PRACTICAL THERAPEUTICS

Drugs 44 (3): 356-367, 1992 0012-666 7 /92/0009-0356/$06.00/0 © Adis International Limited. All rights reserved. DRUl184

Diagnosis and Drug Treatment of Acute Pyelonephritis Alain Meyrier and Jacqueline Guibert Service de Nephrologie, H6pital Avicenne, Bobigny Medical School, Paris North University, Bobigny, and H6pital Saint-Joseph, Paris, France

Contents 356 358 358 358 358 359 359 359 359 360 360 360 360 361 361 363 363 363 363 364 364 365 365 365 366

Summary

Summary I. Primary Versus Secondary Pyelonephritis 1.1 Primary Pyelonephritis 1.2 Secondary Pyelonephritis 2. Bacteriology 3. Prevalence and Clinical Diagnosis 3.1 Typical Acute Primary Pyelonephritis 3.2 Atypical Pyelonephritis 3.3 Pyelonephritis in Pregnancy 3.4 Pyelonephritis in Diabetic or Immunocompromised Patients 3.5 Pyelonephritis in Males 3.6 Pyelonephritis in Children 4. Imaging 5. Drug Treatment of Pyelonephritis 5.1 Goals of Treatment 5.2 Antimicrobial Agents Adapted to the Treatment of Pyelonephritis 5.3 Single-Agent or Combination Treatment 5.4 Acute Primary Pyelonephritis 5.4.1 Initial Treatment 5.4.2 Treatment Duration 5.4.3 Follow-Up 5.5 Severe or Complicated Acute Pyelonephritis 5.6 Pyelonephritis in Pregnancy 5.7 Pyelonephritis in Children 5.8 Prevention of Relapse

The term pyelonephritis, which denotes infection of the renal pelvis and of the renal tissue, covers a spectrum of entities, the gravity and hence treatment of which depend upon the organism, its sensitivity to antibiotics, the presence or absence of urinary tract obstruction, and the host's background. The common form affects young females, is due to uropathogenic but multisensitive strains of Escherichia coli, and is easily treated by a 10- to 20-day course of antibiotic(s). In males, children and immunocompromised patients, renal and urinary tract imaging is necessary to determine the cause of the infection, the severity of the lesions and thus to guide the duration of

Pyelonephritis: Diagnosis and Treatment

357

treatment, which comprises antibiotic combinations for several weeks. Pyelonephritis during pregnancy may be serious, and treatment is restricted to certain antibiotics. Aminoglycosides, amino- or carboxypenicillins (alone or associated with clavulanic acid), ureidopenicillins (e.g. mezlocillin, piperacillin), fluoroquinolones (e.g. ciprofloxacin, ofloxacin, pefloxacin), cephalosporins, monobactams (e.g. aztreonam), carbapenems (e.g. imipenem) and the combination of trimethoprim plus a sulphonamide [e.g. cotrimoxazole (trimethoprim/sulfamethoxazole)] offer a wide choice of bactericidal agents which may be used for the treatment of pyelonephritis. However, the selection among them also depends on availability, antimicrobial spectrum, tolerance and cost.

The term 'pyelonephritis' dates back to Pierre Rayer's nineteenth century Treatise on Diseases of the Kidney (Richet 1991). It denotes inflammation of the renal pelvis (pyelo-) and of the renal tissue (-nephritis). Although bacteriology was unknown in Rayer's- time, he understood that pyelonephritis was of infectious origin and made the discrimination between that originating from the urinary tract and a different, haematogenous variety complicating septicaemia. Since then, the word pyelonephritis has also been wrongly extended to cover several forms of kidney disease, including the miliary abscesses complicating staphylococcal septicaemia and the tubulo-interstitial damage following analgesic abuse, where 'chronic pyelonephritis' is a misnomer for chronic interstitial nephritis. We shall therefore limit this paper to acute pyelonephritis (APN) resulting from infection originating in the urinary tract and affecting both renal pelvis and renal tissue. Curiously, despite the frequency of this condition, there is no consensus on its treatment. However, over the last decade considerable research has been devoted to the experimental pathology, bacteriology and imaging of APN. Such better knowledge is leading to a clearer definition of the goals and modalities of treatment (for review see Antibiotherapie des Infections Urinaires 1991). Our understanding of APN has greatly benefited from animal experiments, where most protocols consisted of flushing pathoge~ic strains of Escherichia coli into the ureter (Roberts 1991). Retrograde infection of the pelvis and the kidney was also obtained after creating vesicoureteric reflux (VUR) in the piglet (Hodson et al. 1984), and the

mechanism of cortical scarring was studied by injecting pathogenic E. coli under the renal capsule (Mackenzie & Asscher 1986). Roberts (1991) analysed the sequence of events following flushing of E. coli unilaterally in the Macaca mu/atta, a species of New World monkey with the same number of receptors for P-fimbriated E. coli on the urothelium as are found in humans. (Fimbriae are filaments present on the cell surface of many bacteria, and are associated with pathogenicity; see section 2.) Comparative determinations of plasma renin activity (PRA) in the ipsilateral and the contralateral renal veins and serum complement determinations were carried out, and the renal tissue was studied by light and electron microscopy. Within minutes following invasion of the interstitium by E. coli, serum complement levels decreased, thromboxane A2 levels rose and PRA increased in the vein on the infected side. Renal histology showed polymorphonuclear invasion, oedema and haemorrhagic streaks, a picture remarkably similar to that observed in human APN. These experiments confirmed earlier ones (for revIew see Meyrier 1990) based on renal histology, microradiographs and vessel injection with neoprene. There is consistent evidence that E. coli infe~tion is immediately followed by vasoconstriction, This notion nicely explains the hypodense images observed with computerised tomodensitometry (CT) in humans, and the defects seen on , 99mTc-dimercaptosuccinic acid (DMSA) or 99mTc_ gluconoheptonate (GH) imaging. It also provides a ready explanation for the mechanism of early cortical scarring (Meyrier et al. 1989).

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1. Primary Versus Secondary

Pyelonephritis

1.1 Primary Pyelonephritis Distinguishing between primary and secondary APN is essential. Primary pyelonephritis occurs in an anatomically sound urinary tract, is mostly restricted to females and is part of the wider problem of urinary tract infection (UTI) in women. The reason is debated why, despite the absence of any urinary tract abnormality, bacteria are able to progress from the perineum to the urethra, then the bladder, and finally to pass the vesicoureteric valve to access the renal pelvis and medulla. Two explanations which are not mutually exclusive are found in the literature. The first focuses responsibility on the host, considering that some women have increased susceptibility to uropathogenic strains of enterobacteria. The argument rests on the notion that cell membrane glycoproteins which share antigenic determinants with some of the nonABO blood group antigens act like receptors for the P fimbriae or, conversely, hinder the adhesion of bacteria to the urothelial cell membranes. The P blood group system has been considered to playa role in favouring bacterial adhesion to the urothelium (Roberts 1987). In contrast, it has been claimed that the genetic capacity for secreting the Lewis substance protects the host against bacterial adhesion (Sheinfeld et al. 1989). In fact, these studies were based on statistical analyses and do not clearly explain the occurrence of individual cases of primary APN. However, in the immunocompromised patient, especially those with diabetes, factors pertaining to the host obviously playa major role in the pathogenesis and severity of APN. The other explanation, which is borne out by our personal experience (Meyrier et al. 1989), puts the major responsibility on the 'uropathogenic' nature of the bacteria, and essentially on the presence of adhesins on the fimbriae and/or the bacterial surface (see section 2). 1.2 Secondary Pyelonephritis Secondary pyelonephritis is more readily explained, as it occurs within an abnormal urinary tract. The responsible organisms need not be uro-

Drugs 44 (3) 1992

pathogenic. The most frequent conditions complicated with secondary APN are VUR, renal stones, tumours, megaureter, renal polycystic disease and neurogenic bladder. In diabetics, pyelonephritis often induces papillary necrosis. The sloughed papilla and the caliceal cavity which it leaves may progress from 'primary' to 'secondary' infection. Any invasive urological manoeuvres into the urinary tract may also be followed by secondary APN. Iatrogenic UTIs are usually due to multiresistant strains. The most serious form is that complicating obstruction, such as renal stone migration, or more generally any condition that increases pressure in the pyelocaliceal system. In such cases suppuration spreads rapidly through the kidney with abscess formation and often papil!ary necrosis. Massive passage of bacteria into the circulation is responsible for Gram-negative sepsis with the attending hazards of shock and disseminated intravascular coagulation. Secondary localisations due to Gram-negative rods usually involve the spinal disks (spondyloarthritis) and the sacroiliac joint. Complications of obstructive APN are particularly severe in diabetics, in whom it may rapidly lead to pyonephrosis.

2. Bacteriology The bacteriology of APN greatly depends on the primary or secondary nature of the UTI. The spectrum of strains causing primary APN is rather monotonous, with an overwhelming predominance of E. coli, in the order of 90%, followed by anecdotal cases where APN is due to Proteus mirabilis, 0trobacter spp. or, rarely, Staphylococcus aureus or S. saprophyticus. The finding of Moraxella, Serratia, Klebsiella, Pseudomonas spp., etc. should be an incentive to seek overlooked urinary abnormalities. Among the 1570 antigens of E. coli, only about 8 are usually found in the uropathogenic strains (Hanson 1982). Similarly, antigen Kl is responsible for 39% of cases of APN. Why certain persons carry such pathogenic strains, and hence are prone to pyelonephritis, is unknown. Bacterial adhesins are glycoproteins which re-

Pyelonephritis: Diagnosis and Treatment

cognise specific receptors on the urothelial cell membranes, and may be fimbrial or nonfimbrial. Adhesion is due to a receptor-ligand interaction which leads to stable attachment to the cells (Roberts 1987). When cultured in vitro, bacteria may lose the phenotypic expression of adhesins, but it is still possible to detect the DNA sequences in the bacterial genome coding for adhesin synthesis. The 3 major adhesin systems responsible for uropathogenicity are denoted pap, sfa and afa. In our experience primary APN is almost invariably due to E. coli strai'ns bearing at least 1 of these 3 adhesins (Meyrier et al. 1989). Conversely, when seemingly primary APN is due to a strain of E. coli devoid of at least 1 of these adhesins, we consider that thorough radiourological work-up is required to diagnose overlooked urinary tract abnormalities. The reader should be aware that the uropathogenic nature of the organisms responsible for APN bears no correlation with sensitivity to antibiotic treatment. In fact, when APN is primary, the responsible bacteria are usually sensitive to a wide array of antibiotics. Secondary pyelonephritis is due to a wider variety of organisms, although E. coli is still the most frequent. When infection follows a urological manoeuvre or occurs in a patient with an indwelling bladder catheter, virtually any kind of organism can be found. They often exhibit mUltiple resistance to antibiotics.

3. Prevalence and Clinical Diagnosis 3.1 Typical Acute Primary Pyelonephritis This is the common form in young females (Johnson & Stamm 1989; Komaroff 1984; Meyrier et al. 1989; Safrin et al. 1988). It may supervene in the absence of cystitis. Onset is sudden, with lumboabdominal pain more or less resembling renal colic, spiking fever, chills, malaise, and occasionally vomiting. The patient may appear acutely ill, but in this setting primary APN is usually not a serious condition, and more severe manifestations such as septic shock are most unusual. Physical examination discloses a swollen and tender kidney. Renal swelling and pain is rarely bilateral, even

359

when imaging discloses bilateral lesions. The diagnosis of APN cannot rest on clinical symptoms alone. UTI must be identified by: (a) the classical Kass criteria, i.e. presence of at least 104 1eucocytes and 105 organisms per ml in a freshly voided ('clean-catch') midstream urine specimen; and (b) an inflammatory reaction shown by a sedimentation rate >25 mm/h and a serum C-reactive protein level at least equal to 20 mgfL. In about half of the cases, blood cultures are positive and show the same organism as found in the urine. This finding should be interpreted as bacteraemia rather than septicaemia, and only in this form of APN, positive blood culture(s} do not imply a more severe disease with need for special treatment modalities. 3.2 Atypical Pyelonephritis APN may be atypical in terms of clinical or laboratory findings. Painless APN is mainly (but not exclusively) observed in diabetics, alcoholics and patients with a renal transplant (June et al. 1985; Meyrier et al. 1989), probably due to impairment of autonomic renal nerve conduction. In such cases APN may be severe and renal imaging confirms the discrepancy between the severity of the renal lesions and the paucity of the patient's complaints, apart from fever and chills. The urine may be sterile. This is usually due to self-medication just before seeking medical advice. In some of our patients, despite negative urine cultures, blood cultures were positive and led to identification of the infecting organism (Meyrier et al. 1989). Atypical cases of APN justify renal imaging with CT scan and/or scintigraphy to provide a firm diagnosis and guide treatment. 3.3 Pyelonephritis in Pregnancy APN in pregnancy occurs essentially in women with previous asymptomatic bacteriuria (Edler & Bint 1987; MacNeeley 1988; Stray-Pedersen et al. 1990); systematic urinalysis reveals bacteriuria in 3.5 to 7.1% of pregnant women (Ampel & Zinner 1983). The risk is higher in lower socioeconomic

Drugs 44 (3) 1992

360

classes and in Black females having the sickle cell trait, and is doubled in cases of UTI before pregnancy. Systematic treatment of asymptomatic bacteriuria detected during pregnancy drastically reduces the incidence of APN. Pyelonephritis is more frequent on the right side. It can be complicated with septicaemia and by spontaneous abortion. 3.4 Pyelonephritis in Diabetic or Immunocompromised Patients Patients with diabetes are prone to severe UTI, and APN may induce ketosis, hyperosmolality and coma, and the condition is often a complication of neglected asymptomatic bacteriuria (Zhanel et al. 1991). Its mechanism is multifactorial, associated with urinary stasis, impairment of phagocytosis, glycosuria and vascular lesions of the renal medulla. Diabetic APN is often accompanied by papillary necrosis and complicated by sepsis, whilst its indolence may retard diagnosis. For all these reasons, it is a serious and possibly life-threatening condition. With regard to pyelonephritis, the renal transplant recipient in many ways resembles the diabetic. Pyelonephritis is frequent, especially during the 2 months following transplantation (Prat et al. 1985). Immunosuppression and the ureterovesical anastomosis form a favourable combination for host vulnerability. The grafted kidney is deprived of nervous connections, and APN may be indolent. Finally, APN may favour rejection. In immunodeficiency induced by drug treatment and in the acquired immunodeficiency syndrome (AIDS), pyelonephritis does not seem to rank among usual opportunistic infections. However, this might not be true in renal insufficiency and concomitant treatment with azathioprine or cyclophosphamide (Higgins 1989). 3.5 Pyelonephritis in Males Pyelonephritis is rarely primary in the male (Lipsky 1989). It is usually accompanied with (or due to) prostatitis and is mostly explained by some urinary tract abnormality, with a predominance of

obstruction due to prostate hypertrophy or cancer, urinary stones, urethral stenosis or urothelial tumours. Catheterisation of a distended bladder is a classic cause of bilateral severe APN in the elderly. 3.6 Pyelonephritis in Children Pyelonephritis is a serious problem in childhood (Burns et al. 1987; Winberg et al. 1982). Infection in a growing kidney entails a high risk of cortical scars and of renal atrophy (or arrest of renal growth). It should systematically be considered secondary to urinary tract abnormality until VUR and obstructive uropathy (hydronephrosis, megaureter, posterior urethral valves in boys, etc.) have been definitely ruled out. The responsible organisms are usually E. coli in girls (more than 80% before age 10) and more varied in boys, including Proteus mirabilis, Klebsiella, Pseudomonas, Staphylococcus, Enterococcus and Citrobacter spp. Childhood APN calls for prompt diagnosis and adequate and protracted antibacterial treatment, followed by surgical correction of the cause.

4. Imaging Urinary imaging in APN has 3 goals: (a) to substantiate the diagnosis of acute renal suppuration and in some instances to evaluate the amount of the bacterial inoculum; (b) to determine the cause of infection which, in children and in males, is most often secondary to urinary tract abnormalities, as specified above; and (c) to determine the sequelae of APN, that is, cortical scars or even renal atrophy. In a young female with no past history of UTI and apparently 'primary' APN, intravenous pyelography (lVP) is not obligatory, as ultrasonography and a plain abdominal film are usually sufficient to rule out a urological cause. In a male, IVP is always indicated. In children, imaging of the urinary tract rests on 2 basic investigations: ultrasonography, and retrograde (or suprapubic) cystography (conventional or isotopic). When one or both are abnormal, IVP is warranted.

361

Pyelonephritis: Diagnosis and Treatment

of investigations. The morphological imaging of the urinary tract rests on IVP and cystography, when indicated by the clinical context. The renal tissue lesions and their sequelae (cortical scars) are best determined using either CT or cortical scintigraphy. When readily available, the latter may prove preferable, as it is sensitive, specific and only a little invasive. Renal tissue imaging is not mandatory to determine the initial modalities of antibacterial treatment. However, the finding of severe renal tissue lesions (such as large abscesses) may indicate the necessity for a long treatment course: Fig. 1. Computerised tomography (CT) scan of a young female with acute primary pyelonephritis. The pyelonephritic left kidney (arrowed) is distinc1y larger than the right, indicating oedema. After contrast medium injection, 2 typical hypodense areas are visible (shown by empty squares). These hypodense images differ from abscesses; before contrast medium injection, no cavity was present in this area. Such 'presuppurative' lesions are hardly detectable by ultrasonography.

Renal imaging is based on 3 methods, not mutually exclusive. Ultrasonography is the least invasive (especially in a pregnant woman) and can be used repeatedly. It provides information on the size and outline of the kidney, and on the renal tissue and perirenal space. However, it may overlook minor caliceal abnormalities, moderate dilatation of the urinary tract, small abscesses, acute lobar nephronia and small cortical scars. CT provides valuable information. The infected areas appear as hypodense images after contrast medium injection, due to intense vasoconstriction (fig. 1). CT scan is also an adequate means of detecting cortical scars, but provides little information on the urinary tract. Gallium-67 or indium-III scintigraphy is cumbersome and of limited interest. Conversely, cortical scintigraphy using 99mTc_GH or 99mTc-DMSA is more sensitive (86%) and specific (81 %) compared with CT (sensitivity 75%), ultrasonography (42%) and IVP (24%). However, cortical scintigraphy cannot distinguish between acute infection and scars. Thus, schematically, in addition to ultrasonography, urinary imaging in APN necessitates 2 kinds

5. Drug Treatment of Pyelonephritis It is beyond the scope of this review to consider the surgical treatment of urinary tract abnormalities responsible for secondary pyelonephritis, or the supportive measures dealing with metabolic problems in a diabetic, treatment of septic shock, and so forth. Regarding medical treatment, we have seen that the term 'pyelonephritis' covers a spectrum of entities, given the possibility of urinary tract abnormalities and the diversity in patients' backgrounds. Even in the case of primary acute renal infection in the young female, imaging has taught us that APN ranges from moderate involvement of the renal pelvis and the adjacent medulla to severe lesions, including widespread CT hypodense images and renal abscesses (fig. I). Obviously, the amount of the bacterial inoculum and hence the duration of treatment are not identical. Investigation and treatment guidelines are given in figure 2. 5.1 Goals of Treatment A survey of the literature (Antibiotherapie des Infections Urinaires 1991; Gleckman 1987; Jernelius et al. 1988; Ronald 1987; Tolkoff-Rubin & Rubin 1987) may deceive the non specialised reader. This is largely because the goals of treatment, and ~~tice the concept of 'successful outcome' are not ~efined. Theoretically, treatment should aim at: I. Sterilising the urine;

Drugs 44 (3) 1992

362

l

Clinical picture compatible with acute pyelonephritis (APN)

Renal scintigraphy andlor CTscan

•

...

.

.......

Abnormal . Call urologist

Secondary APN

11

I

...

.

~

Yes

Possible urinary tract obstruction or stone?

l

No

1

... ......1

-;J

....

Atypical clinical response r--orWrong Initial antibiotic choice

• 1

I

Continue same treatment

.J.

. .

~

+1

Plain abdominal radiograph Ultrasonography

Primary APN Drug therapy only

...I

I

Normal. ConSider drug intolerance

I

I

Further imaging (IVP,CT)

X

Adapt antibiotic treatment

Initial Work-up

No previous history of upper UTI

PreviOus history of upper UTI

1

-.Y

1

~

.....

Stan treatment with first-line an ibiotlcs (see text)

Good cllntcal response and lab. conlirmalton of appropriate inttial antibiotic chOice

•

Positive

" l Normal

Treat infeclton

cause

I

CRP

.

L

Treat

ESR

Renal lesions. Maintain diagnosis olAPN

No renal lesion. Seek other infection

I

X

Urine culture and cytology

Negative. Reconsider diagnosis of APN

~

I

Day 1

Days 2to 40r5

.

Abnormal. Call urologist

Days 5 to 15

I End treatment J

I

Recurrence of bacteriuria

•

L..

I

Radiourological work-up. New treatment

Day 15

Jl urineVerify l sterility J

I

T

No further investigations or treatment

I

Between days 30 and 45

Fig. 2. Investigation and treatment guide for acute pyelonephritis (APN). Abbreviations: ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; UTI = urinary tract infection; IVP = intravenous pyelography; CT = computerised tomography.

Pyelonephritis: Diagnosis and Treatment

2. Relieving pain and fever; 3. Suppressing renal tissue infection and hence precluding early relapse; 4. Normalising images of the renal tissue; 5. Preventing cortical scarring. Sterilising the urine takes a matter of hours, but does not mean that pyelonephritis is cured. Relieving pain and fever is usually achieved within 3 or 4 days, but does not mean that the renal tissue has been cleared of suppuration. Sterilisation of the renal tissue depends on the amount of the bacterial inoculum and especially the presence of abscesses, which in turn has a bearing on the duration of treatment. In fact, confirmation that duration of treatment has been adequate is often retrospective and shown by absence of short term relapses of infection. Persistence of hypodense images on CT fIlms, which may remain visible for 3 or 4 weeks, does not necessarily mean that these foci are still infected. Finally, no study in the literature addresses the issue of avoiding cortical scars following primary APN. 5.2 Antimicrobial Agents Adapted to the Treatment of Pyelonephritis Medical treatment of APN rests on antibiotics. An appropriate drug should conform to the following specifications: 1. It must be bactericidal; 2. It must cover the usual spectrum of enterobacteria with reasonable chance of being effective before such efficacy is confirmed by the laboratory (i.e. it must be effective on an empirical basis); 3. Its pharmacology should include: (a) high penetration and hence concentrations in the renal tissue; (b) predominant urinary excretion; and (c) in case of oral administration, rapid absorption and attainment of peak serum concentrations. Excluding special considerations necessary during pregnancy (see section 5.6), several classes of antibiotics fulfill these specifications and can be used alone or in association: aminoglycosides, aminopenicillins (e.g. amoxicillin, alone or combined with clavulanic acid), carboxypenicillins (e.g. ticarcillin, alone or combined with clavulanic acid),

363

ureidopenicillins, monobactams, carbapenems, cephalosporins, fluoroquinolones and trimethoprim plus sulphonamides (table I). However, the choice depends not only on the antimicrobial spectrum or the pharmacokinetics of the drug, but also on its market availability, cost, tolerability, and potential for inducing emergence of resistant strains. For these reasons the list of first-line antibiotics which seem most appropriate for treating APN is customarily restricted to aminoglycosides, aminoor carboxypenicillins associated with clavulanic acid, the monobactam aztreonam, cephalosporins and fluoroquinolones. 5.3 Single-Agent or Combination Treatment It is debated whether treatment of common forms of APN initially requires both an aminoglycoside and another antibiotic. Antibiotic synergy is not mandatory since a single drug is effective against sensitive organisms. On the other hand, associating an aminoglycoside with another antibiotic presumably speeds the clearing of the bacterial inoculum, and aminoglycosides have a sustained antibacterial effect for several days after ending treatment (Bergeron & Marois 1986). There is however no controversy as to the need for combined treatment in severe or complicated forms of APN. This is especially true in the diabetic, the immunocompromised host, males, children under 18 months of age, and patients with ,severe lesions such as urinary tract obstruction or r~nal abscesses. 5.4 Acute Primary Pyelonephritis 5.4.1 Initial Treatment Initial treatment of primary uncomplicated APN in otherwise healthy females may consist of 3 to 4 days of aminoglycoside injections associated with another antibiotic, or the latter can be used alone. Therapy should be initiated before results of sensitivity tests are available, and oral administration is preferred whenever possible, i.e. in the absence of vomiting. Initial use of aminopenicillins and of trimethoprim plus a sulphonamide is not recommended due to the high frequency of primary· re-

Drugs 44 (3) 1992

364

Table I. Appropriate antibiotic recommendations in APN treatment Drug class

Indication curative treatment of APN

Aminoglycosides Aminopenicillins Carboxypenicillins Ureidopenicillins Quinolones Fluoroquinolones Cephalosporins 1st generation 2nd generation 3rd generation Monobactams Carbapenem Trimethoprim/ sulfamethoxazole a b c d e f g

treatment during pregnancy

treatment of children

preventive treatment

+8

+ + +

+ + + +

+

+

+ + + + +

+

+ + + + +

+9

Aminoglycosides should be prescribed during pregnancy only in cases of particularly severe infection and for the shortest possible time. With the exception of amoxicillin/clavulanic acid, aminopenicillins are not recommended as first-line treatment because of the frequency of primary resistance. Except pipemidic acid. Nalidixic acid only in this indication. Mainly pipemidic acid. Oral formulations only. According to bacterial sensitivity tests.

sistance. From a practical standpoint, oral antibiotics best adapted to initial and subsequent treatment are fiuoroquinolones, or amoxicillin plus clavulanic acid. The latter is not fully accepted, because of the possible development of resistant strains, and also because it can induce diarrhoea. When results of disc sensitivity tests become available, another antibiotic may be substituted, for reasons of better efficacy, cost, tolerance or easier use.

5.4.2 Treatment Duration Hospitalisation is not obligatory provided reliable laboratory and ultrasound/radiographic investigations are readily available in an outpatient setting. Treatment should be in the order of 10 days (Gleckman 1987; Jemelius et al. 1988; Johnson & Stemm 1989; Komaroff 1984; Norrby 1989; Ronald 1987; Safrin et al. 1988; Tolkoff-Rubin & Rubin 1987). A duration of 20 days is often mentioned

in the literature but no randomised studies have yet been performed to substantiate better effectiveness of such a long regime (Gleckman 1987). It is thus usually recommended to treat this type of pyelonephritis for between 10 and 20 days. In this respect, it is noteworthy that many fiuoroquinolones, especially pefioxacin, accumulate in the body, and that after ending treatment urinary excretion persists over several days (Norrby 1989). This means that 10 days of treatment with these compounds may in fact correspond to 15 days of antimicrobial therapy. 5.4.3 Follow-Up Assessment of efficacy is based on several criteria. Pain and fever usually abate within 3 to 5 days. Persistence of clinical srmptoms after 5 days may be due to bacterial resistance to the antibiotics initially prescribed, which will be confirmed by

Pyelonephritis: Diagnosis and Treatment

sensitivity tests. If the initial choice of antibiotic was bacteriologically adequate (i.e. sensitivity tests indicate susceptibility), persistent fever should lead to consideration of several possibilities. The first is drug intolerance. If this is ruled out, IVP and/ or CT scan should be requested to seek some overlooked abnormality, for instance urinary tract obstruction or abscess. Persistence of sterile leukocyturia over several weeks is common and does not indicate treatment failure. Biological signs of inflammation usually disappear within I to 2 weeks. Repeat urine cultures should be carried out approximately 2 to 4 weeks after completion of treatment to detect early relapses. In case of relapse, urinary tract imaging should be performed to find the reason for this recurrence. 5.5 Severe or Complicated Acute Pyelonephritis When pyelonephritis is seemingly severe, occurs in an immunocompromised patient, in a male, or when it is secondary to obstruction of the urinary tract (irrespective of gender), the patient should be hospitalised. Imaging of the urinary tract and of the kidneys is important in determining treatment strategy. Ultrasonography and IVP are usually required. CT sc~n followed by sequential excretory films ranks among the best methods to determine the extent of renal tissue lesions and the patency of the urinary tract. In addition to the possible surgical and metabolic aspects of treatment in such severe or complicated forms of pyelonephritis, the antibiotic regimen should combine an aminoglycoside with another bactericidal antibiotic. Length of treatment depends on the severity oflesions and on the evolution of the disease, but more than 20 days is recommended. Urine cultures should be repeated several times over the ensuing months to verifY stable bacteriological cure. 5.6 Pyelonephritis in Pregnancy Pyelonephritis is a serious condition in a pregnant woman, but pregnancy considerably reduces the choice of antibiotics (Edler & Bint 1987;

365

MacNeeley 1988). However, in individual cases with particularly severe forms of pyelonephritis some risk may be taken. The issue of antibiotic treatment of UTI in pregnancy is further complicated by the fact that the knowledge acquired in this specific indication stems more from retrospective experience than from prospective clinical studies which are virtually nonexistent, for understandable reasons of liability. In addition, legislation varies among countries. In each particular case, treatment strategy should be discussed among the physician in charge, the obstetrician, the bacteriologist and the pharmacologist. The reader should therefore be aware that the following principles must be taken as general indications rather ~han specific recommendations. Keeping in mind these reservations, the antibiotics suitable for UTI during pregnancy can be divided into 3 classes: 1. Antibiotics that can be used without risk to the foetus, e.g. amino- or carboxypenicillins (alone or in combination with clavulanic acid), ureidopenicillins, cephalosporins, aztreonam. 2. Antibiotics that can be used for a short period of time and only in case of special severity, e.g. aminoglycosides. 3. Antibiotics that are contraindicated during pregnancy; this includes virtually all other antibiotics, especially fluoroquinolones and trimethoprim/sulphonamide combinations. 5.7 Pyelonephritis in Children Quinolones are contraindicated in children. Under 18 months of age, treatment usually consists of an aminoglycoside associated with a third generation cephalosporin. Administration is parenteral, and the child should be hospitalised at least at the beginning of treatment. Treatment can be pursued at home when infection is under control. Length of treatment is customarily 10 to 15 days. Except in specific cases, aminoglycosides are not used for longer than a week. In a child aged over 18 months, treatment is similar to that in the adult, although antibiotic prescriptioQ habits of paediatricians may occasionally differ from those of physicians caring for adults.

Drugs 44 (3) 1992

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Two approaches are used. The first initially consists of a single antibiotic: amoxicillin plus clavulanic acid, a third generation cephalosporin, or cotrimoxazole. The second approach combines an aminoglycoside with 1 of the 3 antibiotics listed above, followed by single antibiotic treatment after the third day, guided by laboratory results. In severe forms, including urinary tract abnormalities and postsurgical infection, longer combined antibiotic treatment (including aminoglycoside for 8 days) is recommended. The total length of treatment may be over 2 weeks (Burns et al. 1987; Hanson 1982). Whatever the age of the child, APN is considered secondary unless proven otherwise. Preventive treatment to preclude relapse should therefore be pursued until the absence of urological obstruction or VUR has been shown. 5.8 Prevention of Relapse Relapses of APN may be early and due to the same organism, or late and consist of a new infection. Early recurrence due to the same organism indicates inappropriate antibiotic choice, insufficient length of treatment or persistence of an overlooked urinary tract abnormality. In children this possibility justifies preventive treatment (usually based on nitrofurantoin, cotrimoxazole, nitroxoline or nalidixic acid) until the uroradiological workup has been completed. The latter agent should not be given to children under 18 months of age because of the risk of brain oedema, and the dosages used are much lower (less than 30%) than those recommended for proven lower UTI. The length of preventive therapy depends on the results of urological investigations. New UTI with pyelonephritis may occur in diabetics or renal transplant recipients, usually complicating asymptomatic bacteriuria. This may also be the case in a young female with no immunodeficiency and a normal urinary tract, verified by IVP and retrograde cystography. Basically, this situation is similar to that of recurrent UTI in general. A patient with recurrent episodes of pyelonephritis separated by periods of asymptomatic bacteriuria or cystitis should be treated with pro-

phylactic antibiotics. The principle of such prophylaxis rests on administering a low dosage of an antimicrobial agent, aimed at maintaining subinhibitory concentrations of the drug in the urine. Various protocols have been proposed (for review see Guibert 1991). Treatment may be continuous or intermittent, and the drugs studied include nitrofurantoin, quinolones, cotrimoxazole, cefradine, pivmecillinam, and pivampicillin. Tolerability of intermittent (2 to 3 times weekly) prophylactic regimens seems better than that of continuous (daily) drug administration, with similar efficacy.

References Ampel NM, Zinner SH. Bacterial urinary tract infection in pregnancy. In Fran~ois B, Perrin P (Eds) Urinary infection, pp. 141-160, Butterworths, London, 1983 Antibiotherapie des Infections Urinaires. (Second Consensus Conference on Antimicrobial Therapy, Paris, Nov. 16, 1990). Medecine et Maladies Infectieuses 21: 49-167, 1991 Bergeron MG, Marois Y. Benefit from high intrarenal levels of gentamicin in the treatment of E. Coli pyelonephritis. Kidney International 30: 481-487, 1986 Burns MW, Burns JL, Krieger IN. Pediatric urinary tract infection: diagnosis, classification, and significance. Pediatric Clinics of North America 34: 1111-1120, 1987 Edler SJ, Bint AJ. Management of bacteriuria in pregnancy. Drugs 33: 413-421, 1987 Gleckman RA. Treatment duration for urinary tract infections in adults. Antimicrobial Agents and Chemotherapy 31: 1-5, 1987 Guibert J. Prophylaxie des infections urinaires recidivantes. Medecine et Maladies Infectieuses 21 (N°2 bis): 160-167, 1991 Hanson LA. Prognostic indicators in childhood urinary infections. Nephrology Forum. Kidney International 21: 659-667, 1982 Higgins RM. Infections in a renal unit. Quarterly Journal ofMedicine 70: 41-51, 1989 Hodson CJ, Heptinstall RH, Winberg J. Reflux nephropathy update: 1983. Contributions to Nephrology, VoL 39, Karger, Basel, 1984 Jernelius H, Zbornik J, Bauer CA. One or three weeks' treatment of acute pyelonephritis? Acta Medica Scandinavica. 223: 469: 477, 1988 Johnson JR, Stamm WE. Urinary tract infection in women: diagnosis and treatment. Annals of Internal Medicine III: 906917,1989 June CH, Browning MO, Smith LP, Wenzel OJ, Pyatt RS, et aL Ultrasonography and computed tomography in severe urinary tract infeciion. Archives of Internal Medicine 145: 841-845, 1985 Komaroff AL. Acute dysuria in women. New England Journal of Medicine 310: 369-375, 1984 Lipsky BA. Urinary tract infections in men. Epidemiology, pathophysiology, diagnosis and treatment. Annals of Internal Medicine 110: 138-150, 1989 Mackenzie R, Asscher AW. Progression of chronic pyelonephritis in the rat. Nephron 42: 171-176, 1986 MacNeeley SG. Treatment of urinary tract infections during pregnancy. Clinical & Obstetrical Gynecology 31: 480-487, 1988

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Meyrier A. Long term risks of acute pyelonephritis - Editorial review. Nephron 54: 197-201, 1990 Meyrier A, Condamin MC Fernet M, Labigne Roussel A, Simon P et al. Frequency of development of early cortical scarring in acute primary pyelonephritis. Kidney International 35: 696703, 1989 Norrby SR. Treatment of urinary tract infections with quinolone antimicrobial agents. In Wolfson JS & Hooper DC (Eds) Quinolone antimicrobial agents, pp. 107-123, American Society for Microbiology, Washington DC 1989 Prat V, Horcickova M, Matousovic K, Hatala M, Liska M. Urinary tract infection in renal transplantation . Infection 13: 207210, 1985 Richet G. From Bright's disease to modern nephrology: Pierre Rayer's innovative method of clinical investigation. Kidney International 39:787-792, 1991 Roberts JA. Bacterial adherence and urinary tract infection. Southern Medical Journal 80: 347-351 , 1987 Roberts JA. Etiology and pathophysiology of pyelonephritis. American Journal of Kidney Diseases. 17: 1-9, 1991 Ronald AR. Optimal duration of treatment for kidney infection. Annals of Internal Medicine 106: 467-468, 1987 Safrin S, Siegel D, Black D. Pyelonephritis in adult women: in-

patient vs outpatient therapy. American Journal of Medicine 85: 793-798, 1988 Sheinfeld J, Schaeffer AJ, Cordon-Cardo C Rogatko A, Fair WR. Association of the Lewis blood-group phenotype with recurrent urinary tract infections in women . New England Journal of Medicine 320: 773-777, 1989 Stray-Pedersen B, Blakstad M, Bergan T. Bacteriuria in the puerperium. Risk factors, screening procedures, and treatment programs. American Journal of Obstetrical Gynecology 162: 792797, 1990 Tolkoff-Rubin NE, Rubin RH. New approaches to the treatment of urinary tract infection. American Journal of Medicine 82: 270-277, 1987 . Winberg J, Bollgren I, Kallenius G, Mollby R, Svensson SB. Clinical pyelonephritis and focal renal scarring. Aselected review of pathogens, prevention and prognosis. Pediatric Clinics of North America 29: 801-804, 1982 Zhanel JJ , Harding JKM , Nicolle LE. Symptomatic bacteriuria in patients with diabetes mellitus. Reviews of Infectious Diseases 13: 150-154, 1991 Correspondence and reprints: Dr Alain Meyrier, Service de Nephrologie et D'Hemodialyse, Hopital Avicenne, F-93009 Bobigny, France.

2nd International Symposium

Update in Cardiac Surgery, Anaesthesia and Intensive Care Date: 21-24 September 1993 Venue: Ghent, Belgium For further information, please contact: Dr Eric Mortier and Dr Jan Poelaert, University Hospital Ghent, De Pintelaan 185, B-9000 Ghent, BELGIUM