PRACTICAL THERAPEUTICS

Drugs 44 (6): 972-980, 1992 00 12-6667/92/00 12-0972/$04 .50/0 © Adis International Limited . All rights reserved . ORU1219

Treatment of Bacteriuria in Pregnancy James S. Tan and Thomas M. File Jr Infectious Disease Section, Department of Medicine, Northeastern Ohio Universities College of Med icine, Rootstown, Ohio, and Department of Medicine, Akron City Hospital, Akron, Ohio, USA

Contents 972

973 973 974 974 976 977 977

Summary

Summary I. Diagnosis 2. Microbiology 3. Treatment of Urinary Tract Infection 3.1 Asymptomatic Bacteriuria 3.2 Symptomatic Urinary Tract Infection 4. Safety of Antimicrobial Agents in Pregnancy 5. Recommendations

The presence of bacteriuria during gestation increases the chance of acute pyelonephritis. Treatment of bacteriuria in pregnancy reduces subsequent development of symptomatic disease . Numerous studies have shown that single-dose therapy for asymptomatic bacteriuria is as effective as longer course of treatment. Single-dose therapy also has the advantages of improved compliance, reduced costs, and less adverse effects resulting from long term therapy. Follow-up cultures following antimicrobial treatment should be used for early detection of recurrence or relapse. If the urine culture yields no growth, a urine culture at a monthly interval will suffice. 'If on the other hand bacteriuria is present, a repeat course of antimicrobial therapy should be chosen based on antimicrobial susceptibility testing . A longer course of therapy, possibly with a different drug , is recommended for women with a positive follow-up urine culture. Acute cystitis may be treated with the same regimen as asymptomatic bacteriuria. When upper urinary tract infect ion is suspected, hospitalisation and a longer course of therapy is recommended. If the organism is susceptible to cefalexin or nitrofurantoin, postcoital prophylaxis with either agent for the remainder of the pregnancy I.11ay be benefic ial.

Urinary tract infection is a common medical .problem in women, and is particularly important in pregnancy because of the potential adverse effect on the mother and fetus. The prevalence of asymptomatic bacteriuria ranges from 2 to 10%(Brumfitt 1981 ; Harris & Gilstrap 1981 ; Lenke et al. 1983; Little 1966; McFadyen et al. 1973; Savage et al.

1967). This rate approximates to that in sexually active nonpregnant women (Drazancic et al. 1989; Editorial 1985; Kass 1960a; National Institute of Health 1983; Nnatu et al. 1989). Golan et al. (1989) observed that 5.9%of normal pregnant women, and 60% of pregnant women with diabetes or with a history of previous urinary tract infection, have

973

Bacteriuria in Pregnancy

asymptomatic bacteriuria. Certain features, such as history of past urinary tract infection, chronic renal disease, and diabetes mellitus may suggest a higher chance of symptomatic infection. Between 23 and 40% of these bacteriuric women develop acute pyelonephritis later in pregnancy (Brumfitt 198I; Kunin 1987; Lenke et al. 1983; Little 1966;McFadyen et al. 1973; Savage et al. 1967). Acute pyelonephritis occurs in two-thirds of women with prenatal bacteriuria, and is more frequent in the second and third trimester; a history of past urinary tract infection increases the risk (Golan et al. 1989). Acute cystitis usually occurs in the second trimester and most commonly arises in patients without a positive antenatal screening culture (Harris & Gilstrap 198I). Golan et al. (1989) found only onethird of pregnant woman with cystitis had bacteriuria during the prenatal visit. It appears that antenatal screening, urine cultures, and treatment may not reduce attacks of acute cystitis. Most investigators recommend prenatal screening and treatment of bacteriuria to reduce the risk of acute pyelonephritis during the latter stage of pregnancy (Kass & Zinner 1973; McNeeley 1988; Krieger 1986; Marchant 1978; Patterson & Andriole 1987; Zhanel et aI. 1990). However, screening is not universally accepted. Campbell-Brown et aI. (1987) asked whether screening for bacteriuria was worthwhile. They found that 198 of 4470 pregnant women (4.4%) surveyed had asymptomatic bacteriuria during the initial survey. I 19 patients (2.7%) were confirmed when a second sample was obtained. Screening and treatment prevented only 6 cases of symptomatic infection. Other investigators believe that early antenatal screening and treatment will potentially reduce the clinical infection rate by 66% (Editorial 1985; Golan et aI. 1989). Platt (1987) reported a marked increase in relative risk for acute pyelonephritis, and a slight increase in relative risk in preterm complications, in pregnant women with asymptomatic bacteriuria. When a pregnant woman has asymptomatic bacteriuria and has a history of previous urinary tract infection, she has a 10-foldgreater chance of developing symptomatic disease than a woman lacking either history, and a 4-fold greater risk compared with a

woman with asymptomatic alone (Chng & Hall 1982). The risk is reduced with treatment (Stamey 1980; Platt 1987). This review emphasises the treatment of asymptomatic and clinically symptomatic urinary tract infection in pregnancy, and long and short course therapy for pregnant women with asymptomatic bacteriuria.

1. Diagnosis Ideally, all pregnant women should be screened for bacteriuria at their initial visit. Urine should not be collected by catheter to avoid introducing bacteria into the bladder. Recovery of 105 colony forming units per ml (cfu/ml) of urine obtained by midstream clean catch technique is the most commonly used screening criterion. In nonpregnant women with asymptomatic bacteriuria, the probability of a second specimen containing greater than 105 cfu/ml ofthe same Gram-negative organism is 67% for voided specimen and 90% for catheterised specimen (Kass 1960b). In women with symptomatic urinary tract infections such as acute cystitis or pyelonephritis, 100 cfu/ml is considered significant (Johnson & Stamm 1989). When catheterised urine is used, any count greater than 100 cfu/ml is considered significant (Stark & Maki 1984). Although it is invasive, suprapubic aspiration of bladder urine has been found to be safe and is preferred by some investigators (Campbell-Brown et aI. 1987). Because suprapubic aspiration is less likely to be contaminated, the presence of any bacteria is considered significant. However, most investigators continue to use the midstream technique because it is more convenient and noninvasive (Patterson & Andriole 1987).

2. Microbiology The microorganisms which cause bacteriuria in pregnancy are similar to those in nonpregnant women (Kass & Zinner 1973; Patterson & Andriole 1987). Escherichia coli is by far the most common organism isolated in both symptomatic and asymptomatic women. Other enteric organ-

974

Drugs 44 (6) 1992

Table I. Results of some studies investigating the long and short term treatment of asymptomatic bacteriuria

Reference

Drug and dose

No. of patients

Outcome (failure rate)"

Comments

Campbell-Brown & McFadyen (1983)

Cefalextn 3g

37

30% at 3w

MSCC specimen inoculated on dipslide, SPA used to confirm. > 105 cfu/ml target Exclus ions: those with recurrent UTI. chronic renal disease. or > 25 w of gestation 4 of 11 patients who were retreated with a 5d course using a susceptible antimicrobial agent (dosage not given) had recurrent UTI

Gertsner et al. (1989)

Amoxicillin 3g single dose Amoxicillin 750mg q8h 4d

53

23% at 1w; 26% at 4w 38% at 1 and 4w

MSCC > 105 cfu/ml or cath specimen > 1()4 cfu/m l by dipslide. Randomised study MSCC followed by cath urine both yielding > 105 cfu!ml Sequential assignment of patients based on susceptibility testing Failures were re-treated for 10d with the initial agent No exclusions mentioned

x

38

Ampicillin 2g single dose + probenecid 1g Cefalexin 2g single dose + probenecid 1g Nitrofurantoin 200mg single dose Sulfafurazole (sulfisoxazole) 2g single dose

24

29% at 5d

20

45% at 5d

22

27% at 5d

20

25% at 5d

Jakob i et al, (1987)

Amoxicillin 3g or cefalex in 2gb single dose

50

22% at 1w; 24% at 2w; 34% at > 4w

MSCC > 10S cfu/ ml in 2 cultures No control or comparat ive group High failure rate with enterococci Exclusions not clearly delineated

Masterton et al. (1985)

Amoxicillin 3g single dose Ampicillin 500mg q6h x 7d

52

11.8% at 1-6w 1 9% at 1-6w

MSCC specimen with > 105 cfu/ml ; patients with urinary symptoms were excluded

35% at 203w

MSCC > 105 cfu/ml as initial screening. Confirmation by SPA or cath specimen Exclusions: febrile patients. signs of other infections. chronic renal disease, or antibiotic use Randomised double-blind study

Harris et al. (1982)

McFadyen et al. (1987)

Olsen et al. (1989)

38

Cefalexin 3g single dose 37 Cefalexin 1g single dose + pivmecillinam 100mg + 49 pivampicillin 125mg bid x 3d

Sulfamethizole 2g single dose

15

x

26

Sulfamethizole 19 bid 6d

34% at 2-3w

47% at 1 and 6w 15% at 1w and 38% at 6w

MSCC > 105 cfu/ml twice. Open randomised study Exclusions: symptomatic disease, chronic renal disease, previous UTI, antibiotic treatment within 3w

975

Bacteriuria in Pregnancy

Table I. Contd Reference

Drug and dose

Pedler & Bint (1987)

Amoxicillin/clavulanic acid 31 250mg tid x 7d Cefalexin 250mg tid x 7d 28

No. of patients

a b

Outcome (failure rate)B

Comments

23% at 2w. and 24% at 6w 26% at 2w. and 40% at 6w

MSCC > 105 cfu/ml and pyuria > 20 WBC/ml and a confirmatory specimen taken before treatment Randomised Exclusions: pyelonephritis. antibiotics within 2w of therapy

Time of follow -up culture. Choice of agent was based on susceptibility testing. Abbreviations: d = days; w = weeks; MSCC = midstream clean catch; SPA

isms, and Gram-positive cocci such as Streptococcus agalactiae, Enterococcus faecalis, and Sta phylococcus saprophyticus are less common but potential aetiological agents. Isolation of less conventional organisms, namely, Gardnerella spp., Mycoplasma spp., Ureaplasma spp., and anaerobes, has also been reported. The significance of these organisms not been fully established (Patterson & Andriole 1987).

3. Treatment of Urinary Tract Infection 3.1 Asymptomatic Bacteriuria Most clinicians recommend antimicrobial therapy for symptomatic and asymptomatic urinary tract infection in pregnancy (Patterson & Andriole 1987; Pedler & Bint 1987; Zhanel et al. 1990). The question of short versus longer term treatment is still the subject of some debate , with short course therapy in women with asymptomatic bacteriuria not universally accepted. Table I shows some of the experience with different antimicrobial agents published in the past decade. Campbell-Brown and McFadyen (1983) treated 37 patients with cefalexin 3g. Patients with proven recurrent urinary tract infection or chronic renal disease, and those more than 24 weeks pregnant were excluded. They reported a failure rate of 30% at 2 weeks. Four of the 11 failures continued to have bacteriuria after treatment with a 5-day course. In a randomised study, Gertsner et al. (1989)

= suprapublic aspiration; UTI = urinary tract infection.

claimed a better eradication rate for single dose amoxicillin versus a 4-day course of the drug. Four different single-dose schedules were investigated by Harris et al. (1982), with follow-up after 5 days. The failure rate ranged from 25 to 29%, except for cefalexin which showed a rate of 45%. All patients who failed with a single dose were then treated with the same agent for 10 days. The recurrence rate after therapy was 5% or less in all 4 study groups, with or without treatment. Jakobi et al. (1987) compared single doses of amoxicillin and cefalexin, and reported failure rates of 22% at 1 week and 34% at 4 weeks. Seven of 8 patients responded to a 7-day course using the same drug. Masterton et al. (1985) demonstrated failure rates of 11.8 and 19%, respectively, after 1 and 6 weeks' follow-up after treatment with a single 3g dose of amoxicillin or a 7-day course of ampicillin. McFadyen et al. (1987) compared, in a randomised, double-blind study, single dose and ' 3 days' treatment with cefalexin, and found comparable outcomes after 2 to 3 weeks. Six-weekfailure rates were 47 and 38% after a single dose or a 6-day course of sulfamethizole in an open randomised trial (Olsen et al. 1989). Although the results obtained with cotrimoxazole (trimethoprim/sulfamethoxazole) and trimethoprim appeared promising because of high bacteriuria eradication rates (Bailey 1984; Bailey et al. 1986), these reports were not included in the table because trimethoprim, a folate synthesis inhibitor, is not recommended for routine use in

976

Drugs 44 (6) 1992

Table II. Adverse effects of selected antimicrobial agents in pregnancy Maternal effect

Fetal effect

Allergic reactions

None known

Neuropathy

Haemolysis (glucose-6-phosphate deficiency)

Use with caution Aminoglycos ides Sulfonam ides

Oto- and nephrotoxicity Allergic reactions

Ototoxicity Kernicterus (not recommended near term); haemolysis (glucose-6phosphate deficiency)

Contraindicated in pregnancy Quinolones Tetracyclines Trimethoprim

Allergic reaction Hepatotoxicity Allergic reaction , vasculitis

Arthropathy Tooth and bone growth inhibition Folate antagonism; congenital anornalys

Drug Considered sefe In pregnancy Jj-Lactam antibiotics Penicillins, Jj-Iactamase inhibitor combinations, cephalosporins, imipenem and monobactams Nitrofurantoin

a

No congential anomaly reported in patients treated for UTI.

pregnancy. However, experience with this drug in pregnancy based on placebo-controlled studies and some case reports has failed to reveal an increase in fetal abnormalities (Briggs et al. 1990). Although single-dose therapy using 'different agents appears to be efficacious (Campbell-Brown & McFadyen 1983; Gerstner et al. 1989; Harris et al. 1982; Jakobi et al. 1987; McFadyen et al. 1987; Masterton et al. 1985; Olsen et al.1989), it is difficult to compare the studies. There is lack of uniformity in diagnostic criteria, inclusion and exclusion criteria, method of randomisation, stratification for risk factors which may affect therapeutic outcome, description of outcome measures, duration of follow-up, and adverse effects to the mother as well as the fetus. In spite of these shortcomings, single-dose or short term therapy may provide the advantages of better compliance, reduced cost, and lower incidence of bacterial resistance development [thus reducing the problem of perinatal resistant organisms (Anderson et al. 1979) and of superinfection (Rubin et al. 1980)]. Single doses also appear to be better tolerated than longer courses. The frequency of adverse effects with single doses of amoxicillin 3g was 4% compared with 13% in patients receiving a 4-day course

of 750mg of the drug every 8 hours (Gerstner et al. 1989). Considering the above and a failure rate of 10 to 40%, which is comparable to that oflonger term therapy, it appears that a single-dose approach should be strongly considered as the initial treatment. If bacteriuria persists during follow-up, the patient should be treated with a 7-day or longer course of antimicrobial therapy. {j-Lactam drugs (e.g. amoxicillin 3g or cefalexin 2g) are preferable for both single dose and repeat treatment because of their known safety in pregnancy. For patients allergic to penicillin, sulfafurazole (sulfisoxazole) 2g or nitrofurantoin 200mg are acceptable. Cotrimoxazole (trimethoprim 320mg plus sulfamethoxazole 1600mg) or trimethoprim 600mg may be used with caution. 3.2 Symptomatic Urinary Tract Infection Acute cystitis and acute pyelonephritis occur in approximately I to 2% of pregnant women (McNeeley 1988). Acute cystitis can be treated safely with an oral agent as in the case of nonpregnant women. Acute pyelonephritis is diagnosed clinically by the presence of costovertebral tenderness, fever, ri-

977

Bacteriuria in Pregnancy

gor, pyuria and bacteriuria. Women with urinary tract infection and accompanying bacteraemia are also considered to have upper urinary tracy infection. When acute pyelonephritis in pregnancy is suspected , the patient should be hospitalised. Urine and blood cultures should be obtained before starting empirically with systemic antimicrobial therapy. The primary goal of therapy is to prevent complications to the mother and fetus, with a secondary goal of reducing the chance of recurrence by eradicating bacteriuria. The choice of antimicrobial agent should be based on clinical experience in safety and efficacy to the mother and fetus. Ampicillin has been recommended as the preferred drug because it is safe and effective in pregnancy (Krieger 1986; MeNeeley 1988). Unfortunately, increasing resistance to ampicillin and sulphonamides has been reported (Johnson & Stamm 1989; Tan & File 1990). Amoxicillin/clavulanic acid has increased antimicrobial spectrum and will cover many isolates resistant to ampicillin. Because of the unpredictability of the infecting microorganism and its antimicrobial susceptibility pattern, intravenous antimicrobial agents with broader coverage should be used for empirical coverage (File & Tan 1986). Uriedopenicillins (e.g. mezlocillin, piperacillin), third generation cephalosporins, or a ,B-Iactam/,B-Iactamase inhibitor combination (e.g. ticarcillin/clavulanic acid) with or without gentamicin should be started empirically when the physician is unsure if the patient has acute cystitis or pyelonephritis. Acute cystitis can be treated safely with an oral agent as in the case of the nonpregnant woman. Gentamicin may cause fetal ototoxicity and should be used with caution. When the antimicrobial susceptibility results are available, a more specific antimicrobial agent should be substituted. When the patient is clinically stable and is tolerating food well, oral therapy may be used. A 10- to 14-day course is recommended (Patterson & Andriole 1987), although a shorter course of therapy has been shown to be effective (Faro et al. 1984). Urine culture should be obtained weekly for 4 weeks then monthly until term. If a culture is positive, a repeat

course of 2 weeks' treatment or a suppressive therapy may be considered. A single 50 to 100mg dose of nitrofurantoin, single-dose cefalexin or cefradine 250mg, or any 'safe' antimicrobial agent effective against the isolated organism is acceptable for suppressive therapy. Harris and Gilstrap (1974) reported a 60% recurrence rate (including both reinfections and relapses) in pregnant women who

Screening test for bacteriuria

-=.

~

.

Routine antenatal care

-=.

Routine antenatal care

.

~,

Urineculture after 1 week

r--=.

+

+ Antimicrobial treatment; single dose or short course

History of recurrenturinary tract infection

+

+-

-

Reculture at the beginning of third trimester

Monthly urine culture

-

Monthly urine culture

+ +

.

Treat with a longer course and possibly with a different antimicrobial agent

~

~

.

Urine cultureafter 1 week

~

Monthlyurine culture or postcoital prophylaxis until the end of gestation

+ -,Ir

Suppressive treatment with nightly nitrofurantoin

----.

3-6 monthsafter delivery,do urological evaluation

Fig. 1. Management of bacteriuria in pregnancy (modified

from Patterson and Andriole 1987).

978

Drugs 44 (6) 1992

Table III. Recommended treatment schedules for bacter iuria in pregnancy Drug Asymptomatic bacteriuria Single dose therapy Amox icillin Cefalexin or cefradine Cotrimoxazole (trimethoprim/ sulfamethoxazole)8 Nitrofurantoin Sulfafurazole (sulfisoxazole) TrimethoPrim 8 Short course (3 to 7 days) Amoxicillin Amoxicillin/clavulanic acid Cefalexin or cefradine Cotr imoxazoles Nitrofurantoin Trlmethoprirn"

Dosage

3g 3g 200mg 2g 320mg 600mg

+

1600mg

500mg tid 500mg tid 500mg tid 320mg + 1600mg bid 100mg tid 100mg bid

Symptomatic bacteriuria Acute cystitis (for 3 to 7 days) Amoxicillin Amoxicill in/clavulanic acid Cefalexin or cefradine Cotr imoxazole 8 Nitrofurantoin Trimathoprirn'' Acute pye/onephritis b Broad spectrum penicillins (e.g. piperacillin. mezlocillin. ticarcillin/clavulanic acid) Broad spectrum cephalosporins (e.g. cefotaxime. ceftizoxime. ceftriazone. cefoperazone. ceftazidime) Aztreonam Aminoglycosides c

500mg tid 500mg tid 500mg tid 320mg + 1600mg bid 100mg tid 100mg bid

1 to 2g tid or bid

Postcoital prophylax is (single doses shortly after intercourse) Cefalexin 250mg Nitrofurantoin 50mg a b

Use with caution because of folate synthesis inhibition . Choose the drug with a spectrum of activity that covers the common causative organisms of urinary tract infections based on local epidemiology. Single-dose or short-course therapy are not recommended for upper urinary tract infections. If the severity of infection is unknown, hosp italise and start intravenous therapy, switching to oral therapy when the patient improves clinically and the result of antimicrobial sens itivity testing is available. c May cause ototoxicity in the fetus . Abbrev iations: bid = twice daily; tid = 3 times daily.

did not receive suppressive therapy after acute pyelonephritis. Close surveillance may be indicated, with suppressive therapy reserved for those with underlying renal disease (Lenke & Stamm 1986; Lenke et al. 1983). Another approach in pregnant women with recurrent urinary tract infection caused by susceptible organisms is to use postcoital prophylaxis (Pfau & Sacks 1992). Symptomatic infection should be treated with an appropriate agent for 1 full day, followed, after the urine is sterile, by a single dose of cefalexin 250mg or nitrofurantoin 50mg shortly after intercourse for the remainder of the pregnancy. Although the results appear to be very impressive, this needs to be confirmed. In addition to antimicrobial treatment, ultrasound may be used to look for urological abnormalities. Intravenous pyelogram and other invasive urological procedures should be deferred until after the pregnancy, unless there is a medical indication such as suspected acute obstructive uropathy, renal abscess or intra-abdominal pathology.

4. Safety of Antimicrobial Agents in Pregnancy The safety profile for the mother and fetus is extremely important when a therapeutic agent is considered for bacteriuria in pregnancy. Unfortunately, human data on drug toxicity to mother and fetus are usually limited, and animal studies on the toxic effect to the fetus are notoriously unreliable (Krieger 1986). Chow and Jewesson (1985) reviewed the pharmacokinetics and safety of antimicrobial agents in pregnancy. Table II summarises the safety of selected drugs which are used for urinary tract infection. As a general rule, the penicillins, cephalosporins, and nitrofurantoin are considered safe; tetracyclines and quinolones are generally contraindicated; and trimethoprim and cotrimoxazole are not recommended.

5. Recommendations Figure 1 shows guidelines for the treatment of bacteriuria in pregnancy, and table III gives rec-

Bacteriuria in Pregnancy

ommended treatment schedules. For the management of asymptomatic bacteriuria, first trimester screening urine culture should be performed routinely. A short term or single dose course should be started if the initial urine screening culture by midstream clean catch technique is confirmed by a subsequent culture yielding the same organism. To ensure eradication ofthe bacteria, a I-week posttreatment urine culture should be obtained and repeat culture at each visit thereafter. If the bacteriuria recurs, a longer course of therapy and possibly with a different antimicrobial agent should be given. Urine culture should be repeated I week after treatment is discontinued. If urine culture remains positive, suppressive therapy with nitrofurantoin until delivery is recommended. Postcoital prophylaxis with cefalexin or nitrofurantoin throughout the gestational period has been shown to be effective (Pfau & Sacks 1992). Special attention should be placed on pregnant women with a history of past urinary tract infection, renal abnormality, and diabetes mellitus because of their increased predisposition to symptomatic infection. If the screening urine culture is negative, these patients should be observed closely and a repeat culture is recommended at the beginning of the third trimester. When a patient has urinary symptoms without fever or toxicity, urine culture should be taken and a short course of oral therapy similar to that for asymptomatic bacteriuria should suffice (MeNeeley 1988). Patients with signs of acute symptomatic infection (fever, chills, and/or flank pain) should be given intravenous therapy until clinical improvement is observed. Oral therapy should be given to complete a 14-day course. Subsequent follow-up is similar to that for asymptomatic bacteriuric patients. When bacteriuria persists in spite of repeated therapy, long term suppressive therapy should be considered individually.

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979

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tions during pregnancy. Urologic Clinics of North America 13: 685-693, 1986 Kunin CM. Detection, prevent ion and management of urinary tract infections, 4th ed., pp. 325-374, Lea & Febiger, Philadelphia, 1987 Lenke RR, Stamm WE. Urinary tract infections. In Galask RP & Larsen B (Eds) Infectious diseases in the female patient , pp. 208-220, Springer, New York, 1986 Lenke RR, van Dorsten JP, Schifrin BS. Pyelonephritis in pregnancy: a prospective randomized trial to prevent recurrent disease evaluating suppressive therap y with nitrofurantoin and close surveillance . American Journal of Obstetri cs and Gynaecology 146: 953-957, 1983 Little PJ. The incidence of urinary infection in 5000 pregnant women . Lancet 2: 925-928, 1966 Marchant DJ. Urinary tract infections in pregnancy. Clinical Obstetrics and Gynaecolog y 21: 921-929, 1978 Masterton RG , Evans DC, Strike PW. Single-dose amoxycillin in the treatment of bacteriuria in pregnancy and the puerperium - a controlled clinical trial. British Journal of Obstetrics and Gynaecology 92: 498-505, 1985 McFadyen IR, Campbell -Brown M, Stephenson M, Seal DV. Single-dose treatment of bacteriuria in pregnancy. European Urology 13 (Suppl. I): 22-25, 1987 Mcfadyen IR, Eykyn 51, Gardner NHN , et al. Bacteriuria in pregnancy. Journal of Obstetrics and Gynaecology of British Commonwealth 80: 385-405, 1973 Mcbleeley SG Jr. Treatment of urinary tract infections during pregnancy. Clinical Obstetrics and Gynaecology 31: 480-487, 1988 National Institute of Health . Summary of a workshop on maternal genitourinary infections and the outcome of pregnancy. Journal of Infectious Diseases 147: 596-605, 1983 Nnatu S, Essien EE, Akinkube A, Odum CU. Asymptomatic bacteriuria in pregnant Nigerian patients. Clinical and Experimental Obstetrics and Gynaecology 16: 126-129, 1989

Drugs 44 (6) 1992

Olsen L, Nielsen IK, zachariassen A, Sederberg-Olsen J. Singledose versus six-day therapy with sulfamethizole for asymptomatic bacteriuria during pregnancy: a prospective randomized study. Danish Medical Bulletin 36: 486-487, 1989 Patterson TF , Andriole VT. Bacteriuria in pregnancy. Infectious Disease Clinics of North America I: 807-822, 1987 Pooler 51, Bint AJ. Management of bacteriuria in pregnancy. Drugs 33: 413-421, 1987 Pfau A, Sacks TG. Effective prophylaxis for recurrent urinary tract infections during pregnancy. Clinics in Infectious Disease 14: 810-814, 1992 Platt R. Adverse consequences of asymptomatic urinary tract infections in adults. American Journal of Medicine 82 (Suppl. 6B): 47-52, 1987 Rubin RH, Fang LST, Jones SR, et al. Single dose amoxycillin therapy for urinary tract infection : multicenter trial using antibody coated bacteria localization technique. Journal of American Medical Association 244: 561·564, 1980 Savage WE, Hajj SN, Kass EH. Demographic and prognostic characteristics of bacteriuria in pregnancy. Medicine 46: 385, 1967 Stamey TA. Pathogenesis and treatment of urinary tract infection, pp. 164-165, Williams & Wilkins, Baltimore, 1980 Stark RP, Maki 00. Bacteriuria in the catheterized patien t. What quantitative level of bacteriuria is relevant? New England Journal of Medicine 311: 560-564, 1984 Tan JS, File TM Jr. Urinary tract infections in obstetrics and gynaecology. Journal of Reproductive Medicine 35 (Suppl. 3): 339-342, 1990 Zhanel GG, Hard ing GKM, Guay DRP . Asymptomatic bacteriuria . Which patients should be treated? Archives of Internal Medicine 150: 1389-1396, 1990

Correspondence and reprints : Dr Jam es S. Tan. 75 Arch St, Suite 105, Akron, OH 44304, USA.