprosy and meningococcal carriers. 1971 Vancomycin Glycopolypeptide antibiotic. Binds to the precursor units of bacterial cell walls, inhibiting their synthesis and altering cell wall permeability while also inhibiting RNA synthesis. Because of its dual mechanism of action, bacterial resistance is rare. 1964 FDA, U.S. Food and Drug Administration. 1122 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Amoxicillin Gram-positive aerobes, most gram-positive anaerobes, gram- negative aerobes including some enteric bacilli, Helicobacter, spirochetes, actinomyces* Crosses the human placenta. 5–7 Penicillins transferred to the fetus and amniotic fluid reach therapeutic levels. 5 Excreted in human breast milk in small amounts. 8 Considered "usually compatible with breastfeeding." 9† Following therapeutic doses, mean human milk concentrations were 0.1–0.6 g/mL. 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Chloramphenicol Gram positives, gram negatives, anaerobes, chlamydia, rickettsiae Crosses the human placenta readily. Umbilical cord serum concentrations 29–106% of maternal levels. 12 Excreted in human breast milk. 13–15 In 5 patients with minor obstetrical lacerations who receive d1gPOqDfor8 days, mean milk concentrations were 0.5–2.8 g/mL. In 5 patients receivin g2gPOqDfor8 days for mastitis, mean milk concentrations were 1.8–6.1 g/mL. 13 Human milk concentrations are 51–62% of blood levels. 14 Percentage of administered dose in human breast milk per day is 1.3%. 15 Effect on breastfed infants considered "unknown but may be of concern." 16 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Serum concentrations can be monitored to keep peak and trough levels in the ranges of 10–20 and 5–10 g/mL, respectively. CBC monitored to detect bone marrow depression. Ciprofloxacin Gram-negative aerobes, some staphylococci Crosses the human placenta and concentrates in amniotic fluid (Product information Cipro, 2001). 17 In 20 women at 19–25 weeks of gestation who received two 200-mg IV doses q 12 hours, the mean amniotic fluid level 2–4 hours after dosing was 0.12 0.06 g/mL (n 7; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.57), 0.13 0.07 g/mL at 6–8 hours (n 7; AF:MS ratio 1.44), and 0.10 0.04 g/mL at 10–12 hours (n 6; AF: MS ratio 10.00). 17 Excreted in human breast milk (Product information Cipro, 2001). 17 Considered usually compatible with breastfeeding." 9† In 10 women given 750 mg q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 3.79 1.26, 2.26 0.75, 0.86 0.27, 0.51 0.18, 0.20 0.05, and 0.02 0.006 g/mL at these times and the ratios of breast milk: serum concentration were 1.84, 2.14, 1.60, 1.70, 1.67, and 0.85, respectively. 17 For breastfeeding infants consuming 150 mL/kg per day, the estimated maximum dose is 0.569 mg/kg per day or 2.8% the approved dose for infants of 20 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding ciprofloxacin in pregnant women. 19 It is unknown whether dose adjustments during pregnancy are necessary. Approximately 50–70% of a dose is excreted in the urine and, if renal function is impaired, the serum half- life is slightly prolonged (Product information Cipro, 2001). ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1123 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Clindamycin Gram-positive anaerobes, gram- negative anaerobes, aerobic gram-positive cocci, streptococci, Clostridia strains Crosses the human placenta readily. 44,20–23 In 54 women undergoing cesarean delivery who received 600 mg IV 30 minutes before surgery, umbilical cord blood concentrations were 46% of maternal serum levels. 20 After multiple oral doses prior to therapeutic abortion, fetal blood concentrations were 25% and amniotic fluid levels were 30% of maternal blood levels. 21 Excreted in human breast milk (Product information Clindamycin, 1970). Considered "usually compatible with breastfeeding." 9† At maternal doses of 150 mg orally to 600 mg IV, breast milk concentrations range from 0.7 to 3.8 g/mL (Product information Clindamycin, 1970). Pharmacokinetic parameters do not change during pregnancy in women studied during the 1st, 2nd, and 3rd trimesters of gestation. 20,24 There are no studies to indicate that dosing should be modified during pregnancy. C max and T max (after a single standard dose) and C ss (after multiple doses) do not change appreciably at any time during pregnancy. Doxycycline Gram-positives, gram- negatives, rickettsiae, chlamydiae, mycoplasma, spirochetes, actinomyces Crosses the placenta (Product information Vibramycin, 2001). Excreted in human breast milk. 25 Use for a short period (1 week) during breastfeeding is considered probably safe. 9,16 Breast milk concentrations are 30–40% of that found in maternal blood. 25 Unknown whether dose adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Enterohepatically recirculated. Excreted in urine and feces as unchanged drug. From 29% to 55.4% of a dose can be accounted for in the urine by 72 hours (Product information Vibramycin, 2001). Gentamicin Gram-negative aerobic rods, many streptococci, Staphylococcus aureus , mycobacteria Crosses the human placenta. 20,26–28 In 2 different studies, peak umbilical cord blood levels were 34% 26 and 42% 20 of associated maternal blood concentrations. Excreted in human breast milk. 29,30 Considered "usually compatible with breastfeeding." 9† Poorly absorbed from the GI tract. 29 Only half of nursing newborns had detectable serum levels, which were low and not likely to cause clinical effects. 29 No adverse signs or symptoms in nursing infants as a result of maternal treatment. 9 Increased dosage suggested due to decreased serum half-life in pregnancy and lower maternal serum levels. 20,31 In 54 women undergoing cesarean delivery, levels were lower than nonpregnant women. 20 Eliminated mainly by glomerular filtration (Product information Gentamicin, 1966). Clearance decreased in preeclamptic patients. 32 Dose/ dosing interval adjusted via peak and trough levels (Product information Gentamicin 1966). ( continued ) 1124 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Levofloxacin Gram-positives and gram-negatives Crosses the human placenta and concentrates in amniotic fluid (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 In 20 women at 19–25 weeks of gestation receiving two IV 400-mg doses of ofloxacin q12 hours, mean amniotic fluid concentration 3–6 hours after dosing was 0.25 0.11 g/mL (n 6; amniotic fluid: maternal serum concentration [AF:MS ratio] 0.35), 0.15 0.11 g/mL at 6–10 hours (n 8; AF:MS ratio 0.67), and 0.13 0.11 g/mL at 11–12 hours (n 6; AF:MS ratio 2.57). 17 Excreted in human breast milk in high concentrations (based on data for racemic ofloxacin) (Product information Levaquin, 1996). 17 Considered "usually compatible with breastfeeding." 9† In 10 women given 400 mg of ofloxacin q12 hours PO, serum and milk concentrations were obtained 2, 4, 6, 9, 12, and 24 hours after the 3rd dose. Concentrations were 2.41 0.80, 1.91 0.64, 1.25 0.42, 0.64 0.21, 0.29 0.10, and 0.05 0.02 g/mL at these times, with breast milk: serum concentration ratios of 0.98, 1.30, 1.39, 1.25, 1.12, and 1.66, respectively. 17 For breastfed infants consuming 150 mL/kg per day, the estimated maximum infant dose of ofloxacin is 0.362 mg/kg per day. 18 Circulating fluoroquinolone concentrations are lower in pregnant than in nonpregnant women, but no specific pharmacokinetic data is available regarding levofloxacin in pregnant women. 19 There are no data to support dosing adjustments during pregnancy. Penicillin G Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, spirochetes, actinomyces, some gram negatives* Crosses the human placenta. 5,33,34 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Bicillin, 2001; product information Penicillin V, 1997). 15 Considered "usually compatible with breastfeeding." 9† In women with serum concentrations of penicillin ranging from 6 to 120 g/dL, corresponding breast milk concentrations were 1.2–3.6 g/dL, and the amount of the maternal dose appearing in breast milk per day was estimated at 0.03%. 15 Shorter dosing interval and/ or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, gram- positive anaerobes, gram negatives Crosses the human placenta readily. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 5 Excreted in human breast milk in small amounts (Product information Penicillin V, 1997). 15,36 Considered "usually compatible with breastfeeding." 9† In 18 women, penicillin V milk concentration depended on presence of mastitis, with peak levels 2.6–5.4 hours after a single PO 1,320-mg dose. 35 Peak concentration was 30–72 g/dL with mean concentration 26-37 g/dL. AUC over 8 hours after dosing was 2.1–3.0 mg-h/L. 35 Estimated dose of penicillin V ingested per day by breastfed infants is 40–60 g/kg, or 0.09– 0.14% of maternal dose per kg body weight. 35 Shorter dosing interval and/or increased dose have been suggested during pregnancy to attain similar plasma concentrations as for nonpregnant women. 6,11 Penicillin V is excreted renally, primarily via tubular secretion. Volume of distribution and renal clearance are increased during the 2nd and 3rd trimesters. 6,11 ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1125 Table 2. Current Information for Eleven Broad-Spectrum Antibiotics That May Be Used in Pregnant and Lactating Women ( continued ) Antibiotic Microbiologic Spectrum of Activity* Placental Transmission Transmission Into Breast Milk Possible Pregnancy Dosage/ Schedule Adjustments, Metabolism, Excretion, and Recommendations for Monitoring Rifampin Mycobacteria, Neisseria meningitidis , S aureus , Haemophilus influenzae , Legionella pneumophila , Chlamydia Crosses the human placenta (Product information Rifampin, 1971). 37–39 Umbilical cord concentrations between 12% and 33% of maternal blood levels, with peak levels occurring concurrently after drug administration. 37–39 Excreted in human breast milk (Product information Rifampin, 1971). 15,40,41 Considered "usually compatible with breastfeeding." 9† After a single oral dose of 600 mg, a nursing infant would ingest approximately 0.05% of the maternal dose per day, or approximately 0.3 mg/day. 15,40,41 Unknown whether dosing adjustments during pregnancy are necessary. Pharmacokinetics during pregnancy has not been specifically studied. Hepatically deacetylated to active metabolite. Parent compound and metabolites excreted via biliary elimination (60%). Enterohepatic re-circulation; plasma levels elevated in hepatic disease. Up to 30% excreted in urine; renal clearance is 12% of GFR. 38 Vancomycin Gram positives, S aureus , Staphylococcus epidermidis , streptococci, enterococci, Clostridium , Coryne- bacterium Crosses the human placenta (Product information Vancomycin, 1964). 42,43 Appears in umbilical cord blood after IV maternal treatment (Product information Vancomycin, 1964). 42,43 Amniotic fluid and umbilical cord blood concentrations during the early 3rd trimester comparable to maternal blood levels (fetal-maternal serum concentration ratio of 0.76). 43 Excreted in human breast milk when administered IV (Product information Vancomycin, 1964). 42 When administered orally, vancomycin is poorly absorbed from the GI tract (Product information Vancomycin, 1964). It is, therefore, not likely to cause adverse effects in nursing infants. There are no studies to indicate that vancomycin dosing should be modified during pregnancy. Volume of distribution and plasma clearance both increased, but half-life similar to that for nonpregnant women (4.55 versus 4–6 hours) in a woman administered IV vancomycin twice daily from 26–28 weeks of pregnancy. 43 CBC, complete blood count; AF, amniotic fluid; MS, maternal serum; GI, gastrointestinal; AUC, area under the curve; GFR, glomerular filtration rate . * Listed in the product label and the clinical pharmacology monograph as active against most strains; bacterial resistance occurs commonly in some sp ecies of otherwise susceptible bacteria due to beta-lactamase production. † Based on assessment by the American Academy of Pediatrics. 1126 Nahum et al Antibiotic Use in Pregnancy OBSTETRICS & GYNECOLOGY Table 3. Teratogenic and Toxic Potential of Eleven Broad-Spectrum Antibiotics Based on Available Human and Animal Data Antibiotic Human Data: Teratogenic and Toxic Effects Animal Data: Teratogenic and Toxic Fetal Effects Magnitude of Human Teratogenic Fetal Risk (Based on TERIS Assessment) 44 FDA Pregnancy Category* Amoxicillin OR for major congenital anomalies 1.4 (95% CI 0.9–2.0) for women using amoxicillin clavulanic acid during pregnancy in a case-control study of 6,935 malformed infants (no increased risk). 45 OR (adjusted) for congenital anomalies 1.16 (95% CI 0.54– 2.50) in a Danish study (1991–2000) of 401 primiparous women who filled prescriptions for amoxicillin during pregnancy (rate 4.0%) compared with 10,237 controls who did not redeem any prescription drug (rate 4.1%). 46 No increased rate of congenital malformations among 147 women who received prescriptions for amoxicillin during the 1st trimester. 46 No increased rate of congenital anomalies among 284 infants whose mothers were administered amoxicillin or ampicillin during the 1st trimester, or in 1,060 infants whose mothers were treated at any time during pregnancy. 47 No significantly increased rate of major or minor anomalies in the children of 14 women treated with amoxicillin and probenecid during the first 14 weeks of gestation or among 57 women treated after the 14th week in a controlled clinical trial on the treatment of gonorrhea during pregnancy. 48 No adverse effects in offspring exposed to amoxicillin during the 2nd and 3rd trimesters in 3 controlled clinical trials of antibiotic treatment for premature preterm rupture of membranes. 49–51 An association of necrotizing enterocolitis in newborns and maternal amoxicillin and clavulanic acid treatment during the 3rd trimester was observed in a randomized controlled trial including 4,826 pregnant patients. 52,53 No increased congenital malformations in mice treated with 3–7 times the maximum human therapeutic dose of amoxicillin. 54 No adverse reproductive effects in rats given amoxicillin- clavulanic acid at doses of 400 and 1,200 mg/day prior to fertilization and during the first 7 days of gestation (Product information Amoxil, 2001). 55 No adverse fetal effects in pigs given amoxicillin with clavulanic acid at doses of 600 mg/kg on days 12–42. 56 Increased frequency of embryonic death in mice treated with amoxicillin at 6–7 times the maximum therapeutic human dose. 54 Increased risk of teratogenicity is "unlikely," based on "fair" data. B Chloramphenicol OR for major congenital anomalies 1.7 (95% CI 1.2–2.6) for oral administration at any time during pregnancy in a case- control study of 22,865 malformed infants (risk marginally increased). 57 RR for congenital malformations 1.19 (95% CI 0.52–2.31) in 348 offspring born to women who took chloramphenicol at any time during pregnancy (no statistically increased risk). 58 Potential for both dose-related and idiosyncratic bone marrow toxicity. Caution should be used near term, during labor, and while breastfeeding due to the possibility of inducing "gray-baby" syndrome. 59 No increased congenital anomalies in monkeys. 60 No teratogenicity in mice or rabbits at 10–40 times the recommended human dose. 61 No teratogenicity in rats at 2–4 times the usual human dose, 62 but various fetal anomalies at 10–40 times the human dose. 61,63 Increased fetal death and decreased fetal weight in mice, rats, and rabbits. 61–63 Increased risk of teratogenicity is "unlikely," based on "fair" data. "Therapeutic doses of chloramphenicol are unlikely to pose a substantial teratogenic risk." C ( continued ) VOL. 107, NO. 5, MAY 2006 Nahum et al Antibiotic Use in Pregnancy 1127
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