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DISEASE MANAGEMENT

Standard treatment of pyelonephritis in pregnancy involves parenteral antibacterials and intravenous hydration
Pyelonephritis, one of the most common reasons for hospitalization during pregnancy, is treated with parenteral antibacterials and intravenous hydration. The outcome for both mother and fetus is generally good, but serious complications can arise. Outpatient treatment may be safe and effective in selected patients.
 increased glomerular filtration, elevated urinary glucose and alkalization of urine, which facilitate bacterial growth. The pathogenesis of asymptomatic bacteruria and progression to symptomatic urinary tract infection (UTI) and pyelonephritis are not completely understood, but involve an interplay between the virulence of uropathogenic bacterial species and host defence mechanisms.[1] Women with certain urinary tract anomalies and/or medical conditions (e.g. incompetent vesicourethral valves and renal calculi, diabetes mellitus, sickle cell disease or trait, and neurological problems, such as paralysis from spinal cord injury) are at increased risk of acquiring pyelonephritis in pregnancy.[1] Furthermore, studies show that pyelonephritis occurs more frequently in women from low socioeconomic groups, and that risk factors may include recent sexual intercourse or spermicide use, UTI and incontinence.[1]

Risk is increased during pregnancy

Pyelonephritis occurs in 12% of all pregnancies and is one of the most common indications for antepartum hospitalization.[1] The majority of cases of pyelonephritis in pregnancy occur during the second and third trimesters, with only 1020% of cases being diagnosed in the first trimester. This article summarizes a review of by Jolley and Wing[1] on the management of pyelonephritis in pregnancy. Physiological changes in pregnancy that result in ureteral dilatation and urinary stasis, thereby predisposing women to urinary tract infections include:[1]  ureteral and renal calyceal dilatation, which is understood to be due to progesterone-induced relaxation (may occur as early as 12 weeks gestation);  slowing of ureteral peristalsis and compression of ureters by the enlarging uterus;  increased capacity and incomplete emptying of the bladder due to mechanical compression of the bladder and decreased detrusor tone;

Diagnosis confirmed by urine culture

Common signs and symptoms of acute pyelonephritis include fever, shaking chills, flank pain, nausea and vomiting, and costovertebral angle tenderness (CVAT),[1] while dysuria and increased urinary frequency are less common. The presence of leukocyte esterase and nitrites may be positive on urinary dipstick, and the diagnosis is confirmed by urine culture. Colony counts of 100,000 cfu/mL from cleancatch voided specimens are used to define pyelonephritis in

Table I. Complications of acute pyelonephritis in pregnant patients (pts)[1]

Complication Anaemia Bacteraemia Comments Most common complication (occurs in 25% of pts) Occurs in 1520% of pts Gram-negative bacteria may release endotoxins into the maternal circulation, which can lead to a cascade response of cytokines, histamine and bradykinins The resulting capillary endothelial damage, diminished vascular resistance and altered cardiac output may lead to serious complications (e.g. septic shock, disseminated intravascular coagulation, respiratory insufficiency or adult respiratory distress syndrome) Occurs in 18% of pts Manifests with symptoms of dyspnoea, tachypnoea and hypoxaemia; pulmonary oedema shown on chest x-ray Occurs as a result of endotoxaemia Treatment in intensive care unit is required Occurs in 20% of pts Associated with significant healthcare costs and permanent renal damage Frequency may be reduced by careful post-treatment surveillance and suppressive therapy Incidence uncertain, as difficult to assess In a US study in 368 women with a history of pyelonephritis in pregnancy, 5% delivered at <37 wk and 1% delivered preterm during admission for pyelonephritis[2] Despite the presence of uterine contractions, there is often little or no cervical change

Adult respiratory distress syndrome Septic shock Recurrent pyelonephritis Preterm labour and delivery

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studies, according to the Infectious Diseases Society of America, and provide a sensitivity of 9095%.[3] Pyuria or the presence of leukocyte casts are also diagnostic of the disease.[1] Pathogens causing pyelonephritis are similar to those that cause asymptomatic bacteriuria and cystitis.[1] These include Escherichia coli (identified in 7085% of patients), and other Gram-negative organisms, such as Klebsiella, Enterobacter and Proteus spp. Gram-positive organisms are found more commonly as pregnancy progresses, and include Enterococcus faecalis and group B streptococci.[1] Endotoxin-mediated haemolysis, electrolyte abnormalities and transient renal insufficiency may occur in some women, so laboratory evaluation often includes a complete blood count and serum chemistry.[1] Renal insufficiency, which probably only occurs in 2% of patients, usually resolves spontaneously after treatment of the acute infection. The utility of blood cultures in pregnant women with pyelonephritis has been questioned following the results of studies that showed that the results rarely change clinical practice.[4] Some authors recommend obtaining blood cultures in patients with a high temperature (39C), signs of sepsis or a major co-morbidity.[4-6]

equally effective at treating infection and reducing the incidence of complications.[7] Antibacterial regimens that are acceptable and appear effective are shown in table II.[1]

Penicillins and cephalosporins generally safe

Penicillin derivatives and cephalosporins attain good concentrations in the renal parenchyma and urine, and are active against common uropathogens.[1] Furthermore, amino- and carboxy-penicillin derivatives (alone or in combination with clavulanic acid), ureidopenicillins and cephalosporins are considered to have good safety when used in pregnancy. Ampicillin has historically been the antibacterial of choice for the treatment of pyelonephritis in pregnancy because of its low cost, good safety to mother and fetus, and historical efficacy. However, ampicillin resistance is seen in approximately 4560% of strains of E. coli and the agent has now largely been replaced by cephalosporins as first-line therapy in this setting.[1]

Take care with aminoglycosides

Aminoglycosides are reabsorbed and bound in the proximal tubular epithelium and thus concentrate in renal tissue.[1]
Table II. Selected antibacterials used to treat pyelonephritis in pregnancy[1,8]
Agent Examples of intravenous dosage regimens US FDA pregnancy category Ba Ampicillin (combined with gentamicin) Ampicillin/sulbactam Aztreonamb Cefazolin Cefepime Cefotaxime Cefotetan Ceftriaxone Cefuroxime Mezlocillin Piperacillin 12 g every 6 h 3 g every 6 h 1 g every 812 h 12 g every 68 h 1 g every 12 h 12 g every 812 h 2 g every 12 h 12 g every 24 h 0.751.5 g every 8 h 3 g every 6 h 4 g every 8 h

Complications can be serious

The outcome for both mother and fetus is generally good if pyelonephritis is diagnosed and treated in a timely manner.[1] However, serious complications can arise (table I).

Parenteral antibacterials essential

Parenteral antibacterial agents are the mainstay of treatment of pyelonephritis.[1] The safety of the mother and fetus is of utmost importance when selecting an antibacterial in pregnancy. Unfortunately, human data on the use of drugs in pregnancy are generally limited and animal studies are difficult to extrapolate to humans.[1] The ideal antibacterial regimen for the treatment of acute pyelonephritis in pregnancy would have proven effectiveness in well designed studies, be active against the likely causative uropathogens, be able to maintain adequate tissue and serum concentrations throughout the treatment period, not be associated with the development of antibacterial resistance, be relatively inexpensive, have a good tolerability profile and be safe for the developing fetus.[1] Insufficient data are available to recommend a particular antibacterial regimen for the treatment of pyelonephritis in pregnancy due to the lack of clinical studies.[1] A Cochrane Database review of antibacterials in symptomatic UTIs in pregnancy concluded that all antibacterials studied were
Drugs Ther Perspect 2011; Vol. 27, No. 4

US FDA pregnancy category Cc Gentamicin (may be given 2 mg/kg loading dose, then 1.7 mg/kg alone) in three divided doses every 8 h a Animal reproduction studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal reproduction studies have shown an adverse effect that was not confirmed in controlled studies in women the first trimester.[8] b May be used in the setting of b-lactam allergy. c Studies in animals have revealed adverse effects on the fetus (teratogenic, embryocidal or other) and there are no controlled studies in women, or studies in women and animals are not available.[8]

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Pyelonephritis diagnosed Urine culture sent Consider outpatient treatment

No
Signs of sepsis, urinary tract abnormality, medical co-morbidity

No

>24 wk gestation

Yes

Hospitalize Empirical parenteral antibacterial treatment (see table II) Intravenous fluid hydration Monitor fluid balance Monitor pulse oximetry Uterine activity and fetal monitoring as appropriate

Yes

Afebrile 48 h, symptomatically improved

Clinical deterioration or continued spiking fevers after >72 h of antibacterial therapy

Discharge to home to complete 10- to 14-day course of oral antibacterials

Treat as appropriate

Present

Renal ultrasound to evaluate for nephrolithiasis or abscess

Not present
At completion of treatment send urine culture as test of cure Ensure appropriate treatment based on urine culture sensitivities Evaluate for other sources of infection Continue antibacterial prophylaxis for remainder of pregnancy Check monthly urine culture

Adis Data Information BV 2011

Management of a pregnant patient with pyelonephritis, as suggested by Jolley and Wing[1]

They may have a place in the treatment of pyelonephritis, but their use should be carefully considered in pregnant patients. While gentamicin has been widely used in pregnancy with no reports of congenital complications, it is a US FDA category C drug (table II) and ototoxicity has been seen following fetal exposure related to the aminoglycosides kanamycin and streptomycin.[8] Acute pyelonephritis is associated with a low incidence of acute renal dysfunction,[9] and empirical treatment while awaiting serum creatinine levels may be appropriate.[1] However, close monitoring of serum gentamicin levels and dosage adjustment is essential due to concerns of exacer-

bating renal dysfunction and because maternal serum concentrations near term are more likely to be subtherapeutic due to increased drug clearance.[1]

Some agents contraindicated

Tetracyclines and fluoroquinolones are generally contraindicated during pregnancy.[1] Tetracyclines can chelate calcium in fetal structures and in utero exposure may result in tooth discoloration and inhibition of bone growth.[8] While fluoroquinolones achieve high renal concentrations, there is a risk of fetal arthropathy when administered to the pregnant patient.[1]
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Patient presents with pyelonephritis with pregnancy not beyond 24 wk and is able to comply with outpatient therapy Patient does not have complicating factors: excessive fever ( >38C) severe nausea and vomiting recurrent upper urinary tract disease signs of sepsis compromised immune system significant medical complications history of substance abuse concurrent preterm labour uncertain diagnosis Treatment: hydration intramuscular (IM) ceftriaxone Diagnostic tests: complete blood count serum chemistry including blood urea, creatinine urine culture Observation to assess: ability to tolerate oral intake response to therapy Follow-up within 24 h as an inpatient or outpatient additional dose of IM ceftriaxone assess clinical condition

Change to oral antibacterial (cephalexin or similar) for 10 days

Daily IM ceftriaxone for 5 days Change to oral antibacterial (cephalexin or similar or one to which causative organism sensitive) for 710 days

Clinic follow-up within 2 wk Urine culture as test of cure Monthly review for remainder of pregnancy Prophylactic antibacterials until 46 wk postpartum

Adis Data Information BV 2011

Outpatient management of a pregnant patient with pyelonephritis, as suggested by Jolley and Wing [1]

Treat parenterally until symptom free

Historically, the approach to treatment of pyelonephritis in both pregnant and nonpregnant patients has been hospitalization and the use of intravenous antibacterial therapy until the patient is afebrile for 48 hours and symptoms have improved (Patient care guidelines A).[1] Intravenous hydration should be administered and fluid balance monitored. The patient is then treated with oral antibacterials for 1014 days, although the optimum duration of therapy is unclear. A urine culture should be obtained to confirm resolution of bacteruria. Patients with pyelonephritis treated with the appropriate antibacterial therapy usually respond
Drugs Ther Perspect 2011; Vol. 27, No. 4

within 48 hours. If a clinical response is not seen by 72 hours, evaluation for bacterial resistance, urolithiasis, perinephric abscess formation, or urinary tract abnormalities should be carried out, and antibacterial therapy should be changed to include an aminoglycoside (Patient care guidelines A).[1]

Continue antibacterial prophylaxis

The incidence of recurrent pyelonephritis may be decreased by administering antibacterial suppression for the duration of pregnancy (Patient care guidelines A). Suggested prophylactic regimens include nitrofurantoin 100 mg or cefalexin 250500 mg orally every night during pregnancy

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and for 46 weeks postpartum. Use of cotrimoxazole (sulfamethoxazole/trimethoprim) in this setting is generally restricted to the second trimester due to its inhibitory effect on folate metabolism in the first trimester and the theoretical risk of inducing neonatal hyperbilirubinaemia when given close to the time of delivery. Patients receiving prolonged courses of antibacterials should have monthly urine cultures checked for recurrent bacteria and be monitored for symptoms of vaginal candidiasis (Patient care guidelines A).

strategy, and liberalization of the criteria for outpatient therapy in the absence of supporting data may be detrimental.[1]
Disclosure
This review was adapted from Drugs 2010; 70 (13): 1643-55[1] by Adis editors and medical writers. The preparation of these articles was not supported by any external funding.

References
1. Jolley JA, Wing DA. Pyelonephritis in pregnancy: an update on treatment options for optimal outcomes. Drugs 2010; 70 (13): 1643-55 2. Hill JB, Sheffield JS, McIntire DD, et al. Acute pyelonephritis in pregnancy. Obstet Gynecol 2005 Jan; 105 (1): 18-23 3. Rubin UH, Shapiro ED, Andriole VT, et al. Evaluation of new antiinfective drugs for the treatment of urinary tract infection: Infectious Diseases Society of America and Food and Drug Administration. Clin Infect Dis 1992 Nov; 15 Suppl. 1: S216-27 4. Wing D, Park AS, DeBuque L, et al. Limited clinical utility of blood and urine cultures in the treatment of acute pyelonephritis during pregnancy. Am J Obstet Gynecol 2000 Jun; 182 (6): 1437-41 5. Lucas MJ, Cunningham FG. Urinary infection in pregnancy. Clin Obstet Gynecol 1993 Dec; 36 (4): 855-68 6. Bates DW, Cook EF, Goldman L, et al. Predicting bacteremia in hospitalized patients: a prospectively validated model. Ann Intern Med 1990 Oct; 113 (7): 495-500 7. Vazquez JC, Villar J. Treatments for symptomatic urinary tract infections during pregnancy. Cochrane Database Syst Rev 2003; (4): CD002256 8. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation. 8th ed. Philadelphia (PA): Lippincott Williams & Wilkins, 2008: xxiii-xxiv 9. Sheffield J, Cunningham FG. Urinary tract infection in women. Obstet Gynecol 2005 Nov; 106 (5 Pt 1): 1085-92 10. Scholes D, Hooton TM, Roberts PL, et al. Risk factors associated with acute pyelonephritis in healthy women. Ann Intern Med 2005 Jan; 142 (1): 20-7 11. Nicolle LE, Friesen D, Harding GK, et al. Hospitalization for acute pyelonephritis in Manitoba, Canada, during the period from 1989 to 1992: impact of diabetes, pregnancy, and aboriginal origin. Clin Infect Dis 1996 Jun; 22 (6): 1051-6 12. Foxman B, Klemstine KL, Brown PD. Acute pyelonephritis in US hospitals in 1997: hospitalization and in-hospital mortality. Ann Epidemiol 2003 Feb; 13 (20): 144-50 13. Angel JL, OBrien WF, Finan MA, et al. Acute pyelonephritis in pregnancy: a prospective study of oral versus intravenous antibiotic therapy. Obstet Gynecol 1990 Jul; 76 (1): 28-32 14. Sanchez-Ramos L, McAlpine KJ, Adair CD, et al. Pyelonephritis in pregnancy: once-a-day ceftriaxone versus multiple doses of cefazolin. Am J Obstet Gynecol 1995 Jan; 172 (1 Pt 1): 129-33 15. Brooks AM, Garite TJ. Clinical trial of the outpatient management of pyelonephritis in pregnancy. Infect Dis Obstet Gynecol 1995; 3 (2): 50-5 16. Millar LK, Wing DA, Paul RH, et al. Outpatient treatment of pyelonephritis in pregnancy: a randomized controlled trial. Obstet Gynecol 1995 Oct; 86 (4 Pt 1): 560-4 17. Wing DA, Hendershott CM, DeBuque L, et al. Outpatient treatment of acute pyelonephritis in pregnancy after 24 weeks. Obstet Gynecol 1999 Nov; 94 (5 Pt 1): 683-8

Outpatient care possible in selected patients

A number of observational or randomized controlled studies that have demonstrated the safety of outpatient management of acute pyelonephritis in nonpregnant patients and have challenged the recommendation that patients with this condition are hospitalized.[1] Indeed, the hospitalization rate for this patient group has decreased from 100% to 730% in recent decades.[10-12] Few trials have been published on the ambulatory management of pyelonephritis in pregnancy. Two studies that simulated outpatient treatment following initial therapy using oral cefalexin every 6 hours (n = 90) or once-daily intravenous ceftriaxone (n = 178) showed treatment success in 90% and 95% of patients, similar to that seen with conventional inpatient care.[13,14] Two further studies showed treatment success in 88% and 90% of patients receiving outpatient care.[15,16] After initial evaluation and treatment, the first study treated patients at 26 weeks gestation with intramuscular ceftriaxone until fever and CVAT resolved, followed by a 10-day course of oral antibacterials.[15] The same authors further refined outpatient care in patients at 24 weeks gestation by following initial intramuscular treatment with 10 days of oral cefalexin.[16] However, the success of outpatient care appears to be substantially lower in patients with pregnancies after 24 weeks gestational age. In a study in this patient group, >60% of evaluable women were ineligible for outpatient care for reasons such as preterm labour, sepsis, respiratory compromise, pre-existing medical conditions or fetal malformation.[17] Inpatients were treated with oral cefalexin for 10 days following daily intramuscular ceftriaxone for 2 days. Almost 30% of planned outpatients remained in hospital after 24 hours because of of sepsis, bacteraemia, leukocytosis, preterm labour and other medical complications.[17] This small body of evidence supports the ambulatory treatment of pyelonephritis in patients less than 24 weeks pregnant and a suggested algorithm for outpatient treatment is shown in Patient care guidelines B.[1] Careful patient selection for outpatient treatment is the key to the success of this

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