Practical Therapeutics
Drugs 17: 56-65 (1979) 0012-6667/79/0100-0056/$02.50/0 © ADIS Press Australasia Pty Ltd. All rights reserved.
Treatment of Bacterial Infections in Pregnancy Allan J. Weinstein Cleveland Qinic Foundation, Cleveland, Ohio
Summary
Treatment of bacterial infections in pregnancy requires an understanding of the unique problems related to the administration of antibacterial agents to pregnant women. The clinician must be aware not only of the antibiotic-associated untoward effects which may develop in the mother, but also of the possibility that adverse reactions may occur in the fetus. Precise knowledge of the microbial aetiology of those infections which occur during pregnancy and an understanding of the intricacies of antibiotic administration to pregnant women will assure the greatest likelihood that bacterial infections in pregnancy will be effectively, and safely, treated.
Bacterial infections in pregnancy pose special difficulties for the clinician. The selection of an antibiotic must be based both on an understanding of the metabolism and excretion of this group of drugs in the mother, and on consideration of their possible effects upon the fetus. Treatment of bacterial infections in pregnancy requires knowledge of both the types of infection with which. the woman may be afflicted, and the unique problems associated with the use of antibacterial agents in pregnant women.
J. Common Maternal Infections and their Effects on the Fetus Some maternal infections have direct effects upon the fetus. At the present time, the micro-organisms most commonly associated with infection both of mothers and the newborn are Neisseria gonorrhoeae and group B streptococci (Baker et al., I 973; Eickhoff
et al., 1964). Other micro-organisms that have the ability to infect the fetus are Mycobacterium tuberculosis, Treponema pallidum, Listeria monocytogenes, Vibrio fetus, Salmonella typhi, and Pasteurella tularensis. Some infections, such as asymptomatic
bacteriuria, are associated with an increased risk of premature birth (Norden and Kass, 1968). Others, such as vaginal infection, pyelonephritis, bacterial pneumonia, and infections of the amniotic fluid and uterus, involve the mother but do not have a serious effect upon the developing fetus.
2. Special Considerations Relating to Antibiotic Administration in Pregnancy The administration of antibiotics to the pregnant woman must be based on an understanding of the special physiological and concomitant pharmacokinetic conditions which are present in pregnancy.
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Treatment of Bacterial Infections in Pregnancy
For example, the maternal extravascular volume may expand during the second and third trimesters of pregnancy, accounting in part for lower serum antibiotic concentrations in pregnant women than in others. Because renal blood flow and glomerular f1ltration rate may increase during pregnancy, there is also the possibility of greater urinary loss of antibiotics. In addition, since many antibiotics rapidly cross the placenta, the quantity of drug available for maternal perfusion may be lower than predicted because some of it has been distributed to the fetus (Ledger, 1977). In most respects, the administration of antibiotics in pregnancy does not differ from the use of these compounds in other conditions. However, the unusual susceptibility of pregnant women to certain drug related untoward effects, and the dangers to the fetus of those antibiotics that cross the placenta, create special problems that do not occur in other patients. The purpose of this review therefore is to discuss guidelines for treatment of the major bacterial infections of pregnancy: pneumonia, urinary tract infection, group B streptococcal infection, syphilis, gonorrhoea, amnionitis, and septic abortion.
3. The Major Bacterial Infections of Pregnancy: Treatment Considerations 3.1 Pneumonia Bacterial pneumonia is an uncommon cause of serious illness in pregnant women. In the past, the prognosis for a pregnant woman with pneumococcal pneumonia was significantly worse than that for an individual who was not pregnant (Finland and Dublin, 1939). With the widespread availability of antibiotics, however, this difference in prognosIs no longer exists. The evaluation of the patient with pneumonia, whether pregnant or not, must include careful evaluation of a Gram-stained specimen of sputum. Selection
of antibacterial agents is based upon the results of the sputum Gram stain, the sputum culture, and the radiographic fmdings.
3.1.1 Pathogenic Organisms Streptococcus pneumoniae remains the most prevalent micro-organism in community-acquired bacterial pneumonias (Austrian, 1968; Fekety et al., 1971), and penicillin G is the antibiotic of first choice for these infections. In hospitalised patients, however, other bacteria must be considered. Since the upper respiratory flora of the hospitalised patient may convert rapidly from predominantly Gram-positive to one which contains large numbers of Gram-negative bacteria, the possibility of Gram-negative pneumonia is heightened when pulmonary infection has been acquired in hospital (Johanson et al., 1972). Infections due to Escherichia coli, Klebsiella species, Proteus species, and Pseudomonas aeruginosa are common in this clinical setting, and the antibacterial agents which must be considered are quite different from those in the patient with community-acquired pneumonia (Johanson et al., 1972; Stevens et al., 1974).
3.1.2 Treatment o/Community-Acquired Pneumonias Because the likelihood of pneumococcal infection is so high in the patient with community-acquired pneumonia, the choice of an antibiotic is usually not difficult. None of the currently available penicillins has been demonstrated to. be hazardous to pregnant women; all pass the placenta, but none are harmful either to the fetus or to the newborn child (Weinstein, 1975a). Alternative therapy must be administered to the penicillin-allergic patient. If the patient's penicillin hypersensitivity is of the immediate type (anaphylaxis or urticaria), erythromycin is a safe substitute, both for the mother and the fetus. Cephalosporin antibiotics are usually not administered to patients who have bad immediate reactions to penicillins; however, jf the penicillin allergy has been manifest by a late reaction, such as skin rash, cephalosporins may be given (Weinstein, 1975b).
Treatment of Bacterial Infections in Pregnancy
3.1.3 Treatment of Hospital-Acquired Pneumonias The treatment of hospital-acquired pneumonias in pregnant women is considerably more difficult. Since many of these infections are due to Gram-negative bacteria, the antibiotics which must be administered are often those which may be associated with a significant risk of untoward effects either for the mother or the fetus, or both. If the infection is due to Escherichia coli or Proteus mirabilis, and the isolate has been demonstrated to be susceptible either to ampicillin/ amoxycillin or to a cephalosporin antibiotic, one of these compounds may be administered safely. However, increasing numbers of strains of E. coli and most indole-positive Proteus species, such as Proteus vulgaris, Proteus morgan;;, and Proteus rettgeri, are resistant both to ampicillin and to cephalosporins (McGowan et al., 1974). When infection has been produced by one of these micro-organisms, the drugs of first choice are either chloramphenicol or an aminoglycoside antibiotic. Chloramphenicol does not pose special risks for pregnant women. The incidence of haematological toxicity is equal in pregnant and non-pregnant individuals. Dose related anaemia or leucopenia may occur following the administration of chloramphenicol (Gussoff and Lee, 1966) and very rarely (approximately once in 40,000 courses of therapy), fatal bone marrow aplasia may develop (Best, 1967). Chloramphenicol passes the placenta, but is not harmful to the fetus. Although fatal chloramphenicol toxicity may develop in neonates, particularly premature babies, when they have been given excessive doses of the drug, toxic effects have not been observed in newborns when as much as I g of the antibiotic has been administered every two hours to women in labour (Weinstein, I 975c). Aminoglycosides: If the Gram-negative organism is not susceptible to chloramphenicol, serious consideration must be given to the use of one of the aminoglycoside group of antibiotics. The currently available aminoglycosides include neomycin, streptomycin, kanamycin, gentamicin, tobramycin and amikacin. Although these drugs cross the placenta poorly, their administration to pregnant women may
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Table I. Summary of the use of antibiotics in pregnancy
1. Selection of antibiotic must be based on: a) An understanding of the metabolism and excretion of antibiotics in the mother b) Consideration of their possible effects on the fetus 2. The unusual susceptibility of pregnant women to certain drug related untoward effects, and the dangers to the fetus of those antibiotics that cross the placenta, create special problems 3. Penicillins have not been demonstrated to be hazardous to pregnant women, or to the fetus or newbom child 4. Erythromycin is a safe altemative to penicillin, both for the mother and fetus 5. Chloramphenicol does not pose special risks for the pregnant woman and is not harmful to the fetus 6. Co-trimoxazole best avoided in early pregnancy and sulphonamides (and co-trimoxazole) in late pregnancy 7. Aminoglycosides cross the placenta poorly, but their administration may pose risks for the fetus (e.g. in the form of ototoxicity) 8. Because of significant hazards both to the mother and fetus, tetracyclines must never be administered in pregnancy
pose risks for the fetus, e.g. in the form of ototoxicity (Conway and Birt, 1965; Yoshioka et al., 1972). Neomycin and streptomycin no longer playa significant role in the modern therapy of bacterial infections. Kanamycin is active against a broad range of Gram-negative bacteria, but increasing numbers of hospital-acquired infections are produced by organisms such as Enterobacter species, Pseudomonas aeruginosa and Serratia marcescens which are resistant to kanamycin (McGowan et al., 1974). Although their antibacterial superiority is well established, the most effective aminoglycosides, gentamicin, tobramycin and amikacin, have been used too infrequently to permit their unqualified recommendation for the treatment of Gram-negative pneumonia in pregnant women. Tetracyclines: Although many of the Gram-negative bacteria responsible for hospital-acquired pneu-
Treatment of Bacterial Infections in Pregnancy
59
monias are susceptible to the tetracyclines, this group women from low socio-economic classes (who have a of antibiotics must not be administered to pregnant higher prematurity rate), is a manifestation of social women. The tetracyclines are associated with a sig- status and is not important itself as a cause of prenificant risk of the development of hepatic injury in maturity. pregnant women, particularly when administered for 3.2. J Treatment ofAsymptomatic Bacteriuria the treatment of pyelonephritis, but also when Although the precise relationship between bacemployed in other infections (Kunelis et al., 1965). Fatalities have occurred; jaundice develops initially, teriuria and prematurity remains to be established, and azotaemia. acidosis and shock may ensue. The the treatment of bacteriuria of pregnancy is usually so liver is diffusely infiltrated with fat. and although simple and safe that it must be recommended for the hepatic fat is increased during pregnancy, the quantity majority of patients. Administration of the common appears to be even greater after exposure to tetra- sulphonamides, ampicillin/ amoxycillin, nitrofurancyclines (Davis and Kaufman, 1966). In many toin, or co-trimoxazole (trimethoprim-sulphamethoxwomen pyelonephritis appears to be the critical azole) will result in eradication of bacteriuria in 70 to factor. This infection may be associated with 90 % of patients without bacteriological recurrence, if decreased renal function and consequent diminished the treatment is administered for two weeks excretion of the tetracycline; this results in the ac- (Williams et al., 1969). Most of these infections are produced by E. coli. Klebsiella species, and Encumulation of toxic concentrations of the antibiotic. Tetracycline administration in pregnancy also terobacter species, which are susceptible to these composes risks for the fetus. The treatment of pregnant paratively non-toxic antibacterial drugs. Although there is no strong evidence to suggest patients with tetracyclines may produce discoloration of the teeth of their offspring. The period of greatest that co-trimoxazole causes dysmorphogenicity danger is from mid-pregnancy to about 4 to 6 months (Brumfitt and Pursell, 1973), this agent is best of the postnatal period for the deciduous anterior avoided in early pregnancy due to its possible antiteeth, and from 6 months to 5 years of age for the .folate effect and the risk of associated congenital permanent anterior teeth (Weyman, 1965). Tetra- abnormalities. The sulphonamides (including the cyclines are also deposited in the skeleton of the fetus sulphamethoxazole component of co-trimoxazole) are and may produce depression of bone growth (Cobian best avoided in late pregnancy because of the inet al., 1963). Thus, because of the significant hazards creased risk of kernicterus in the neonate. both to the mother and to the developing fetus, tetracyclines must never be administered in pregnancy. 3.2.2 Treatment ofPyelonephritis Despite the elimination of asymptomatic maternal bacteriuria, some pregnant women still develop pyelonephritis. The signs and symptoms of infection 3.2 Urinary Tract Infections are similar to those which occur in non-pregnant inAlthough urinary tract infections in pregnancy dividuals, and the diagnosis of acute pyelonephritis in may produce morbidity in the mother, such illnesses pregnant women is usually not difficult to establish. are important also because an association has been Fever, costovertebral angle tenderness, and clinical observed between asymptomatic maternal bacteriuria manifestations compatible with bacteraemia may be and prematurity (Norden and Kass, 1968). However, present. E. coli is the micro-organism most comit has not been demonstrated that treatment of bac- monly associated with acute pyelonephritis in 'pregteriuria decreases the rate of prematurity (Elder et al., nancy (Gibbs and Weinstein, 1976); Streptococcus 1970, and it is possible that asymptomatic bac- faecalis. staphylococci, Klebsiella species, Enteriuria, which occurs more commonly in pregnant terobacter species, Proteus species, Pseudomonas
Treatment of Bacterial Infections in Pregnancy
species, and other Gram-negative bacteria may also be responsible. A distinction can be made between the patient whose urinary tract infection has been communityacquired, and the individual whose infection was acquired in the hospital. It is very likely that the patient with a ftrst episode of community-acquired pyelonephritis has infection due to E. coli, and either ampicillin/ amoxycillin or a cephalosporin could be administered in such a case. Co-trimoxazole or chloramphenicol would be reasonable alternatives when the patient is unable to tolerate either penicillins or cephalosporins or when the micro-organism is resistant to these antibiotics. It would be unusual for community-acquired urinary tract infections to require the use of an aminoglycoside antibiotic. The micro-organisms responsible for urinary tract infections are quite different in patients with complicated pregnancies who have been admitted to the hospital in advance of the expected time of delivery. Such individuals usually require the insertion of urinary catheters, and the bacteria which produce urinary infections in these women are distinct from those which produce infection in non-catheterised women (Feingold, 1970). Infections due to Pseudomonas aeruginosa, Serratia marcescens, and indole-positive Proteus strains are common in these patients. Often the infection will abate if the catheter is removed. When the condition of the patient does not permit removal of the catheter, systemic antibiotic therapy may not only result in exposure of the mother and the fetus to the risk of untoward effects, but also, rather than eradicating infection, may permit the urine to become colonised with an organism resistant to the antibiotic given. In this case, administration of drugs such as hexamine (methenamine) mandelate or hippurate, nitrofurantoin or co-trimoxazole, or urinary acidiftcation, may be preferable to the use of an aminoglycoside antibiotic. 3.3 Group B Streptococcal Infections Group B streptococci (Streptococcus agalactiae) may produce neonatal sepsis, meningitis and death
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(Baker et aI., 1973; Eickhoff et aI., 1964). Illness in the newborn may be fulminant. The micro-organisms are frequently recovered from the lower genital tract of pregnant women, and appear to be acquired by the neonate during passage through the birth canal. Although group B streptococcal infections remain uncommon, they have been observed with increasing frequency in recent years. It has been suggested that antibiotics be administered both to the culture-positive pregnant woman and to her male sexual partner (McCracken, 1973), but the efficacy of such therapy has not been demonstrated (Eickhoff et al., 1973). Group B streptococci are uniformly susceptible to penicillins, and these antibiotics may be administered with safety to pregnant women. In patients with immediate hypersensitivity to penicillins (to whom cephalosporin antibiotics would not be administered), erythromycin is an effective, safe alternative. 3.4 Syphilis When Treponema pallidum produces infection in a pregnant woman, the potential exists for signiftcant adverse effects upon the fetus. Spirochaetes may cross the placenta and infect the fetus in utero, and the signs and symptoms of congenital syphilis may not be apparent even at birth. Because of recent dramatic rises in the incidence of venereal disease, it has become increasingly important that the clinician understand the methods of diagnosis and therapy of syphilis in the pregnant woman. Dark fteld examination of material obtained from skin and genital lesions is usually sufficient to establish the diagnosis of syphilis. In clinical practice, however, diagnosis is based primarily on the results of serological tests. If the test results are positive and the patient has not previously been treated for syphilis, antibiotic therapy must be administered and the drug of ftrst choice is penicillin. However, two difficulties arise in the diagnosis and therapy of syphilis in pregnant women. The ftrst occurs when maternal exposure to syphilis has taken place either just prior to or just after the ftrst prenatal visit, before serological tests have become positive. For this
Treatment of Bacterial Infections in Pregnancy
reason, serological studies must be repeated both during the third trimester of pregnancy and at the time that the woman is admitted to the hospital in labour. Such repeated serological testing permits identification of women who have become seropositive during pregnancy and allows appropriate therapy both for the mother and for the infant (Monif et al., 1973). The second area of concern involves therapy of the seropositive pregnant woman who is allergic to penicillin. Tetracyclines are the usual first alternatives for treatment of patients with syphilis who are allergic to penicillin, but these compounds must not be administered to pregnant women. Erythromycin is another alternative; although experience with this antibiotic indicates that it is effective in maternal syphilis, it has been observed that congenital syphilis may occur after maternal treatment with erythromycin (Fenton and Light, 1976; South et al., 1964). It has therefore been suggested that while oral erythromycin may be utilised for maternal syphilis during the first four months of pregnancy when the fetus is not yet infected, intravenous erythromycin may be required to achieve blood concentrations sufficient to effect adequate placental transfer after the first four months. If an oral erythromycin preparation is employed, erythromycin estolate should not be selected because of its potential for causing cholestatic hepatitis.
3.5 Gonorrhoea
Neisseria gonorrhoeae may be acquired by the fetus during passage through the birth canal, and lower genital tract gonorrhoea may be associated with serious infection of the newborn infant. Because many pregnant women with gonorrhoea are asymptomatic, and maternal infection is unsuspected by the clinician, prophylactic treatment of the eyes of a newborn has become increasingly important at a time when the incidence of gonococcal infections is rising. Early diagnosis and treatment are essential. Although gonorrhoea in the pregnant woman must
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be recognised in order to avoid adverse fetal effects, it must also be remembered that it is during pregnancy that the risk of developing disseminated gonococcal infection in the mother may be highest (Brown, 1973; Watring and Vaughn, 1976).
3.5.1 Treatment 0/ Uncomplicated Gonorrhoea Uncomplicated gonorrhoea is effectively treated with penicillin G. Although the dose of penicillin which is required for eradication of uncomplicated gonococcal infection has increased in recent years, this antibiotic remains the keystone of therapy for gonorrhoea. Recently, penicillin-resistant strains of Neisseria gonorrhoeae have been isolated (Phillips, 1976), and in the future modifications in the recommended regimen of penicillin therapy for gonorrhoea may be necessary. Spectinomycin is a useful alternative for the penicillin-allergic patient; this antibiotic is highly effective in uncomplicated gonorrhoea, but little information is available concerning the incidence or type of untoward effects which might develop when it is administered to pregnant women (Schroeter et al., 1975). Although the tetracyclines are frequently employed for the treatment of gonococcal infections in penicillin-allergic patients, these antibiotics must not be administered to pregnant women. Other antibiotics, such as erythromycin, cephalexin, kanamycin, and co-trimoxazole have been demonstrated to be effective in the therapy of gonorrhoea, but have been used infrequently (Dans, 1975). The selection of one of these agents for administration to the penicillin-allergic pregnant woman with acute gonococcal infection must be based on an assessment of the likelihood of untoward effects which may be associated with its use. 3.5.2 Treatment 0/Disseminated Gonococcal Infection Pregnancy confers an increased risk for the dissemination of gonococci. Penicillin G and ampicillin (or amoxycillin) are highly effective in the therapy of disseminated gonococcal infection. Either parenteral penicillin G or oral ampicillin/ amoxycillin, in
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Treatment of Bacterial Infections in Pregnancy
Table II. Summary of treatment of the major bacterial infections of pregnancy
1. Pneumonia a) Evaluation of Gram-stained specimen of sputum important b) For community-acquired pneumonias, penicillins are first choice (since Su. pneumoniae remains the most prevalent pathogen); use erythromycin in penicillin hypersensitive patients c) In hospital-acquired pneumonias, Gram-negative infection must be suspected. If infection is due to ampicillin or cephalosporin-resistant organisms, chloramphenicol or aminoglycosides are drugs of first choice d) If aminoglycosides used, potential for toxicity must be considered e) Tetracyclines contraindicated in pregnancy 2. Urinary tract infections a) Although precise relationship between maternal bacteriuria and prematurity remains to be established, treatment of asymptomatic bacteriuria is recommended for majority of patients b) 2 weeks' treatment with a sulphonamide, ampicillin/amoxycillin, nitrofurantoin or co-trimoxazole will eradicate bacteriuria in 70 to 90% of cases c) If pyelonephritis present, ampicillin/amoxycillin or a cephalosporin are appropriate if infection is community-acquired; use co-trimoxazole or chloramphenicol if patient is unable to tolerate these drugs or if organism resistant d) In catheterised patients, hexamine (methenamine), nitrofurantoin or co-trimoxazole may be preferred treatment 3. Group B streptococcal infections a) Treatment essential as group B streptococcus may produce neonatal sepsis, meningitis and death b) Penicillins are first choice treatment c) Use erythromycin in penicillin hypersensitive patients 4. Syphilis a) Serological testing should be carried out at first prenatal visit, during third trimester and on admission in labour b) In seropositive women, penicillin is first choice treatment c) Use erythromycin in penicillin hypersensitive patients - orally during first 4 months of pregnancy (not estolate); IV route recommended thereafter
Table II.
(continued) 5. Gonorrhoea a) Early diagnosis and treatment essential to avoid adverse effects on fetus b) For uncomplicated gonorrhoea, penicillin G is first choice; in penicillin hypersensitive patients spectinomycin is a useful alternative (although little information is available on untoward effects in pregnant women) c) For disseminated gonococcal infection, give parenteral penicillin G or oral ampicillin/amoxycillin for 3 to 14 days; use erythromycin in penicillin hypersensitive patients 6. Amnionitis a) Institute treatment as soon as diagnosis suspected b) Combination of penicillin with chloramphenicol or an aminoglycoside is suitable for initial therapy c) Alternatively, give a cephalosporin or clindamycin with an aminoglycoside 7. Septic abortion a) Combination of penicillin or ampicillin with chloramphenicol effective against most pathogens b) Alternatively, give clindamycin or a cephalosporin with an aminoglycoside c) Antibiotic therapy must be combined with evacuation of uterine contents, IV fluids and vasopressor agents
courses of therapy lasting from 3 to 14 days, may be administered (Hands field et al., 1976). Tetracycline is given to non-pregnant penicillin-allergic women but in pregnant patients who are unable to tolerate penicillins, erythromycin should be given. 3.6 Amnionitis Intrapartum infection is produced primarily by the ascent of vaginal bacteria into the amniotic cavity, usually after rupture of the membranes. Transmission of infection to the fetus then takes place by way of its mouth or nose, with the most common and severe lesions found in the fetal lungs. Amniotic infection may also be responsible for the production of fetal sepsis, following passage of bacteria through the mucosa of the gastrointestinal or respiratory tract of
63
Treatment of Bacterial Infections in Pregnancy
the mother, or as the result of direct invasion of chorionic vessels on the placental surface, occurring by means of extraovular spread between the membranes and the uterine wall. Rarely, haematogenous dissemination from placenta to fetus takes place by way of the fallopian tube (Benirschke, 1960; Blanc, 196 I). Haematogenous placentofetal infections developing as the result of maternal sepsis may be produced by a great variety of micro-organisms. Ascending infection, both amniotic and placentofetal, are usually caused by vaginal bacteria. Simultaneous bacterial invasion of both maternal and fetal tissues is common in ascending placentofetal infections, but is rare in amniotic infections. Premature rupture of the membranes, particularly when there has been a long delay before the onset of labour, enhances the possibility that bacteria will ascend from the vagina (Shubeck et al., 1966). Prolonged labour and excessive digital and instrumental manipulation also predispose to ascending infection. 3.6.1 Pathogenic Organisms The bacteria most commonly found in the amniotic fluid and in the cord blood are E. coli. Streptococcus !aecalis. Staphylococcus epidermidis and Staphylococcus aureus. These micro-organisms are inhabitants of the normal vaginal microflora. With advances in the techniques of anaerobic bacteriology, the importance of anaerobic Gram-positive and Gram-negative micro-organisms in amnionitis has also been established (Gorbach and Bartlett, 1974). 3.6.2 Treatment Because amnionitis in labour is particularly hazardous to the infant, antibiotic therapy must be instituted as soon as the diagnosis is suspected. In view of the micro-organisms most commonly responsible for such infections, broad spectrum therapy should be administered until the results of cultures become available. The combination of a penicillin with chloramphenicol or with one of the aminoglycoside antibiotics, may be employed for initial therapy.
Alternatively, a cephalosporin antibiotic or clindamycin could be administered in combination with an aminoglycoside. The antibacterial spectra of erythromycin and tetracyclines are too limited to make them useful in this situation.
3.7 Septic Abortion Septic abortion remains an important cause of maternal mortality; it is through its production of septic shock that this infection is most lethal. Effective therapy of septic abortion requires more than the administration of antibacterial agents. Evacuation of the uterine contents, and administration of fluid and electrolyte solutions and vasopressor agents, must be combined with antibiotic therapy. Gram-negative bacteria, especially E. coli. are responsible for the majority of these infections, but Gram-positive bacteria, particularly Clostridium per!ringens. have also been cultured from septic abortion cases (Gibbs and Weinstein, 1976). The combination of penicillin or ampicillin with chloramphenicol will provide activity against most of the micro-organisms responsible for septic abortion, prior to the receipt of culture results. Other antibiotics which could be administered in this situation are elindamycin or a cephalosporin in combination with an aminoglycoside.
4. Conclusion The treatment of bacterial infections in the pregnant woman confronts the clinician with unique problems. Although many of the infections with which pregnant women are affiicted are similar to those which affect others, consideration of the very special circumstances of the pregnant woman, her unique predisposition to certain antibiotic-related untoward effects, and the possibility of transplacental transfer of antibiotics with subsequent risk to the fetus, make this one of the most challenging areas of modern antibiotic use.
Treatment of Bacterial Infections in Pregnancy
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mycoplasmas in acute pneumonias in adults. American Review of Respiratory Disease 104: 499-507 (197 n. Fenton. L.J. and Light. l.J.: Congenital syphilis after maternal treatment with erythromycin. Obstetrics and Gynecology 47: 492-494 (1976). Finland. M. and Dublin, T.D.: Pneumococcic pneumonias complicating pregnancy and the puerperium. Journal of the American Medical Association 112: 1027-1032 (1939). Gibbs. R.S. and Weinstein. AJ.: Puerperal infection in the antibiotic era. American Journal of Obstetrics and Gynecology 124: 769-787 (1976). Gorbach. S.L. and Bartlett. J.G.: Anaerobic infections. New England Journal of Medicine 290: 1289-1294 (1974). Gussoff. B.D. and Lee. S.L.: Chloramphenicol-induced hematopoietic depression: A controlled comparison with tetracycline. American Journal of the Medical Sciences 251: 8-15 (1966). Handsfield. H.H.; Wiesner, PJ. and Holmes, KK.: Treatment of the gonococcal arthritis-dermatitis syndrome. Annals of Internal Medicine 84: 661-667 (] 976). Johanson. W.G.; Pierce. A.K; Sanford. J.P. and Thomas. G.D.: Nosocomial respiratory infections with Gram-negative bacilli: The significance of colonization of the respiratory tract. Annals of Internal Medicine 77: 701-706 (] 972). Kunelis. C.T.; Peters, R.L. and Edmondson. H.A.: Fatty liver of pregnancy and its relationship to tetracycline therapy. American Journal of Medicine 38: 359-377 (1965). Ledger. WJ.: Antibiotics in pregnancy. Clinical Obstetrics and Gynecology 20: 411-421 (] 977). McCracken. G.H .• Jr.: Group B streptococci. The new challenge in neonatal infections. Journal of Pediatrics 82: 703-706 (1973). McGowan, J.E.; Garner. C.; Wilcox, C. and Finland. M.: Antibiotic susceptibility of Gram-negative bacilli isolated from blood cultures. American Journal of Medicine 57: 225-238 (1974). Monif. G.R.G.; Williams, B.R .• Jr.; Shulman. S.T. and Baer. H.: The problem of maternal syphilis after serologic surveillance during pregnancy. American Journal of Obstetrics and Gynecology 117: 268-270 (1973). Norden. C.W. and Kass. E.H.: Bacteriuria of pregnancy--a critical appraisal. Annual Review of Medicine 19: 431-470 (] 968). Phillips, l.: B-Iactamase producing penicillin-resistant gonococcus. Lancet 2: 656-657 (1976). Schroeter. A.L.; Reynold. G.H.; Holmes. K.K; Pyke. T. and Wiesner. PJ.: Spectinomycin in the treatment of gonorrhea. Journal of the American Venereal Disease Association I: 139-145 (]975). Shubeck. F.; Benson R.C.; Clark. W.W.; Berendes. H.; Weiss. W. and Deutschberger. J.: Fetal hazard after rupture of the membranes. Obstetrics and Gynecology 28: 22-3 I (] 966). South. M.A.; Short, D.H. and Know. J.M.: Failure of erythromycin estolate therapy in in utero syphilis. Journal of the American Medical Association 190: 70-71 (] 964).
Treatment of Bacterial Infections in Pregnancy
Stevens, R.M.; Teres, D.; Skillman, J.1. and Feingold, D.S.: Pneumonia in an intensive care unit. Archives of Internal Medicine 134: 106-111 (J 974). Watring, W.G. and Vaughn, D.L.: Gonococcemia in pregnancy. Obstetrics and Gynecology 48: 428-430 (J 976). Weinstein, L.: Antimicrobial agents: Penicillins; in Goodman and Gilman (Eds.> The Pharmacological Basis of Therapeutics, pp.1130-1158 (MacMillan, New York I 975a). Weinstein, L.: Antimicrobial agents: Cephalosporins; in Goodman and Gilman (Eds'> The Pharmacological Basis of Therapeutics, pp.1158-1166 (MacMillan, New York I 975b).
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Weinstein L.: Antimicrobial agents: Chloramphenicol; in Goodman and Gilman (Eds.> The Pharmacological Basis of Therapeutics, pp.1194-1200 (MacMillan, New York 1975cl. Weyman, J.: Tetracyclines and teeth. Practitioner 195: 661-665 (J 965).
Author's address: Dr Allan J. Weinstein. Department of Infectious Disease, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland. Ohio 44106 (USA).
Drugs 17: 56-65 (1979) 0012-6667/79/0100-0056/$02.50/0 © ADIS Press Australasia Pty Ltd. All rights reserved.
Treatment of Bacterial Infections in Pregnancy Allan J. Weinstein Cleveland Qinic Foundation, Cleveland, Ohio
Summary
Treatment of bacterial infections in pregnancy requires an understanding of the unique problems related to the administration of antibacterial agents to pregnant women. The clinician must be aware not only of the antibiotic-associated untoward effects which may develop in the mother, but also of the possibility that adverse reactions may occur in the fetus. Precise knowledge of the microbial aetiology of those infections which occur during pregnancy and an understanding of the intricacies of antibiotic administration to pregnant women will assure the greatest likelihood that bacterial infections in pregnancy will be effectively, and safely, treated.
Bacterial infections in pregnancy pose special difficulties for the clinician. The selection of an antibiotic must be based both on an understanding of the metabolism and excretion of this group of drugs in the mother, and on consideration of their possible effects upon the fetus. Treatment of bacterial infections in pregnancy requires knowledge of both the types of infection with which. the woman may be afflicted, and the unique problems associated with the use of antibacterial agents in pregnant women.
J. Common Maternal Infections and their Effects on the Fetus Some maternal infections have direct effects upon the fetus. At the present time, the micro-organisms most commonly associated with infection both of mothers and the newborn are Neisseria gonorrhoeae and group B streptococci (Baker et al., I 973; Eickhoff
et al., 1964). Other micro-organisms that have the ability to infect the fetus are Mycobacterium tuberculosis, Treponema pallidum, Listeria monocytogenes, Vibrio fetus, Salmonella typhi, and Pasteurella tularensis. Some infections, such as asymptomatic
bacteriuria, are associated with an increased risk of premature birth (Norden and Kass, 1968). Others, such as vaginal infection, pyelonephritis, bacterial pneumonia, and infections of the amniotic fluid and uterus, involve the mother but do not have a serious effect upon the developing fetus.
2. Special Considerations Relating to Antibiotic Administration in Pregnancy The administration of antibiotics to the pregnant woman must be based on an understanding of the special physiological and concomitant pharmacokinetic conditions which are present in pregnancy.
57
Treatment of Bacterial Infections in Pregnancy
For example, the maternal extravascular volume may expand during the second and third trimesters of pregnancy, accounting in part for lower serum antibiotic concentrations in pregnant women than in others. Because renal blood flow and glomerular f1ltration rate may increase during pregnancy, there is also the possibility of greater urinary loss of antibiotics. In addition, since many antibiotics rapidly cross the placenta, the quantity of drug available for maternal perfusion may be lower than predicted because some of it has been distributed to the fetus (Ledger, 1977). In most respects, the administration of antibiotics in pregnancy does not differ from the use of these compounds in other conditions. However, the unusual susceptibility of pregnant women to certain drug related untoward effects, and the dangers to the fetus of those antibiotics that cross the placenta, create special problems that do not occur in other patients. The purpose of this review therefore is to discuss guidelines for treatment of the major bacterial infections of pregnancy: pneumonia, urinary tract infection, group B streptococcal infection, syphilis, gonorrhoea, amnionitis, and septic abortion.
3. The Major Bacterial Infections of Pregnancy: Treatment Considerations 3.1 Pneumonia Bacterial pneumonia is an uncommon cause of serious illness in pregnant women. In the past, the prognosis for a pregnant woman with pneumococcal pneumonia was significantly worse than that for an individual who was not pregnant (Finland and Dublin, 1939). With the widespread availability of antibiotics, however, this difference in prognosIs no longer exists. The evaluation of the patient with pneumonia, whether pregnant or not, must include careful evaluation of a Gram-stained specimen of sputum. Selection
of antibacterial agents is based upon the results of the sputum Gram stain, the sputum culture, and the radiographic fmdings.
3.1.1 Pathogenic Organisms Streptococcus pneumoniae remains the most prevalent micro-organism in community-acquired bacterial pneumonias (Austrian, 1968; Fekety et al., 1971), and penicillin G is the antibiotic of first choice for these infections. In hospitalised patients, however, other bacteria must be considered. Since the upper respiratory flora of the hospitalised patient may convert rapidly from predominantly Gram-positive to one which contains large numbers of Gram-negative bacteria, the possibility of Gram-negative pneumonia is heightened when pulmonary infection has been acquired in hospital (Johanson et al., 1972). Infections due to Escherichia coli, Klebsiella species, Proteus species, and Pseudomonas aeruginosa are common in this clinical setting, and the antibacterial agents which must be considered are quite different from those in the patient with community-acquired pneumonia (Johanson et al., 1972; Stevens et al., 1974).
3.1.2 Treatment o/Community-Acquired Pneumonias Because the likelihood of pneumococcal infection is so high in the patient with community-acquired pneumonia, the choice of an antibiotic is usually not difficult. None of the currently available penicillins has been demonstrated to. be hazardous to pregnant women; all pass the placenta, but none are harmful either to the fetus or to the newborn child (Weinstein, 1975a). Alternative therapy must be administered to the penicillin-allergic patient. If the patient's penicillin hypersensitivity is of the immediate type (anaphylaxis or urticaria), erythromycin is a safe substitute, both for the mother and the fetus. Cephalosporin antibiotics are usually not administered to patients who have bad immediate reactions to penicillins; however, jf the penicillin allergy has been manifest by a late reaction, such as skin rash, cephalosporins may be given (Weinstein, 1975b).
Treatment of Bacterial Infections in Pregnancy
3.1.3 Treatment of Hospital-Acquired Pneumonias The treatment of hospital-acquired pneumonias in pregnant women is considerably more difficult. Since many of these infections are due to Gram-negative bacteria, the antibiotics which must be administered are often those which may be associated with a significant risk of untoward effects either for the mother or the fetus, or both. If the infection is due to Escherichia coli or Proteus mirabilis, and the isolate has been demonstrated to be susceptible either to ampicillin/ amoxycillin or to a cephalosporin antibiotic, one of these compounds may be administered safely. However, increasing numbers of strains of E. coli and most indole-positive Proteus species, such as Proteus vulgaris, Proteus morgan;;, and Proteus rettgeri, are resistant both to ampicillin and to cephalosporins (McGowan et al., 1974). When infection has been produced by one of these micro-organisms, the drugs of first choice are either chloramphenicol or an aminoglycoside antibiotic. Chloramphenicol does not pose special risks for pregnant women. The incidence of haematological toxicity is equal in pregnant and non-pregnant individuals. Dose related anaemia or leucopenia may occur following the administration of chloramphenicol (Gussoff and Lee, 1966) and very rarely (approximately once in 40,000 courses of therapy), fatal bone marrow aplasia may develop (Best, 1967). Chloramphenicol passes the placenta, but is not harmful to the fetus. Although fatal chloramphenicol toxicity may develop in neonates, particularly premature babies, when they have been given excessive doses of the drug, toxic effects have not been observed in newborns when as much as I g of the antibiotic has been administered every two hours to women in labour (Weinstein, I 975c). Aminoglycosides: If the Gram-negative organism is not susceptible to chloramphenicol, serious consideration must be given to the use of one of the aminoglycoside group of antibiotics. The currently available aminoglycosides include neomycin, streptomycin, kanamycin, gentamicin, tobramycin and amikacin. Although these drugs cross the placenta poorly, their administration to pregnant women may
58
Table I. Summary of the use of antibiotics in pregnancy
1. Selection of antibiotic must be based on: a) An understanding of the metabolism and excretion of antibiotics in the mother b) Consideration of their possible effects on the fetus 2. The unusual susceptibility of pregnant women to certain drug related untoward effects, and the dangers to the fetus of those antibiotics that cross the placenta, create special problems 3. Penicillins have not been demonstrated to be hazardous to pregnant women, or to the fetus or newbom child 4. Erythromycin is a safe altemative to penicillin, both for the mother and fetus 5. Chloramphenicol does not pose special risks for the pregnant woman and is not harmful to the fetus 6. Co-trimoxazole best avoided in early pregnancy and sulphonamides (and co-trimoxazole) in late pregnancy 7. Aminoglycosides cross the placenta poorly, but their administration may pose risks for the fetus (e.g. in the form of ototoxicity) 8. Because of significant hazards both to the mother and fetus, tetracyclines must never be administered in pregnancy
pose risks for the fetus, e.g. in the form of ototoxicity (Conway and Birt, 1965; Yoshioka et al., 1972). Neomycin and streptomycin no longer playa significant role in the modern therapy of bacterial infections. Kanamycin is active against a broad range of Gram-negative bacteria, but increasing numbers of hospital-acquired infections are produced by organisms such as Enterobacter species, Pseudomonas aeruginosa and Serratia marcescens which are resistant to kanamycin (McGowan et al., 1974). Although their antibacterial superiority is well established, the most effective aminoglycosides, gentamicin, tobramycin and amikacin, have been used too infrequently to permit their unqualified recommendation for the treatment of Gram-negative pneumonia in pregnant women. Tetracyclines: Although many of the Gram-negative bacteria responsible for hospital-acquired pneu-
Treatment of Bacterial Infections in Pregnancy
59
monias are susceptible to the tetracyclines, this group women from low socio-economic classes (who have a of antibiotics must not be administered to pregnant higher prematurity rate), is a manifestation of social women. The tetracyclines are associated with a sig- status and is not important itself as a cause of prenificant risk of the development of hepatic injury in maturity. pregnant women, particularly when administered for 3.2. J Treatment ofAsymptomatic Bacteriuria the treatment of pyelonephritis, but also when Although the precise relationship between bacemployed in other infections (Kunelis et al., 1965). Fatalities have occurred; jaundice develops initially, teriuria and prematurity remains to be established, and azotaemia. acidosis and shock may ensue. The the treatment of bacteriuria of pregnancy is usually so liver is diffusely infiltrated with fat. and although simple and safe that it must be recommended for the hepatic fat is increased during pregnancy, the quantity majority of patients. Administration of the common appears to be even greater after exposure to tetra- sulphonamides, ampicillin/ amoxycillin, nitrofurancyclines (Davis and Kaufman, 1966). In many toin, or co-trimoxazole (trimethoprim-sulphamethoxwomen pyelonephritis appears to be the critical azole) will result in eradication of bacteriuria in 70 to factor. This infection may be associated with 90 % of patients without bacteriological recurrence, if decreased renal function and consequent diminished the treatment is administered for two weeks excretion of the tetracycline; this results in the ac- (Williams et al., 1969). Most of these infections are produced by E. coli. Klebsiella species, and Encumulation of toxic concentrations of the antibiotic. Tetracycline administration in pregnancy also terobacter species, which are susceptible to these composes risks for the fetus. The treatment of pregnant paratively non-toxic antibacterial drugs. Although there is no strong evidence to suggest patients with tetracyclines may produce discoloration of the teeth of their offspring. The period of greatest that co-trimoxazole causes dysmorphogenicity danger is from mid-pregnancy to about 4 to 6 months (Brumfitt and Pursell, 1973), this agent is best of the postnatal period for the deciduous anterior avoided in early pregnancy due to its possible antiteeth, and from 6 months to 5 years of age for the .folate effect and the risk of associated congenital permanent anterior teeth (Weyman, 1965). Tetra- abnormalities. The sulphonamides (including the cyclines are also deposited in the skeleton of the fetus sulphamethoxazole component of co-trimoxazole) are and may produce depression of bone growth (Cobian best avoided in late pregnancy because of the inet al., 1963). Thus, because of the significant hazards creased risk of kernicterus in the neonate. both to the mother and to the developing fetus, tetracyclines must never be administered in pregnancy. 3.2.2 Treatment ofPyelonephritis Despite the elimination of asymptomatic maternal bacteriuria, some pregnant women still develop pyelonephritis. The signs and symptoms of infection 3.2 Urinary Tract Infections are similar to those which occur in non-pregnant inAlthough urinary tract infections in pregnancy dividuals, and the diagnosis of acute pyelonephritis in may produce morbidity in the mother, such illnesses pregnant women is usually not difficult to establish. are important also because an association has been Fever, costovertebral angle tenderness, and clinical observed between asymptomatic maternal bacteriuria manifestations compatible with bacteraemia may be and prematurity (Norden and Kass, 1968). However, present. E. coli is the micro-organism most comit has not been demonstrated that treatment of bac- monly associated with acute pyelonephritis in 'pregteriuria decreases the rate of prematurity (Elder et al., nancy (Gibbs and Weinstein, 1976); Streptococcus 1970, and it is possible that asymptomatic bac- faecalis. staphylococci, Klebsiella species, Enteriuria, which occurs more commonly in pregnant terobacter species, Proteus species, Pseudomonas
Treatment of Bacterial Infections in Pregnancy
species, and other Gram-negative bacteria may also be responsible. A distinction can be made between the patient whose urinary tract infection has been communityacquired, and the individual whose infection was acquired in the hospital. It is very likely that the patient with a ftrst episode of community-acquired pyelonephritis has infection due to E. coli, and either ampicillin/ amoxycillin or a cephalosporin could be administered in such a case. Co-trimoxazole or chloramphenicol would be reasonable alternatives when the patient is unable to tolerate either penicillins or cephalosporins or when the micro-organism is resistant to these antibiotics. It would be unusual for community-acquired urinary tract infections to require the use of an aminoglycoside antibiotic. The micro-organisms responsible for urinary tract infections are quite different in patients with complicated pregnancies who have been admitted to the hospital in advance of the expected time of delivery. Such individuals usually require the insertion of urinary catheters, and the bacteria which produce urinary infections in these women are distinct from those which produce infection in non-catheterised women (Feingold, 1970). Infections due to Pseudomonas aeruginosa, Serratia marcescens, and indole-positive Proteus strains are common in these patients. Often the infection will abate if the catheter is removed. When the condition of the patient does not permit removal of the catheter, systemic antibiotic therapy may not only result in exposure of the mother and the fetus to the risk of untoward effects, but also, rather than eradicating infection, may permit the urine to become colonised with an organism resistant to the antibiotic given. In this case, administration of drugs such as hexamine (methenamine) mandelate or hippurate, nitrofurantoin or co-trimoxazole, or urinary acidiftcation, may be preferable to the use of an aminoglycoside antibiotic. 3.3 Group B Streptococcal Infections Group B streptococci (Streptococcus agalactiae) may produce neonatal sepsis, meningitis and death
60
(Baker et aI., 1973; Eickhoff et aI., 1964). Illness in the newborn may be fulminant. The micro-organisms are frequently recovered from the lower genital tract of pregnant women, and appear to be acquired by the neonate during passage through the birth canal. Although group B streptococcal infections remain uncommon, they have been observed with increasing frequency in recent years. It has been suggested that antibiotics be administered both to the culture-positive pregnant woman and to her male sexual partner (McCracken, 1973), but the efficacy of such therapy has not been demonstrated (Eickhoff et al., 1973). Group B streptococci are uniformly susceptible to penicillins, and these antibiotics may be administered with safety to pregnant women. In patients with immediate hypersensitivity to penicillins (to whom cephalosporin antibiotics would not be administered), erythromycin is an effective, safe alternative. 3.4 Syphilis When Treponema pallidum produces infection in a pregnant woman, the potential exists for signiftcant adverse effects upon the fetus. Spirochaetes may cross the placenta and infect the fetus in utero, and the signs and symptoms of congenital syphilis may not be apparent even at birth. Because of recent dramatic rises in the incidence of venereal disease, it has become increasingly important that the clinician understand the methods of diagnosis and therapy of syphilis in the pregnant woman. Dark fteld examination of material obtained from skin and genital lesions is usually sufficient to establish the diagnosis of syphilis. In clinical practice, however, diagnosis is based primarily on the results of serological tests. If the test results are positive and the patient has not previously been treated for syphilis, antibiotic therapy must be administered and the drug of ftrst choice is penicillin. However, two difficulties arise in the diagnosis and therapy of syphilis in pregnant women. The ftrst occurs when maternal exposure to syphilis has taken place either just prior to or just after the ftrst prenatal visit, before serological tests have become positive. For this
Treatment of Bacterial Infections in Pregnancy
reason, serological studies must be repeated both during the third trimester of pregnancy and at the time that the woman is admitted to the hospital in labour. Such repeated serological testing permits identification of women who have become seropositive during pregnancy and allows appropriate therapy both for the mother and for the infant (Monif et al., 1973). The second area of concern involves therapy of the seropositive pregnant woman who is allergic to penicillin. Tetracyclines are the usual first alternatives for treatment of patients with syphilis who are allergic to penicillin, but these compounds must not be administered to pregnant women. Erythromycin is another alternative; although experience with this antibiotic indicates that it is effective in maternal syphilis, it has been observed that congenital syphilis may occur after maternal treatment with erythromycin (Fenton and Light, 1976; South et al., 1964). It has therefore been suggested that while oral erythromycin may be utilised for maternal syphilis during the first four months of pregnancy when the fetus is not yet infected, intravenous erythromycin may be required to achieve blood concentrations sufficient to effect adequate placental transfer after the first four months. If an oral erythromycin preparation is employed, erythromycin estolate should not be selected because of its potential for causing cholestatic hepatitis.
3.5 Gonorrhoea
Neisseria gonorrhoeae may be acquired by the fetus during passage through the birth canal, and lower genital tract gonorrhoea may be associated with serious infection of the newborn infant. Because many pregnant women with gonorrhoea are asymptomatic, and maternal infection is unsuspected by the clinician, prophylactic treatment of the eyes of a newborn has become increasingly important at a time when the incidence of gonococcal infections is rising. Early diagnosis and treatment are essential. Although gonorrhoea in the pregnant woman must
61
be recognised in order to avoid adverse fetal effects, it must also be remembered that it is during pregnancy that the risk of developing disseminated gonococcal infection in the mother may be highest (Brown, 1973; Watring and Vaughn, 1976).
3.5.1 Treatment 0/ Uncomplicated Gonorrhoea Uncomplicated gonorrhoea is effectively treated with penicillin G. Although the dose of penicillin which is required for eradication of uncomplicated gonococcal infection has increased in recent years, this antibiotic remains the keystone of therapy for gonorrhoea. Recently, penicillin-resistant strains of Neisseria gonorrhoeae have been isolated (Phillips, 1976), and in the future modifications in the recommended regimen of penicillin therapy for gonorrhoea may be necessary. Spectinomycin is a useful alternative for the penicillin-allergic patient; this antibiotic is highly effective in uncomplicated gonorrhoea, but little information is available concerning the incidence or type of untoward effects which might develop when it is administered to pregnant women (Schroeter et al., 1975). Although the tetracyclines are frequently employed for the treatment of gonococcal infections in penicillin-allergic patients, these antibiotics must not be administered to pregnant women. Other antibiotics, such as erythromycin, cephalexin, kanamycin, and co-trimoxazole have been demonstrated to be effective in the therapy of gonorrhoea, but have been used infrequently (Dans, 1975). The selection of one of these agents for administration to the penicillin-allergic pregnant woman with acute gonococcal infection must be based on an assessment of the likelihood of untoward effects which may be associated with its use. 3.5.2 Treatment 0/Disseminated Gonococcal Infection Pregnancy confers an increased risk for the dissemination of gonococci. Penicillin G and ampicillin (or amoxycillin) are highly effective in the therapy of disseminated gonococcal infection. Either parenteral penicillin G or oral ampicillin/ amoxycillin, in
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Treatment of Bacterial Infections in Pregnancy
Table II. Summary of treatment of the major bacterial infections of pregnancy
1. Pneumonia a) Evaluation of Gram-stained specimen of sputum important b) For community-acquired pneumonias, penicillins are first choice (since Su. pneumoniae remains the most prevalent pathogen); use erythromycin in penicillin hypersensitive patients c) In hospital-acquired pneumonias, Gram-negative infection must be suspected. If infection is due to ampicillin or cephalosporin-resistant organisms, chloramphenicol or aminoglycosides are drugs of first choice d) If aminoglycosides used, potential for toxicity must be considered e) Tetracyclines contraindicated in pregnancy 2. Urinary tract infections a) Although precise relationship between maternal bacteriuria and prematurity remains to be established, treatment of asymptomatic bacteriuria is recommended for majority of patients b) 2 weeks' treatment with a sulphonamide, ampicillin/amoxycillin, nitrofurantoin or co-trimoxazole will eradicate bacteriuria in 70 to 90% of cases c) If pyelonephritis present, ampicillin/amoxycillin or a cephalosporin are appropriate if infection is community-acquired; use co-trimoxazole or chloramphenicol if patient is unable to tolerate these drugs or if organism resistant d) In catheterised patients, hexamine (methenamine), nitrofurantoin or co-trimoxazole may be preferred treatment 3. Group B streptococcal infections a) Treatment essential as group B streptococcus may produce neonatal sepsis, meningitis and death b) Penicillins are first choice treatment c) Use erythromycin in penicillin hypersensitive patients 4. Syphilis a) Serological testing should be carried out at first prenatal visit, during third trimester and on admission in labour b) In seropositive women, penicillin is first choice treatment c) Use erythromycin in penicillin hypersensitive patients - orally during first 4 months of pregnancy (not estolate); IV route recommended thereafter
Table II.
(continued) 5. Gonorrhoea a) Early diagnosis and treatment essential to avoid adverse effects on fetus b) For uncomplicated gonorrhoea, penicillin G is first choice; in penicillin hypersensitive patients spectinomycin is a useful alternative (although little information is available on untoward effects in pregnant women) c) For disseminated gonococcal infection, give parenteral penicillin G or oral ampicillin/amoxycillin for 3 to 14 days; use erythromycin in penicillin hypersensitive patients 6. Amnionitis a) Institute treatment as soon as diagnosis suspected b) Combination of penicillin with chloramphenicol or an aminoglycoside is suitable for initial therapy c) Alternatively, give a cephalosporin or clindamycin with an aminoglycoside 7. Septic abortion a) Combination of penicillin or ampicillin with chloramphenicol effective against most pathogens b) Alternatively, give clindamycin or a cephalosporin with an aminoglycoside c) Antibiotic therapy must be combined with evacuation of uterine contents, IV fluids and vasopressor agents
courses of therapy lasting from 3 to 14 days, may be administered (Hands field et al., 1976). Tetracycline is given to non-pregnant penicillin-allergic women but in pregnant patients who are unable to tolerate penicillins, erythromycin should be given. 3.6 Amnionitis Intrapartum infection is produced primarily by the ascent of vaginal bacteria into the amniotic cavity, usually after rupture of the membranes. Transmission of infection to the fetus then takes place by way of its mouth or nose, with the most common and severe lesions found in the fetal lungs. Amniotic infection may also be responsible for the production of fetal sepsis, following passage of bacteria through the mucosa of the gastrointestinal or respiratory tract of
63
Treatment of Bacterial Infections in Pregnancy
the mother, or as the result of direct invasion of chorionic vessels on the placental surface, occurring by means of extraovular spread between the membranes and the uterine wall. Rarely, haematogenous dissemination from placenta to fetus takes place by way of the fallopian tube (Benirschke, 1960; Blanc, 196 I). Haematogenous placentofetal infections developing as the result of maternal sepsis may be produced by a great variety of micro-organisms. Ascending infection, both amniotic and placentofetal, are usually caused by vaginal bacteria. Simultaneous bacterial invasion of both maternal and fetal tissues is common in ascending placentofetal infections, but is rare in amniotic infections. Premature rupture of the membranes, particularly when there has been a long delay before the onset of labour, enhances the possibility that bacteria will ascend from the vagina (Shubeck et al., 1966). Prolonged labour and excessive digital and instrumental manipulation also predispose to ascending infection. 3.6.1 Pathogenic Organisms The bacteria most commonly found in the amniotic fluid and in the cord blood are E. coli. Streptococcus !aecalis. Staphylococcus epidermidis and Staphylococcus aureus. These micro-organisms are inhabitants of the normal vaginal microflora. With advances in the techniques of anaerobic bacteriology, the importance of anaerobic Gram-positive and Gram-negative micro-organisms in amnionitis has also been established (Gorbach and Bartlett, 1974). 3.6.2 Treatment Because amnionitis in labour is particularly hazardous to the infant, antibiotic therapy must be instituted as soon as the diagnosis is suspected. In view of the micro-organisms most commonly responsible for such infections, broad spectrum therapy should be administered until the results of cultures become available. The combination of a penicillin with chloramphenicol or with one of the aminoglycoside antibiotics, may be employed for initial therapy.
Alternatively, a cephalosporin antibiotic or clindamycin could be administered in combination with an aminoglycoside. The antibacterial spectra of erythromycin and tetracyclines are too limited to make them useful in this situation.
3.7 Septic Abortion Septic abortion remains an important cause of maternal mortality; it is through its production of septic shock that this infection is most lethal. Effective therapy of septic abortion requires more than the administration of antibacterial agents. Evacuation of the uterine contents, and administration of fluid and electrolyte solutions and vasopressor agents, must be combined with antibiotic therapy. Gram-negative bacteria, especially E. coli. are responsible for the majority of these infections, but Gram-positive bacteria, particularly Clostridium per!ringens. have also been cultured from septic abortion cases (Gibbs and Weinstein, 1976). The combination of penicillin or ampicillin with chloramphenicol will provide activity against most of the micro-organisms responsible for septic abortion, prior to the receipt of culture results. Other antibiotics which could be administered in this situation are elindamycin or a cephalosporin in combination with an aminoglycoside.
4. Conclusion The treatment of bacterial infections in the pregnant woman confronts the clinician with unique problems. Although many of the infections with which pregnant women are affiicted are similar to those which affect others, consideration of the very special circumstances of the pregnant woman, her unique predisposition to certain antibiotic-related untoward effects, and the possibility of transplacental transfer of antibiotics with subsequent risk to the fetus, make this one of the most challenging areas of modern antibiotic use.
Treatment of Bacterial Infections in Pregnancy
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Treatment of Bacterial Infections in Pregnancy
Stevens, R.M.; Teres, D.; Skillman, J.1. and Feingold, D.S.: Pneumonia in an intensive care unit. Archives of Internal Medicine 134: 106-111 (J 974). Watring, W.G. and Vaughn, D.L.: Gonococcemia in pregnancy. Obstetrics and Gynecology 48: 428-430 (J 976). Weinstein, L.: Antimicrobial agents: Penicillins; in Goodman and Gilman (Eds.> The Pharmacological Basis of Therapeutics, pp.1130-1158 (MacMillan, New York I 975a). Weinstein, L.: Antimicrobial agents: Cephalosporins; in Goodman and Gilman (Eds'> The Pharmacological Basis of Therapeutics, pp.1158-1166 (MacMillan, New York I 975b).
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Weinstein L.: Antimicrobial agents: Chloramphenicol; in Goodman and Gilman (Eds.> The Pharmacological Basis of Therapeutics, pp.1194-1200 (MacMillan, New York 1975cl. Weyman, J.: Tetracyclines and teeth. Practitioner 195: 661-665 (J 965).
Author's address: Dr Allan J. Weinstein. Department of Infectious Disease, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland. Ohio 44106 (USA).
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