RESISTANCE IN ANTIBIOTICS DEVELOPED : MAINLY USED IN PREGNANCY

About Author:
Shambhavi Singh
B.Pharm (IV) School of Pharmaceutical Science,
Jaipur national university, Jaipur(RAJ.)
*shambhavisingh3111@gmail.com

Abstract
Broad-spectrum antibiotics are prescribed in one third patients for urinary tract infection, and use of third-generation cephalosporins has doubled in the past decade.
Bacteria in pregnancy frequently produce the risk of pyelonephritis, preterm labour, and low birth weight infants. Commonly prescribed antibiotics such as ampicillin (pivampicillin), amoxicillin, fluroqunin, trimethoprim, and sulphonamide are currently associated with development of a high degree of resistance towards most common pathogen responsible for causing urinary tract infection, Escherichia coli. During the past few decades new researches have been made against development of resistance in antibiotic and new drugs are synthesised. The presumption that if a specific drug is safe for the both pregnant woman and the foetus depends on how widely the drug has been used. A recent survey among general practitioners and obstetricians in confirmed that the beta-lactam antibiotic pivmecillinam and ciphalosporins are the most commonly used agents in the treatment of bacteriuria in pregnancy However, a surprisingly high number of physicians reported that they prescribe TMP/SMX during the first two trimesters in spite of resistance of E. coli and possible adverse effects on the foetus.

REFERENCE ID: PHARMATUTOR-ART-1282

INTRODUCTION
Pregnancy is the fertilization and growth of one or more offspring, known as an embryo, in a woman's uterus. Pregnancy take place in 38 weeks althrough it is considered from the last menstrual period so 2 extra weeks are considered (40weeks)¹. It is divided in 3 trimester,nearly
about three month each.²
The word antibiotic comes from the Greek anti meaning 'against' and bios meaning 'life' .Antibiotics are also known as antibacterials, and they are drugs used to treat infections caused by bacteria. Bacteria are minute organisms that cause sickness to humans and animals. The singular word for bacteria is bacterium. ⁵¹
Antibiotics are among the most commonly prescribed medications in modern medicine. Antibiotics cure disease by killing or destructing bacteria. The first antibiotic was penicillin, discovered accidentally from a mold culture. Today, over 100 different antibiotics are available to cure various infections.
Although antibiotics are useful in variety of infections, it is important to know that antibiotics only treat bacterial infections.
UTI is a bacterial infection of the urinary tract. The urinary tract consists of the urethra (a narrow membrous wall), bladder (muclomembraneous sac), ureters (two muscular tube) and kidneys. Bacteria  can enter any of these urinary tract locations and produce infection. UTIs generally affect both either the lower or the upper urinary tract.³⁹ In pregnant women, the incidence of UTI can be above 8 percent.^36,37 The most common cases of UTI are due to infection of the lower urinary tract affect mainly bladder,  known as cystitis. And pyelonephritis is an infection of the upper urinary tract consists of ureter and kidney.  A UTI in pregnant women, is considered complicated.38 And if left untreated it leads to develop serious problem.⁴⁶
The most common pathogen in UTIs is Escherichia coli--both in upper and lower tract infections--accounting for approximately 85% of all cases.¹⁰ Staphylococcus saprophyticus is also a common pathogen, accounting for about 10% of infections in young women.¹⁴ Other pathogens include the Proteus species, Klebsiella species, Enterobacter species, Pseudomonas species, and group B beta-hemolytic streptococcus. Enterococci are less common gram-positive pathogens and are often found in complicated UTI.^10,14,15

Discussion
Tetracycline - broad spectrum antibiotic.  Treatment with tetracycline in early pregnancy has not been found relaated with any specific malformation but tetracycline use in the second or third trimester may result in discolouration of teeth( If anyone take tetracycline after  fourth month of pregnancy, there may be peril for discoloration (graying) of the "baby" teeth.⁵³ and bones.  Tetracycline may irretate fatty liver of pregnant women.
Tetracyclines are  not drugs of choice for treatment of UTI in pregnancy and should be avoided after the fourth month unless compellingly indicated. ⁵²
Intake, of tetracyclines along with doxycycline, minocycline during the second or third trimester of pregnancy can give rise to staining of the teeth of the child and up to a 40% suppression of bone growth (especially to the calf bone in preterm pregnancies) (Rendle-Short, 1962; Kline et al., 1964; Kutscher et al., 1966 penicillin). However, following in utero exposures to tetracyclines, rapid remunerative bone growth has been observed once antibiotic prescription is terminated (Cohlan et al., 1961).³

Nitrofurantoin
Numerous studies have demonstrated the safety of nitrofurantoin in pregnancy. Case-control studies and case series involving thousands of women who received nitrofurantoin in pregnancy reported no increase in major malformations among the newborns.^44,45,40 In addition, a meta-analysis conducted by Motherisk failed to show teratogenic risk with first-trimester use of nitrofurantoin.⁴³ The drug can theoretically induce hemolytic anemia in the fetus or newborn, particularly in those with glucose-6-phosphate dehydrogenase deficiency; however, cases of this toxicity are rare.^41,42
Nitrofurantoin should not be administered near time of delivery (38-42weeks gestation) since it distrupt with immatureenzyme activity in RBCs of newborn.It damage the RBCs and result in anemia.⁴⁸
FDA pregnancy category B.This  medication is not harmful to use in pregnancy,unless it is used in last 4 weeks of pregnancy.⁴⁷

Penicillin
Drugs are known from different names and are generally safe in use.some that are commonly prescribed named as amoxicillin,clavulin and pivmecillinam.
The sensitivity of E. coli causing acute uncomplicated
UTI in 1999/2000, to several antimicrobial
agents has been resolved in the ECO /SENS project.[9]
Acc. to a study done in 16 countries,observed that resistance of E.coli  developed, averaged:
• 30% to ampicillin
• 29% to sulphamethoxazole,
• 15% to trimethoprim
• and 14% to TMP/SMX.

In an another surveillance  the activities of TMP/SMX, ampicillin, ciprofloxacin and nitrofurantoin against urinary of E. coli from female patent from 1995 to 2001 are available in The Surveillance Network (TNS) Database-USA [10].
Resistance rates of E. coli to :
o    ampicillin (36.0 -37.4% per year),
o    TMP/SMX (14.8 -/17.0%),
o    ciprofloxacin (0.7_-2.5%)
o    and nitrofurantoin (range, 0.4- 0.8%) varied very minute over these 7 years period.
o     Ciprofloxacin was the only drug studied that establised a consistent increase in resistance from 1995 (0.7%) to 2001 (2.5%).
o     In 2001, TMP/SMX resistance to E. coli found was >10% in all nine US Bureau of the Census regions.
o    Due to increased resistance of amoxicillin(>35% in SK)4 leads to its failure and new penicillin antibiotics are exposed nowdays.
o    Amoxicillin/clavulanate  - Clavulin - Less E.coli resistance than amoxil (~20%)1 - E.coli > 82% .4

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to PharmaTutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

Ampicillin and amoxycillin  leads to excessive growth of resistant Enterobacteriaceae while pivmecillinam reduces the number of E. coli without selecting resistant strains.^[17] Pivmecillinam work as a pro-drug and thus has a low affect on the endogenous microflora ^[18]. Mecillinam (active form of the drug) is also biodegradable, and thus environmentally responsible ^[19]. These properties lead to depress potential  for development of resistance, an important affair towards the the increasing global concerns over increasing bacterial resistance. Although
pivmecillinam has been a first-line drug for UTI in Scandinavia for more than 20 years, the level of mecillinam resistance among uropathogens has remained at the same low level ^[9].

Pivmecillinam is a solitary b-lactam antibiotic for UTI treatment. It has selective activity towards Gram-negative bacteria, particularly E. coli, the bacteria most commonly responsible for UTI.^[5]

Fluoroquinolones
Fluoroquinins are prescribed for tretment of uti by keeeping in view safety of fluroquinolones drugs originated from reports of arthropathy in animal studies.^[22];  whereas such reports are rare in human cases.^{27 28} However, the safety of fluoroquinin drugs in pregnancy has been studied in a number of cashes.^29-34 but several other studies list number of conditions in use of these drugs.⁷ 8Resistance developing in fluoroquinins are also predict its failure.
Norfloxacin has been result in embryonic loss in monkeys when administered in doses 10 times the maximum routine human dose.There are, however well-controlled studies in pregnant women. Norfloxacin should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.⁶
Surveillance study on the use of fluoroquinolones during pregnancy was conducted by the Toronto Motherisk Program among members of the Organization of Teratology Information Services and briefly reported in 1995 (10). Pregnancy outcome data were available for 134 cases, of which 61 were exposed to norfloxacin, 68 to ciprofloxacin, and 5 to both drugs. Most (90%) were exposed during the first 13 weeks postconception.
Fluoroquinolone-exposed pregnancies were compared with matched controls and there were no differences in live births (87% vs. 86%), terminations (3% vs. 5%), miscarriages (10% vs. 9%), abnormal outcomes (7% vs. 4%), cesarean section rate (12% vs. 22%), fetal distress (15% vs. 15%), and pregnancy weight gain (15 kg vs. 16 kg). The birth weights of exposed infants was a mean 162 g higher than those in the control group and their gestations were a mean 1 week longer.^[10]
In a prospective study conducted by the European Network of Teratology Information Services (ENTIS), data on 549 pregnancies exposed to fluoroquinolones (318 to norfloxacin) were described in a 1996 Reference ^[7].  Based on mentioned data, fluoroquinolone prescription during pregnancy is not related with increased risk of major deformity, adverse effects in the fetal musculoskeletal system, spontaneous abortions, prematurity, intrauterine growth retardation, or postnatal disorders are seen in some cases.[8] However,  fluoroquinolones such as ciprofloxacin,norfloxacin should not routinely be employed as first-line agents in UTIs.^[11]
Althrough resistance is still low but it is expected that if resistance continue to grow,it will no longer in use after 5-10 years.^[12] Inspite of fluroquines good activity,their is need to preserve them because of increasing resistance.Moxifloxacin is not prescribed in pregnancy because it does not reach sufficient concentration in urine.^[4]

Trimethoprim-sulfamethoxazole
Cotrimoxazole is a combination of sulfamethoxazole and trimethoprim in a ratio of 5:1 or 1:2. Trimethoprim and sulfamethoxazole both block the production of folic acid.^[49]
In a surveillance study of Michigan Medicaid recipients 2,624 womens had been treated with clotrimazole (vaginal infection use) during the 1st 3 months of pregnancy (F. Rosa, personal communication, FDA, 1993). Total of 118 (4.5%) major birth deformalities were observed more than expected (112 expected).
Of all the birth defect that are found six are major that are (observed/expected) :
•    22% - cardiovascular defects,
•    0.3% - oral clefts,
•    0.3% - spina bifida,
•    0.5% - polydactyly,
•    0.3% - limb reduction defects, and
•    0.4% - hypospadias.
•  These data do not show any relation between vaginal use of clotrimazole and congenital defects.^[20]
Clotrimoxazole treatment is only prescribed in settings where the prevalence of TMP/SMX resistance is <10-20%.  Studying the  economic impact of TMP/SMX and quinolone exposure have presented data supporting the use of TMP/SMX  when the local rate of resistance to TMP/SMX does not more than 22% ^[13].
Due to the fact that it crosses the placenta and can affect folate metabolism, trimethoprim is relatively contraindicated during pregnancy, especially the first trimester.^[14] It may be involved in a reaction similar to disulfiram when alcohol is consumed after it is used, particularly when used in combination sulfamethaxazole^[14][15]
Oral clotrimazole is in the FDA pregnancy category C. This means that it is not known whether clotrimazole will harm an unborn baby.^[21]

Cephalosporin
Cephalosporins are the most frequently prescribed class of antibiotics. They are structurally and pharmacologically related to the penicillins.^[23]
Although there is limited data available at this time, it is thought that most of the first and second generation cephalosporins are not associated with any known or suspected teratogenic effects and are assumed safe for use during pregnancy (Landers et al.1983)^[3]
Cephalosporins are alternative antibiotics for treating UTIs. Cephalexin is among the most commonly prescribed oral cephalosporin for this indication.^[24] In the Michigan Medicaid surveillance study, a total of 176 (4.9%) major birth defects were observed (154 expected) among the 3613 newborns exposed to cephalexin during the first trimester.[25]The results of a Hungarian case-control study did not indicate human teratogenic potential for oral cephalexin.^[26]
Acc.indian medical ass. Cephalosporins are most commonly prescribed and are safe to use.Resistance develop in cefadroxil and ciprofloxacin still averaged under 3%.50
The Cochrane database author have adviced that both ampicillin and first generation cephalosporins in 1 or 2 doses are good choices for  uti in pregnancy.
Most costly broad spectrum penicillin and second and third generation cephalosporins on combination regimes has been found  not more effective.^[2-9]
The practise of gynaecologest in a study done by some medical students in Indian hospital shows that cephalosporin was prescribed for 3 days in 34.4% and 33.3% cases;for 5 days in 35.5% and 41.1% cases in both elective and emergency caesarean section.

Carbapenems
Acc. to pathologist at  the University of Calgary has warned about multi-drug resistant strain of E.coli responsible for urinary ract infection. Dr.Johann Pitout said  that antibiotics carbapenems that are costly can effectively affect this stain of bacteria.Has raised an alarm that by using carbapenems treatment would be very coastly ,putting heavy stress on health care budgets.And overusing the antibiotics can results to new strain of antibiotics resistant bugs.Pitout said the spread of the bacterium is associated with  the Indian subcontinent which is risky area.It was first detected in India in 2001 and now it has spread to North and South America,Europe,Africa,Itely and Australia.

Conclusion
Antibiotic resistance found to be developed in penicillins, fluoroquinolone,TMP/SMX altrough there percentage of resistance development found somewhat different from each other.
Bacteria can acquire tolerance and resistance in a number of different ways. Bacteria are very susceptible to genetic mutations and insertions from generation to generation.
Many experts says that antibiotic drugs have been missused ,not treated properly.  Over-use, misuse and non-medical use of antibiotics are problems to blame for the development of resistance since from first exposure to antibiotics will increase resistant strains of bacteria ¾ both pathogenic and non-pathogenic. Over-exposure, or over-use, must be prohibited . Many patients ask for antibiotic prescriptions from doctors with no proof  that they are in need and doctors sometimes prescribe, with thought that the drugs will do no harm. And also, it has been noticed that antibiotics are often exposed before the presence of an infection verification.Other problem is that patients tend to discontinue administration of antibiotics as soon as they feel better, without any consultanting with doctors.Either the, improper dosing will fail to eradicate the causetive agent completely and will pramote growth of both tolerant and resistant strains.
Antibiotic resistance can be a result of laternal gene transfer 51 and also of unlinked point mutations in the genome of pathogen at a high  rate of chromosomal replication.
Environmental condition affect antibiotic action against the pathogen,those bacteria  which develop resistance a mutation are survived and reproduce.They will pass this mutation to their offspring,that result in evolution of a completely resistant colony.
Deactivation or modification of drug example,penicillin G deactivation due to production of enzyme b-lactamases in penicillin resistance bacteria.
•        Active site deactivation or alteration.
•        Change in metabolic pathway.
•        Decrease in drug accumulation.52
In fluoroquinolone resistance mainly three mechanisms take place.In Gram-negative bacteria,action of quinolone is resist by plasmid mediated genes that produces proteins that can bind with DNA gyrase.53

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to PharmaTutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE

Reference:
1.Robicsek, A; Jacoby, GA; Hooper, DC (October 2006). "The worldwide emergence of plasmid-mediated quinolone resistance". Lancet Infect Dis 6 (10): 629–40. doi:10.1016/S1473-3099(06)70599-0. PMID 17008172
2.Li, X; Nikadio, H (2009). "Efflux-Mediated Drug Resistance in Bacteria: an Update". Drug 69 (12): 1555–623. doi:10.2165/11317030-000000000-00000. PMC 2847397. PMID 19678712
1.Use of tetracycline in pregnancy Publisher: UK Teratology Information Service Date published: 03/06/2011 14:26
2.Tetracycline and Pregnancy - Organization of Teratology Information ...otispregnancy.org. -
3.Illinois Teratogen Information Service 1-800-252-4847 fetal-exposure.org.
4. Rx files: Drugs for Urinary Tract Infections. Feb 2005. www.rxfiles.ca
5.Pivmecillinam*/therapy of choice for lower urinary tract infection
W. Graninger * Department of Infectious Diseases, Internal Medicine I, University of Vienna, Vienna, Austria # 2003 Published by Elsevier B.V. and the International Society of Chemotherapy
6.a b c d e f g Merck Sharp & Dohme (September 2008). "TABLETS NOROXIN (NORFLOXACIN)" (PDF). USA: FDA
7.Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, Rodriguez-Pinilla E, Pexieder T, Prapas N, Merlob P. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS). Eur J Obstet Gynecol Reprod Biol 1996;69:839.
8.Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol 1994;84:5358.
9.Kahlmeter G. An international survey of the antimicrobial susceptibility of pathogens from uncomplicated urinary tract infections: the ECO SENS project. J Antimicrob Chemother 2003;53:69  /76.
10.Pastuszak A, Andreou R, Schick B, Sage S, Cook L, Donnenfeld A, Koren G. New postmarketing surveillance data supports a lack of association between quinolone use in pregnancy and fetal and neonatal complications. Reprod Toxicol 1995;9:584.
11.accessdata.fda.gov/drugsatfda_docs/label/201
12.Rx files: Fluroquinolones .Too Valuable to Overuse. Feb
13.Minassian MA, Lewis DA, Chattopadhyay D, Bovill B, Duckworth G, Williams JD. A comparison between single-dose fosfomycin trometamol (Monuril) and a 5-day course of trimethoprim in treatment of uncomplicated lower urinary tract infection in women. Int J Antimicrob Agents 1998;10:39 /47.
14."Trimethoprim". netdoctor.co.uk.
15.Edwards DL, Fink PC, Van Dyke PO (February 17, 1986). "Disulfiram-like reaction associated with intravenous trimethoprim-sulfamethoxazole and metronidazole". J Clinical pharmacy 5 (12): 999.
16.Heelon MW, White M (February 17, 1998). "Disulfiram-cotrimoxazole reaction". J Pharmacotherapy 18 (4): 869.
17.Edlund C, Nord CE. Effect on the human normal flora of oral antibiotics for treatment of urinary tract infections. J Antimicrob Chemother 2000;46(Suppl. S1):41 /8.2001;13:313 /22.
18.Sullivan AA, Edlund C, Svennungsson B, Emtestam L, Nord CE. Effect of perorally administered pivmecillinam on the normal oropharyngeal, intestinal and skin microflora. J Chemother
19.Halling-Sorensen B, Holten Lutzhoft H-C, Andersen HR, Ingerslev F. Environmental risk assessment of antibiotics: comparison of mecillinam, trimethoprim and ciprofloxacin. J Antimicrob Chemother 2000;46(Suppl. S1):53 /8
20.Thedrugsafety.com/faq/index/group/category/Antibiotics/ referencing: T.P. Dowling, personal communication, Merck & Co, Inc., 1987
21.Clotrimazole drug.com
22. Ingham B, Brentnall DW, Dale EA, McFadzean JA. Arthropathy induced by antibacterial fused N-alkyl-4-pyridone-3-carboxylic acids. Toxicol Lett. 1977;1:21–6.
23.Cephalosporin Antibiotics www.emedexpert.com › Comparisons
24.Christensen B .Which antibiotic are appropiate for treating bacteriuria in pregnancy?antimicrob chemother 2000;46(supp1):29-34
25.Briggs GG,Freeman R K,Yaffe SJ.Drugs in pregnancy and lactation 7.Philadelphia,PA:Lippincott Williams & Wilkins;2005.p.74.p.268.p.1153
26.Czeizel AE,Rockenbauer M,Sorensen HT,Olsen J.Use of cephalosporin during pregnancy and in presence of congenital abnormality:a population based case control study.Am J Obstet Gynecol 2001.184(6)1289-96[Pubmed]
27 Chysky V, Kapila K, Hullmann R, Arcieri G, Schacht P, Echlos R. Safety of ciprofloxacin in children: worldwide clinical experience based on compassionate use. Emphasis on joint evaluation. Infection. 1991;19(4):289–96. [PubMed]
28. Chevais MP, Reinert P, Rondeau MC, Tobelem R, Albengres E, Riant P, et al. Critical risk/benefit analysis of pefloxacine use in children under 15 years—the problem of arthralgias. Int J Clin Pharmacol Ther Toxicol. 1987;25(6):306–9. [PubMed]
29. Larsen H, Nielsen GL, Schønheyder HC, Olesen C, Sørensen HT. Birth outcome following maternal use of fluoroquinolones. Int  2001;18(3):259–62.J Antimicrob Agents. [PubMed]
30. Wilton LV, Pearce GL, Mann RD. A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies. Br J Clin Pharmacol. 1996;41(4):277–84. [PMC free article] [PubMed]
31. Loebstein R, Addis A, Ho E, Andreou R, Sage S, Donnenfeld AE, et al. Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study. Antimicrob Agents Chemother. 1998;42(6):1336–9. [PMC free article] [PubMed]
32. Schaefer C, Amoura-Elefant E, Vial T, Ornoy A, Garbis H, Robert E, et al. Pregnancy outcome after prenatal quinolone exposure. Evaluation of a case registry of the European Network of Teratology Information Services (ENTIS) Eur J Obstet Gynecol Reprod Bio. 1996;69(2):83–9. [PubMed]
33. Pastuszak A, Andreou R, Schick B, Sage S, Cook L, Donnenfeld A, et al. New postmarketing surveillance data supports a lack of association between quinolone use in pregnancy and fetal and neonatal complications. Reprod Toxicol. 1995;9:584.
34. Berkovitch M, Pastuszak A, Gazarian M, Lewis M, Koren G. Safety of the new quinolones in pregnancy. Obstet Gynecol. 1994;84(4):535–8. [PubMed]
35. Sulfamethoxazole and trimethoprime medicine.com
36. Mikhail  MS, Anyaegbunam  A.  Lower urinary tract dysfunction in pregnancy: a review.  Obstet Gynecol Surv.  1995;50:675–83.
37. Patterson  TF, Andriole  VT.  Bacteriuria in pregnancy.  Infect Dis Clin North Am.  1987;1:807–22.
38. Hooton TM, Stamm WE. Acute cystitis in women. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate; 2007. Available at: www.uptodate.com.
39. Hooton TM, Stamm WE. Urinary tract infections and asymptomatic bacteriuria in pregnancy. In: Rose BD, ed. UpToDate. Waltham, MA: UpToDate; 2007. Available at: www.uptodate.com.
40. Briggs GG, Freeman RK, Yaffe SJ. Drugs in pregnancy and lactation. 7. Philadelphia, PA: Lippincott Williams & Wilkins; 2005. p. 74.p. 268.p. 1153
41. Bruel H, Guillemant V, Saladin-Thiron C, Chabrolle JP, Lahary A, Poinsot J. [Hemolytic anemia in a newborn after maternal treatment with nitrofurantoin at the end of pregnancy.] Arch Pediatr. 2000;7(7):745–7. French. [PubMed]
42. Gait JE. Hemolytic reactions to nitrofurantoin in patients with glucose-6-phasephate dehydrogenase deficiency: theory and practice. DICP. 1990;24(12):1210–3. [PubMed]
43. Ben David S, Einarson T, Ben David Y, Nulman I, Pastuszak A, Koren G. The safety of nitrofurantoin during the first trimester of pregnancy: meta-analysis. Fundam Clin Pharmacol. 1995;9(5):503–7. [PubMed]
44. Czeizel AE, Rockenbauer M, Sørensen HT, Olsen J. Nitrofurantoin and congenital abnormalities. Eur J Obstet Gynecol Reprod Biol. 2001;95(1):119–26. [PubMed]
45. Hailey FJ, Fort H, Williams JC, Hammers B. Foetal safety of nitrofurantoin macrocrystals therapy during pregnancy: a retrospective analysis. J Int Med Res. 1983;11(6):364–9. [PubMed]
46.Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy Valerie T Guinto1,*, Blanca De Guia1, Mario R Festin2, Therese Dowswell3 Editorial Group: Cochrane Pregnancy and Childbirth Group Published Online: 8 SEP 2010 Assessed as up-to-date: 19 JUL 2010 DOI: 10.1002/14651858.CD007855.pub2
47.”Nitrofurotoin” drug.com
48.Nitrofurantoin index .medicinenet.com
49.Sulfamethoxazole and trimethoprime medicinenet.com
50 Urinary tract infection about.com
51.Ochiai, K.; Yamanaka, T; Kimura, K; Sawada, O (1959). "Inheritance of drug resistance (and its transfer) between Shigella strains and Between Shigella and E.coli strains" (in Japanese). Hihon Iji Shimpor, 34: 1861
52.Use of tetracycline in pregnancy Publisher: UK Teratology Information Service Date published: 03/06/2011 14:26
53.Tetracycline and Pregnancy - Organization of Teratology Information ...otispregnancy.org.-3.Illinois Teratogen Information Service 1-800-252-4847 fetal-exposure.org

NOW YOU CAN ALSO PUBLISH YOUR ARTICLE ONLINE.

SUBMIT YOUR ARTICLE/PROJECT AT articles@pharmatutor.org

Subscribe to PharmaTutor Alerts by Email

FIND OUT MORE ARTICLES AT OUR DATABASE