Antimicrobial Chemotherapy, 5th Edition
Part 4 - Therapeutic Use of Antimicrobial Agents
Sexually Transmitted Infections
Sexually transmitted infections (Table 29.1) formerly referred to as venereal diseases, are common (Fig. 29.1) but remain underdiagnosed because of the reluctance of some to seek medical help when genital symptoms develop. Some, such as syphilis and human immunodeficiency virus (HIV) infection (see Chapter 27), are potentially serious and have life-threatening complications; others, such as trichomonal vaginal discharge, are merely a nuisance. The stigmatization of sexually transmitted infections has been reduced in many societies particularly following the rapid emergence of HIV infection in the last two decades of the twentieth century. Realization that prevention of transmission of pathogens, notably by practising safe sex, is of paramount importance has eroded taboos that have existed for centuries. The explosive increase in sexually transmitted diseases worldwide makes it important for all doctors to have knowledge of their treatment. While genito-urinary medicine clinics specialize in their diagnosis, management, and follow up, community-based doctors deal with an increasingly large proportion of cases.
Direct microscopic examination is of utmost importance in genito-urinary medicine as it confirms many clinical diagnoses, and for this reason many clinics have some laboratory function on site. In most cases a sufficiently accurate microbiological diagnosis can be made to enable specific chemotherapy to be given. Microscopy of a genital discharge can give accurate, rapid confirmation of a clinical diagnosis in many cases. Typical Gram-negative intracellular diplococci in a Gram-stained film of a urethral discharge are strongly supportive of the diagnosis of acute gonorrhoea in a man. Conversely, in a patient with dysuria and discharge, large numbers of neutrophils (pus cells), but no diplococci, in ‘threads’ of urethral discharge that are present in an early stream urine sample suggest non-specific (probably chlamydial) urethritis. The examination of exudate from a syphilitic chancre must be done by dark ground microscopy within a few minutes of collecting the specimen; the presence of motile spirochaetes confirms the diagnosis; it is not possible to cultivate these organisms in artificial media. The unstained ‘wet’ film of vaginal secretions is the most widely used method for the diagnosis of trichomoniasis and may also revealCandida or bacteria-laden epithelial cells (‘clue’ cells) suggestive of bacterial vaginosis.
Table 29.1 Common genital tract infections and their treatment
Fig. 29.1 Relative prevalences of sexually transmitted infections diagnosed in genito-urinary medicine clinics in England and Wales in 2004.
For several reasons culture or direct detection of the presence of sexually transmitted pathogens should also be attempted. Multiple infections may be present simultaneously and it is routine practice therefore to screen patients with symptoms or signs of genital infection for the common causes. The antimicrobial susceptibility of pathogens can give important case-specific and epidemiological information (seeGonorrhoea below). Culture of cervical swabs from women and from extragenital sites in both sexes is necessary because examination of Gram-stained smears is unreliable. Few genital pathogens can be cultivated easily. The most commonly sought, Neisseria gonorrhoeae, is a fastidious organism requiring special media and growth conditions. Selective media containing antibiotics to inhibit commensal bacteria are used. Isolation of Chlamydia trachomatis requires cell culture. Alternatively, the antigenic particles may be detected by enzyme immunoassay techniques. Both these detection methods have been displaced in favour of more rapid and sensitive DNA amplification methods. These improved detection methods can be applied to urine samples, so diagnosis is not reliant on invasive sampling, for example involving a swab inserted into the urethra; such approaches make it more likely that a patient will (re)seek medical help.
Genital tract infections and their treatment
Some patients with sexually transmitted infections either default treatment or do not remain abstinent until the antimicrobial treatment course has been completed, risking disease transmission and/or re-infection. It is therefore important to render as many patients as possible non-infectious after a single visit to the clinic. Short course or ideally single dose treatment, where therapy compliance is directly observed, is therefore increasingly preferred. Concomitant treatment of the sexual partner(s) is essential to prevent re-infection, and the value of contact tracing has been shown, particularly in the control of spread of antibiotic-resistant strains of N. gonorrhoeae.
Acute gonococcal urethritis occurs 2-10 days after contact and in men is nearly always obvious, presenting as a visible thick yellow discharge accompanied by dysuria. Asymptomatic cases represent less than 5% of male infections, but about 50% of female infections. Prompt treatment with appropriate antibiotics will cure patients with no residual effects: it is hard to imagine that gonorrhoea was once treated by weeks of local irrigation and many sufferers were left with urethral strictures. Nowadays, the major problems of the disease are seen in women, especially with disseminated gonococcaemia. It is one of the main causes of infertility in the world.
- gonorrhoeaewas originally sensitive to many antimicrobial agents. However, the emergence of resistance has led to changes in the recommended treatment options. Penicillin replaced sulphonamides as the drug of choice once it became available in the later stages of the Second World War. In the late 1950s in-vitro testing showed that some strains of N. gonorrhoeaewere becoming less sensitive to penicillin. Increasing the dose of penicillin to keep ahead of bacterial resistance worked successfully until the emergence of high-level, plasmid-mediated resistance in the 1970s.
In acute disease, in areas in which resistance is uncommon or when susceptibility is already known, a single dose of a penicillin giving high tissue concentrations for 12h is sufficient. Intramuscular injections of procaine penicillin were often used for this purpose, but these have been largely replaced by single oral doses of amoxicillin together with probenecid to delay renal excretion. In the 1980s and 1990s widespread penicillin, resistance led to a switch in empirical therapy to a fluoroquinolone, such as a single dose (250-500 mg) of ciprofloxacin. As happened with penicillin, disseminated resistance to fluoroquinolones occurred, leading to many clinics having again to alter empirical therapy for gonorrhoea in the late 1990s and early part of the this century (Fig. 29.2). β-Lactamase-producing strains of N. gonorrhoeae still respond to intramuscular treatment with cephalosporins such as ceftriaxone, or to oral therapy with cefixime or co-amoxiclav. If there is known hypersensitivity to penicillin, cephalosporins may be used, but if the reaction was previously severe the danger of cross-allergy is too great and a non-β-lactam alternative (e.g. ciprofloxacin, azithromycin, or spectinomycin) can be employed. Data on the prevalence of antibiotic resistance in N. gonorrhoeae (Table 29.2) confirm the sustained activity of ceftriaxone and cefixime. Fluoroquinolone resistance is still increasing in prevalence, and although azithromycin-resistant strains remain uncommon the rate has increased significantly. This may reflect increased use of this antibiotic to treat chlamydial infection and consequent greater exposure of N. gonorrhoeae to macrolides.
Antibiotic treatment usually results in a rapid and complete cure in acute gonorrhoea. Occasional complications such as epididymitis, arthritis, and pelvic infection in women require admission to hospital and prolonged antibiotics. Non-genital gonococcal infection also requires more than a single dose of penicillin to achieve cure (see below).
Fig. 29.2 Relative prescribing of cephalosporins and fluoroquinolones for the treatment of gonorrhoea in genito-urinary medicine clinics in England and Wales, and prevalence of resistance to ciprofloxacin, 2000-2004.
Table 29.2 Prevalence of resistance in N. gonorrhoeae isolates from laboratories in England and Wales, 2003 and 2004
Non-gonococcal (non-specific) urethritis or cervicitis
After penicillin became available for the treatment of gonorrhoea it was evident that some treated individuals still had symptoms of urethritis or cervicitis or both. The terms non-specific or non-gonococcal urethritis were used to refer to such cases or when gonococci could not be demonstrated despite symptoms. It is now clear that most of these infections are caused by C. trachomatis, an obligate intracellular pathogen that is difficult to diagnose, requiring culture in cell lines. Indeed, numbers of C. trachomatis sexually transmitted infections now far exceed cases of gonorrhoea in most developed countries. Of great concern, C. trachomatis is a major cause of pelvic inflammatory disease in women (see below), which can lead to infertility. Some cases of non-gonococcal urethritis are probably due to ureaplasmas or mycoplasmas, but as these cell wall deficient bacteria may be found in some healthy individuals diagnosis of infection is difficult and not routinely practised. Trichomonas vaginalis, herpesvirus, urinary tract infection, and local causes such as trauma also account for some cases of urethritis/cervicitis.
- trachomatisinfection can now be detected by nucleic acid amplification tests on cervical or urethral swabs and, because of the greatly improved sensitivity of this approach compared with culture or enzyme immunoassays, on urine. The availability of urine testing means that cumbersome invasive sampling, and internal examination in females, is no longer required for the detection of chlamydia infection. Furthermore, screening of urine samples from young sexually active people, particularly those frequently changing sexual partners, is increasingly used to detect subclinical chlamydia infection.
Tetracyclines, especially doxycycline, given for at least 7 days are effective. Failure of therapy occurs and may reflect poor compliance or re-infection. A single dose of azithromycin is as effective as 1-2 weeks of tetracycline therapy and clearly overcomes compliance problems. It is considerably more expensive than tetracyclines, but improved overall compliance and efficacy may mean that it is cost-effective. Erythromycin can also be used for 1-2 weeks, but the relatively poor gastrointestinal side effect profile does not encourage compliance. Genuine relapses of infection are possibly due to latent phase chlamydial infection. Antimicrobial resistance is thought to be rare, but as routine culture and susceptibility testing of C. trachomatis is not practised limited data are available. Chlamydiae are eukaryotic cells, and although these bacteria lack a peptidoglycan cell wall, ampicillin and penicillin still achieve some cellular penetration. In pregnancy, erythromycin is the preferred treatment option for C. trachomatis infection, but amoxicillin or clindamycin can be used if it is not tolerated. Azithromycin has not been approved for use in pregnancy.
Pelvic inflammatory disease
In women, upper genital tract infection with sexually transmitted pathogens, anaerobes, streptococci or Gram-negative bacilli commonly results in pelvic inflammatory disease, which gives rise to serious complications of tubal blockage or dysfunction. The condition is difficult to diagnose because of the variety of symptoms, its often chronic nature, and difficulty in obtaining microbiological confirmation of the presence of pathogens in the peritoneal cavity. The disease is becoming more common, primarily because of the increases in sexually transmitted infections: it develops in 10-40% of women with inadequately treated chlamydial or gonococcal cervicitis. Pelvic inflammatory disease increases the chance of ectopic pregnancy seven-fold, as a result of tubal damage. Also, the risk of subsequent infertility increases with each episode. Chronic disease, a condition with considerable morbidity, commonly occurs, typified by chronic lower abdominal or pelvic pain.
Unless there is a known cause combination antimicrobial therapy is usually prescribed to cover the many different pathogens. In severe cases intravenous therapy with a cephalosporin such as cefotaxime, combined with a tetracycline with or without metronidazole is used. Oral therapy can comprise a fluoroquinolone, such as levofloxacin, moxifloxacin, or gatifloxacin with or without metronidazole. Therapy duration is usually 2 weeks.
Throughout the world chlamydiae cause substantial morbidity in terms of pelvic infection and infertility as well as the blinding eye disease, trachoma. Trachoma is treated using 1% tetracycline eye ointment (applied twice daily for 6 weeks), oral erythromycin, or if affordable with single-dose azithromycin.
Neonatal gonococcal or chlamydial infection
Ophthalmia neonatorum occurs within the first month, and usually a few days of birth, in babies born to infected mothers. Gonococci in the female genital tract are implanted in the conjunctivae during delivery and the neonate develops a purulent discharge from one or both eyes. There may be considerable cellulitis and if untreated the infection may lead to destruction of the cornea. Treatment should be prompt, with parenteral penicillin if the strain is sensitive and frequent local instillations of saline. Silver nitrate drops placed in the eyes immediately after birth may prevent the condition, but this has no activity against chlamydiae (see below). This therapy (Credé's method) is still used in areas where the danger of infection is high but carries a risk of inducing a chemical conjunctivitis especially if the concentration of silver nitrate is too high. Topical povidone iodine (Betadine) is an inexpensive alternative used to prevent eye infection in developing countries, and has the advantage of broader antimicrobial activity than silver nitrate.
Neonatal conjunctivitis due to chlamydiae is a less severe form of ophthalmia neonatorum than gonococcal infection. It may be so mild as to be unsuspected clinically and, like all the conditions due to chlamydiae, it is underdiagnosed. In spite of its mild, self-limiting course it can cause permanent eye damage and, whenever suspected, chlamydial conjunctivitis should be treated. Without appropriate laboratory facilities an accurate diagnosis cannot be made, but an index of suspicion is an indication for using erythromycin or tetracycline eye ointment. Local treatment is often difficult to apply adequately and many clinicians also advise giving erythromycin orally to prevent the development of chlamydial pneumonia. Erythromycin is used to treat infants because systemic tetracycline stains teeth and bones. Therapy needs to be for at least 2 weeks as with all complicated chlamydial infections. It is self-evident that the parents should be examined and treated as for non-specific urethritis (see above).
Syphilis may manifest as a primary illness, typified by the painless ulcer (chancre), or in more chronic forms (secondary or tertiary syphilis) that can affect nearly every organ. The old student adage ‘know syphilis and you will know medicine’ reflects the many ways in which syphilis can present and how it can mimic many other conditions. The progression of the infection varies greatly; even in untreated cases, latent periods of many years frequently occur. A diagnosis of syphilis used to be viewed with dread, in a similar way to identifying HIV infection, at least prior to the discovery of effective and non-toxic antimicrobial options.
Heavy metals, in particular mercury, were used for many centuries to treat syphilis. The development early in the twentieth century of arsenicals such as Salvarsan heralded the start of modern chemotherapy. Penicillin has been the mainstay of therapy since 1943 when the drug was first used to treat the disease. Treponema pallidum is exquisitely sensitive to penicillin: as little as 0.002 mg/l is bactericidal. There is no evidence of resistance to penicillin, but occasional treatment failures do occur. The aim of treatment is to maintain tissue levels of penicillin above 0.03 mg/l to ensure treponemal killing. Early syphilis is treated with intramuscular procaine penicillin usually given with probenecid for 2 weeks. In countries where it is still available, benzathine penicillin is used. Doxycycline, azithromycin, or ceftriaxone are alternatives in patients hypersensitive to penicillin. Erythromycin is associated with treatment failure and should not be used. Many antimicrobial agents may only suppress the disease, which can reappear in its later manifestations. This danger exists in treating a patient with non-syphilitic sexually transmitted infections who may also be incubating syphilis. For this reason serological tests for syphilis should be done on all high-risk patients.
In tertiary syphilis treatment for several weeks is necessary. Slow-release penicillins do not achieve adequate cerebrospinal fluid concentrations and frequent high doses of benzylpenicillin are recommended in the treatment of neurosyphilis. Similarly, high doses and longer duration of penicillin administration are recommended in patients co-infected with HIV, in whom a higher incidence of treatment failure has been noted. This presumably reflects the importance of the natural T-cell response in combating syphilis infection.
A common hazard of syphilis therapy is the Jarisch-Herxheimer reaction observed within a few hours of treatment with penicillin (or arsenicals). This is a hypersensitivity reaction due to spirochaetal endotoxin and is not related to penicillin allergy. The Herxheimer response is of little significance in primary cases, but may occasionally be fatal in some tertiary or late cases.
Genital herpes simplex virus
Herpes simplex virus types 1 and 2 generally cause infection ‘above and below the belt’ respectively, although sexual practices obscure this association. Genital infection is characterized by vesicles, usually on the penis or labia, similar to ‘cold sores’ found around the mouth. Proctitis is common in men who have sex with men. The painful vesicles burst to form superficial erosions, which can be secondarily infected. Women may carry the virus in the cervix and this may be a source of infection to the newborn, which may occasionally be fatal. Topical aciclovir can be used, or oral therapy for severe attacks or to reduce the frequency of symptoms.
The normal bacteria flora of the adult vagina before the menopause consists of numerous lactobacilli, diphtheroids, and anaerobes. These maintain a local pH of 4-5, which is inhibitory to coliforms. However, yeasts can flourish in such relatively acidic conditions.
Candida albicans, the commonest pathogenic yeast, may be found in up to a quarter of healthy women of child-bearing age and frequently the delicate balance between the resident flora and intruding Candida is disturbed to produce clinical ‘thrush’. Oral antibiotics, in particular tetracyclines, are prone to produce this side effect, which is also more common in pregnancy. Men, especially if uncircumcised, may occasionally have clinical balanitis caused by Candida and healthy individuals frequently carry the organism. Sexual transmission is probable in these circumstances, but thrush can occur without intimate contact. Local applications of nystatin or one of the imidazoles such as clotrimazole are sufficient, but prolonged and repeated courses are required. Persistent infections are sometimes treated with oral fluconazole, along with therapy for the partner.
Trichomonas vaginalis is a flagellate protozoon commonly found throughout the world. It favours a more alkaline pH than Candida and causes a foul-smelling yellow vaginal discharge often noticed because of staining of clothes and itching. It has been found in a high proportion of asymptomatic women in antenatal clinics, but may cause symptoms subsequently, especially after menstruation. In some patients the organism invades the anterior urethra and symptoms of dysuria and frequency may lead the clinician to make a tentative diagnosis of urinary tract infection. Some patients labelled as having ‘urethral syndrome’ may be suffering from trichomoniasis. The organism is sometimes carried transiently and asymptomatically by men, but a low-grade non-specific urethritis may occur.
Trichomonal infection is treated with a single oral high dose (2 g) of metronidazole or tinidazole. Longer courses of therapy are not more effective. Treatment of partners is required to reduce the risk of recurrence. Metronidazole used to be avoided during pregnancy because of a possible, albeit unproven, teratogenic effect. However, a possible association between trichomoniasis and premature rupture of membranes means that its use can be justified in this setting.
This is a term employed for a symptomatic discharge for which no obvious cause can be found. As with non-specific urethritis there are likely to be many possible aetiological agents, not all microbial. Bacterial vaginosis is now known to be associated with an increased risk of premature delivery, and with pelvic inflammatory disease in women undergoing termination of pregnancy. There is evidence that a proportion of these cases are associated with a pleomorphic, Gram-variable rod, Gardnerella (formerly Haemophilus) vaginalis, although the bacterium can be found in normal healthy individuals. Oral metronidazole given for 7 days is the treatment of choice for bacterial vaginosis, even though G. vaginalis is relatively resistant to this agent; its role may be to inhibit associated anaerobic, curved bacteria called Mobiluncus. Topical metronidazole or clindamycin can also be used. In treatment-resistant cases intravaginal boric acid has been successful. In recurrent infection of women, male partners are sometimes treated.
Genital (condylomata acuminata) and common skin warts are caused by human papillomaviruses. Importantly, certain types of virus, e.g. types 16 and 18 are carcinogenic and can cause cervical, vulval, penile, or anal cancer in some infected individuals. The treatment of genital warts occupies a good part of the work of genito-urinary medicine clinics and is often unrewarding. A long course of chemical applications such as podophyllin, trichloracetic acid, or salicylic acid, or burning the lesions with diathermy or liquid nitrogen, is often required; in some patients the warts disappear spontaneously. Imiquimod cream may be helpful by inducing the production of interferon-α and other cytokines. Genital warts in immunocompromised patients, including HIV-infected individuals, are relatively refractory to treatment; combinations of the above options are often required. Successful trials of a human papillomavirus vaccine have been reported heralding the opportunity to introduce mass population vaccination.
Chancroid (soft sore)
Chancroid is caused by Haemophilus ducreyi but is rarely seen in the UK. In tropical and subtropical countries epidemics occur and the infection enhances the spread of HIV. The genital lesions are painful and often multiple with large associated inguinal glands, which may suppurate to form a ‘bubo’. Erythromycin for 7 days or single-dose azithromycin is usually effective. Ceftriaxone can also be used but may be less efficacious in HIV-infected individuals. Tetracyclines and co-trimoxazole work in most cases unless bacterial resistance is common. Short courses (3 days) of co-amoxiclav or fluoroquinolones have also been used successfully.
This is also a predominantly tropical condition, caused by specific serovars of Chlamydia trachomatis. It starts as a small ulcer, which may be unnoticed until inguinal glands enlarge and become matted together. Associated inflammation may give the appearance of elephantiasis as a late complication and breakdown of abscesses may give rectovaginal fistulae. Tetracyclines, sulphonamides, or erythromycin may be used but, as with other chlamydial infection, 2-3 weeks of therapy is required.
Centers for Disease Control and Prevention. Sexually transmitted diseases: treatment guidelines, 2002. http://www.cdc.gov/std/treatment/TOC2002TG.htm
Geneva Foundation for Medical Education and Research. Genital infection, sexually transmitted diseases: guidelines, reviews, position statements, recommendations, standards. http://www.gfmer.ch/Guidelines/Genital_infections_sexually_transmitted_diseases/Genital_infections_sexually_transmitted_diseases_mt.htm
Health Protection Agency. HIV and sexually transmitted infections.