Antimicrobial Chemotherapy, 4th Edition
The therapeutic use of antimicrobial agents
- C. B. Slack
Types of infection
Symptoms of urinary tract infection are usually frequency of micturition and dysuria. Lower abdominal pain, loin pain, and fever are less often seen with acute uncomplicated cystitis—in which infection is confined to the bladder—but are found in acute pyelonephritis, or other upper tract disease involving the kidney. Diagnosis of urinary tract infection requires bacteriological examination of urine.
The presence of bacteria in a freshly passed mid-stream specimen of urine is a laboratory finding. When more than 105organisms/ml (108/l) are cultured from a specimen of urine, the term ‘significant’ bacteriuria is used. This figure correlates well with urinary infection, but should not be taken to imply that lower numbers are necessarily ‘insignificant’. The figure of 105has been established as the cut-off point for significance in order to exclude perineal contaminants which may be present in urine in considerable numbers.
This is found frequently in surveys of normal populations and the prevalence increases with age. Except at both extremes of life it is found more frequently in women—an indication of the ease of ascent of organisms from the introitus to the bladder. Asymptomatic infection does not need to be treated except where it has been shown to lead to upper tract infection as, for example, in pregnancy.
Infection confined to the lower urinary tract is usually self limiting. The hydrodynamic effect of continual urine production and micturition tends to wash organisms out of the bladder. The natural defences of the urinary epithelium, both phagocytic and humoral, also limit the natural history of urinary infection. Unless there are anatomical abnormalities—partial obstruction or an inability to empty the bladder completely—or a focus of infection such as a renal calculus (stone) or abscess, infection of the urinary tract often lasts only a few days, although the duration of symptoms may be shortened by appropriate chemotherapy. Indeed, old remedies such as high fluid intake may be as efficacious as the newest antibiotic!
In some patients recurrent bacteriuria may be shown to be associated with pyelonephritis. This is an indication for treatment and further investigation.
In general practice about half the patients presenting with frequency and dysuria have sterile urine cultures. This abacteriuric condition is sometimes referred to as the urethral syndrome—a common, but largely unexplained condition. Some cases may be due to sexually transmitted organisms, such as chlamydia, and some may represent the early stages of urinary infection.
Bacterial infection following surgery or instrumentation of the urinary tract is often seen in hospitalized patients and presents special problems in therapy because of the relatively antibiotic-resistant organisms found in many of these cases. The presence of foreign material such as a urinary catheter, which may act as a focus of infection, also makes treatment more difficult.
Urinary infection in children
This is especially important in the very young whose kidneys are growing, because of the possible sequela of pyelonephritis, an important cause of terminal renal failure. Making an accurate laboratory diagnosis is difficult; collecting an uncontaminated urine from an infant requires patience and skill. In some cases it is necessary to collect supra-pubic aspirates by direct needle puncture through the abdominal wall. This method is of particular value in babies, where it is relatively easy to perform.
The confirmation of urinary tract infection is made in the laboratory by quantitative culture of an uncontaminated specimen. Skin and perineal flora shed into urine in sufficient numbers will multiply in a few hours at room temperature and give false positive results. These can be reduced by refrigeration and rapid processing in the laboratory. Alternatively, the possibility of contaminants growing in the urine during transit can be circumvented by culturing the urine as soon as it is passed. This is achieved by using dip-inoculum methods which consist of agar attached to slides or spoons which are dipped in the urine, drained, and transported in a stoppered bottle to the laboratory where any bacterial cultures are counted after overnight incubation at 37 °C. A rough quantification is possible by this method or by other simple methods of direct plating of a fixed volume of urine on appropriate culture media. Simple identification of the resulting significant isolates is made and antimicrobial susceptibility tests performed as described in Chapter 8.
The common bacterial causes of urinary infection and their usual antibiotic sensitivity patterns are listed in Table 21.1. Many of the bacteria listed may be present as truly infecting organisms or as contaminants. This is a particular problem in urine collected from women, which is commonly contaminated with perineal or vaginal organisms. Mixtures of bacteria usually indicate contamination, although mixed infections do occur in catheterized patients.
Table 21.1 Frequency of isolation and usual antibiotic susceptibility of organisms causing urinary tract infection
Choice of agent
In a condition with such a high spontaneous cure rate it may not be always possible to judge comparative efficacy of different regimens. For most antibiotics a cure rate of over 80 per cent is expected. In acute, uncomplicated cystitis seen in general practice, over 90 per cent of patients would be expected to be asymptomatic after a few days' antibiotic therapy, and remain free from bacteri-uria for some weeks following. It is an advantage to know the susceptibility of the infecting strain before starting treatment, but delay is justified only in asymptomatic and chronic recurrent cases.
The vast majority of acute urinary infections present with painful symptoms and treatment should start before sensitivity results are available. A ‘best guess’ antibiotic should be selected based on past history, knowledge of likely pathogens, and local resistance patterns. In domiciliary practice Escherichia coli predominates and most will be fully sensitive to all the commonly used antimicrobials listed in Table 21.1. However, ampicillin-resistant organisms are now sufficiently common for this drug to be abandoned in favour of trimethoprim or one of the other oral agents. The use of co-trimoxazole is not recommended in the treatment
of urinary infection, since the sulphonamide component plays an insignificant role and trimethoprim alone is less toxic.
Two agents, nitrofurantoin and nalidixic acid, achieve adequate concentrations only in urine and are exclusively of use in urinary tract infection. Nitrofurantoin is cheap, but it often causes nausea; the macrocrystalline formulation is better in this respect. It is only effective in an acidic urine; thus in Proteus infections, where the ammonia-producing bacteria raise the pH to over 8, it is ineffective. Nalidixic acid and its early congeners (including cinoxacin, oxolinic acid, flume-quine, and pipemidic acid) are inactive against staphylococci and streptococci, and may also exhibit some unpleasant side-effects. Fluoroquinolones, such as ciprofloxacin, norfloxacin, and ofloxacin, combine much improved intrinsic activity with an expanded spectrum which covers not only Gram-positive cocci, but also problem bacteria such asPseudomonas aeruginosa.
Alternative oral agents to the drugs so far mentioned are often less effective. The older oral cephalosporins (e.g. cephalexin, cephradine) and pivmecillinam fail to produce better results than traditional agents. However, cefuroxime axetil, cefixime, co-amoxiclav, and fosfomycin trometamol exhibit broad-spectrum activity against most urinary pathogens and are increasingly used in place of trimethoprim.
In the special circumstances of urinary infection, unlike those in other parts of the body, the drugs used are often preferentially excreted into the urine and may attain very high concentrations there, sometimes for long periods. Moreover, in the treatment of bacterial cystitis (in contrast to pyelonephritis or infections complicating urinary tract abnormalities) antibacterial drugs are generally needed only to tip the balance in favour of normal clearance mechanisms. Several studies have shown that much-curtailed regimens, lasting 1–3 days, are as successful as prolonged therapy in curing acute urinary infections. Indeed, longer courses are wasteful of resources especially since many patients, wiser than their doctors, abandon treatment once the symptoms abate.
Short-course treatment has an additional potential benefit in serving to identify those few patients (the ones who fail short-course therapy) who are likely to require more extensive urological investigation. Many of the commonly used antibacterial agents are suitable for this type of approach, although those such as trimethoprim and the newer fluroquinolones or trometamol fosfomycin which are slowly excreted into urine over a long period have an advantage over rapidly excreted compounds (β-lactam agents and nitrofurantoin) which achieve high, but transient, concentrations in bladder urine. The practice of giving one or two massive doses of amoxycillin, which is sometimes advocated, would seem to have little to recommend it, since the enormous urinary levels produced are no more bactericidal than are those achieved by conventional doses.
Symptomatic abacteriuria (urethral syndrome)
The ‘urethral syndrome’ is usually seen in young women and, although the patients are generally given antibiotics, the symptoms are probably self limiting. Some patients get intractable symptoms and seek relief from non-medical practitioners; as there may be a psychological element to the urethral syndrome this is reasonable practice. It is, however, important to exclude any known microbial cause. A proportion of women suffering from the urethral syndrome do display intermittent bacteriuria, and sexually transmitted diseases may mimic the frequency and dysuria syndrome.
Sexual and emotional difficulties may aggravate symptoms, and counselling is important. Frequency and dysuria are sometimes related to vaginal hygiene and deodorants or to sexual technique. It is probably worth investigating such patients and monitoring their response to antibiotics if symptoms persist after excluding other organic causes. Those with no bacteria or pus cells in any urine sample require ‘talking therapy’, whereas a positive laboratory test should alert the physician to a condition amenable to ‘swallowing therapy’.
The chronic sufferer from frequency and dysuria is a persistent visitor to the surgery and may consume more antibiotics than most patients, hoping for relief from this distressing condition.
In a small minority of patients, symptoms persist or rapidly recur after short-course therapy. Inappropriate choice of agent accounts for a few of these, but many of them will be shown to have abnormalities on intravenous urogram. Radiological or ultrasonic assessment of patients failing therapy or presenting with recurrent urinary infection is important and must be considered mandatory in children and young adult males. Urograms and micturating cystograms often show an anatomical abnormality such as vesico-ureteric reflux or a contracted kidney indicative of pyelonephritis. Bacteriuria in such patients is an indication for antibiotics even in the absence of symptoms. If repeated conventional courses of treatment fail to prevent relapse and bacteriuria relatively soon after stopping the drug there is a case for long-term antibiotics to suppress the infection.
There is some debate about how long this prophylaxis should continue and which patients should receive it. In adults the decision should not be taken lightly and it should be reviewed every 6 months. It is common practice to maintain children with vesico-ureteric reflux and evidence of kidney damage on suppressive antibiotics until they reach puberty. Co-trimoxazole and, more recently, trimethoprim alone are the most widely used agents for this purpose. There is very little evidence for the emergence of trimethoprim-resistant strains on this regimen. Drugs which rapidly select resistant mutants during a course of treatment, such as nalidixic acid, are not suitable, but nitrofurantoin may be useful, if tolerated, in patients who develop infection with trimethoprim-resistant organisms. Adverse reactions and superinfection limit the choice of antimicrobial when used long term and it may be necessary to ring the changes after a few years.
Stones in the collecting system are a common cause of urinary tract obstruction and this may predispose to urinary infection. Some calculi, especially those containing hydroxyapatite, may harbour the infecting organism within the substance of the stone. Urease-positive bacteria such as Proteus species are commonly incriminated because the alkaline conditions produced by the production of ammonia by the bacterial enzyme favour stone formation. Large infected calculi cannot be treated by chemotherapy, and surgery or lithotripsy is necessary. Infection often relapses after lithotomy and there may be small stones left in the kidneys which can act as a further source of bacteriuria. Long-term drug suppression is indicated for these patients. Trimethoprim is the most favoured drug for this indication as nitrofurantoin is ineffective against Proteus infections.
Urinary catheterization is an essential and commonly performed procedure, but it is not without complications to the patient, the commonest of which is infection.
Organisms may be introduced into the bladder on insertion of the catheter or may ascend between the catheter and urethra or up the lumen of the tube. Ascending infection results first in bladder colonization with no symptoms except a ‘cloudy’ urine, followed by cystitis which may lead to bladder calculi. In some cases with long-term indwelling catheters, infection may reach the kidneys to result in pyelonephritis. Instrumentation or catheter removal from an infected urine may give rise to bacteraemia, which may present as a mild ‘catheter fever’ or a life-threatening Gram-negative septicaemia.
Prevention of bacterial colonization is obviously a desirable goal, but, even with careful aseptic technique and the use of closed drainage systems, bacteri-uria is a frequent finding in patients after the catheter has been in position for a few days. The decision to use an indwelling urinary catheter should be tempered by awareness of this complication. In the management of young chronically sick people with neurogenic bladders, many authorities advocate intermittent self-catheterization to overcome the inherent problems of a foreign body in the bladder. Attempts at chemoprophylaxis with antibiotics inevitably lead to colonization with resistant organisms including, eventually,Candida. Hexamine (methenamine), the oldest antibacterial drug used in urinary infection, may have some benefit when used prophylactically since the active component, formaldehyde, which is released in the acid conditions of the urine, is active against all bacteria and yeasts. In the face of established infection, however, hexamine is. ineffective. Prophylactic bladder irrigation with antiseptics, such as chlorhexi-dine, is sometimes advocated, but this has the disadvantage of breaking the closed drainage system which offers the best means of keeping infection at bay, and infection rates are not improved. Again, in the face of long-term bacteriuria the procedure is of limited value and may provoke bacteraemia.
Treatment of catheter-associated urinary infection with antibiotics is only of short-term value. However, in the symptomatic febrile patient Gram-negative septicaemia may supervene and it is important to abort this complication. The chances of treatment being successful are considerably improved if the catheter can be removed. Symptomless infection present at the time of removal of a catheter can be treated as an ordinary urinary infection. In patients with indwelling urinary catheters and minimal symptoms there is little to be gained by chemotherapy as candiduria will inevitably follow.
Choice of antimicrobial agent to treat infection in a catheterized patient may be severely limited as the organisms responsible are often antibiotic resistant nosocomial strains and infections are frequently due to mixed organisms.