Klebsiella granulomatis (Granuloma inguinale)
Authors: Nigel O'Farrell, M.D.
Microbiology
Calymmataobacterium granulomatis is an intracellular organism which causes an ulcerating sexually transmitted infection, known as donovanosis or granuloma inguinale (1). However, there is some debate about the classification of the causative organism. A link between C. granulomatis and Klebsiella species was suggested on the evidence of antigenic cross reactivity some time ago (40). A more recent report has demonstrated a close similarity between C. granulomatis and Klebsiella pneumoniae and K. rhinoscleromatis with the authors suggesting that the causative organism be reclassified as K. granulomatis comb nov (4, 9).
Epidemiology
Transmission of C. granulomatis is usually sexual. Rare transmission during delivery and occasional non-sexual transmission have been reported. The main endemic areas for donovanosis have been in India, Brazil, South Africa, Papua New Guinea and among Australian aboriginals. Over the last twenty years the prevalence of donovanosis has decreased significantly and few cases are reported nowadays even in countries where the prevalence was once high.
Donovanosis has been associated with an increased risk of HIV infection. In Durban where HIV infection had been introduced only recently, the proportion of men with donovanosis and HIV infection increased significantly as the duration of lesions increased suggesting that HIV was acquired via sexual intercourse in the presence of ulcers (34).
Clinical Manifestations
Donovanosis usually commences with ulceration in the ano-genital region. Spread to local lymph nodes is followed by ulceration of skin overlying the lymph nodes. The ulcers are characterized by slow growth, absence of pain and friability. Hypertrophic lesions which stand out from the surrounding skin are common. Primary oral lesions have been described. In women, lesions may involve the cervix and upper reproductive tract. Complications include tissue destruction, scarring, the development of genital lymphoedema, haematogenous dissemination to bones and viscera and squamous carcinoma.
Laboratory Diagnosis
There are no established protocols for routine isolation and antibiotic susceptibility testing of C. granulomatis, although it is possible to culture C. granulomatis in human peripheral blood monocyte culture and in Hep 2 cells after decontaminating biopsy specimens with suitable antibiotics (10, 23). The diagnosis of donovanosis depends primarily on demonstrating the presence of intracellular organisms (termed Donovan bodies) in large mononuclear cells as Gram negative intracytoplasmic cysts filled with deeply staining bodies that may have a safety pin appearance (33).
Polymerase chain reaction (PCR) analysis using a colorimetric detection system can now be used in routine diagnostic laboratories and a genital ulcer multiplex PCR that includes C. granulomatis has been developed (11, 29).
Pathogenesis
C. granulomatis is an intracellular infection in which the organism is seen in the form of Donovan bodies sequestered within large histiocytes. It has been suggested that the inability of C. granulomatis to grow extracellularly is linked to the lack of the sucrose transporter gene (scrA) found in other Klebsiella species. A granulomatous inflammatory response is seen which leads to local tissue destruction and cutaneous ulceration.
SUSCEPTIBILITY IN VITRO AND IN VIVO
Only three papers report results of in vitro experiments with chemotherapeutic agents (6, 12, 39). Chen et al. (12) demonstrated that streptomycin, penicillin, chlortetracycline and chloramphenicol have additive effects against C. granulomatis in vitro when administered in combination (Table 1).
Numerous unsuccessful attempts have been made to find an animal model for donovanosis. In 1931 DeMonbreun et al. reported successful infection of the eyelids of macaques with tissue taken from human lesions of donovanosis but these lesions resolved spontaneously (15). It has not been possible so far to assess antibiotic activity against C. granulomatis in an animal model.
ANTIMICROBIAL THERAPY
C. granulomatis is found mainly within large histiocytes. The logical choice of therapy is thus an antibiotic with good activity against Gram negative bacteria, with good lipid solubility and capable of achieving a high intracellular to extracellular concentration ratio. Relapse may occur if treatment is taken for too short a time. Donovanosis may in the future prove a suitable infection for treatment with liposome-encapsulated antibiotics.
Drug of Choice
Table 2 summarizes data from the most important therapeutic trials. For a comprehensive bibliography of drug trials for donovanosis up to 1991 readers are referred to a review paper (44).
Drugs of the tetracycline group have been used extensively in the treatment of donovanosis for many years, generally with excellent results. Many published guidelines for the treatment of donovanosis (e.g., World Health Organization, Centers for Disease Control) recommend use of tetracyclines as first choice therapy. Individual well-documented cases of tetracycline resistance have been reported (35) and the drug appeared ineffective in infections contracted in Vietnam (47). It may be assumed that the different forms of tetracycline have equivalent efficacy. Doxycycline is now generally preferred over alternatives for ease of administration (twice daily).
Excellent results with co-trimoxazole have been reported from India (26) and Africa (28). Two treatment failures with co-trimoxazole have been reported from South America (38).
Chloramphenicol is widely used for treatment of donovanosis in Papua New Guinea (30), generally with good results. Lengthy experience with the use of chloramphenicol for a variety of infections in Papua New Guinea has shown that haematological toxicity is rare in this population. While chloramphenicol may be considered a treatment of choice in Melanesians, concerns about potential toxicity would limit its use elsewhere. Recent work from South America suggests that thiamphenicol, a congener of chloramphenicol, which has the convenience of once daily administration and reputedly does not carry the risk of haematological toxicity, is of comparable efficacy (5).
Ceftriaxone can give good results in chronic relapsing cases which have failed to respond a variety of other antibiotics (32). Weekly or daily azithromycin has useful activity which may make it a valuable drug for use in poorly compliant patients (7). Good results with azithromycin have been also been reported in patients who have failed on other therapies (31). In India, an initial study using norfloxacin showed good results (43).
Erythromycin and lincomycin both give good results in donovanosis although only a few trials have been conducted and experience is limited. Streptomycin was for many years the main drug used in the treatment of donovanosis. It continued in use in India up to 1971 (27) and more recently it has been evaluated in combination with tetracycline (28). Most clinicians now prefer to select antibiotics with less toxicity and greater ease of administration. Gentamicin also shows useful activity but has not been used much (30).
Ampicillin gave good results when used in American soldiers in Vietnam (8) but results in other trials have been poor. A treatment failure with ampicillin was reported by Johnson in 1991 (22). On the strength of available evidence ampicillin cannot be recommended as first line treatment.
Combination Therapy
Only one trial has been reported comparing monotherapy with combination therapy in the treatment of donovanosis (28). In this study streptomycin with tetracycline was compared to co-trimoxazole and no significant difference in outcome was noted in the two groups. Good results in the treatment of pregnant women using combined erythromycin and lincomycin have been reported from Australia (3). Small numbers of patients have been treated with combinations of streptomycin plus penicillin or chloramphenicol and with chloramphenicol plus tetracycline.
The efficacy of antibiotics in the treatment of donovanosis has largely been assessed in small-scale open trials. No randomized comparisons of therapy have been reported and the trial of streptomycin and tetracycline compared with co-trimoxazole described above (28) is one of a very small number of non-randomized comparisons published. Published treatment guidelines tend to favor antibiotics of the tetracycline group over alternatives but they do not offer explicit reasons for adopting this choice. On the basis of the published data set out in Table 2, and known adverse reaction profiles, the following antibiotics should be considered first line therapies for donovanosis: azithromycin, erythromycin, fluorinated quinolones, doxycycline. The dosage used in reported trials is set out in Table 2. In general most antibiotics are given at conventional dosage. Most clinicians continue therapy until lesions heal and some extend the treatment period further in the hope of reducing relapse. One or two weeks of therapy is often sufficient for small early lesions but therapy may need to be continued for 2-3 months for female patients with extensive pelvic infection.
Special Situations
Disseminated Infection
Hematogenous disseminated spread is a life-threatening complication of donovanosis. In a case report and review of 18 earlier published reports, 7 of the 19 cases died, including the subject of the case report (37).Among those cured, five were cured with tetracycline, two with streptomycin and one with chloramphenicol.Two authors have reported successful treatment of disseminated disease with combined streptomycin and tetracycline (13, 14). Paterson suggests the effectiveness of azithromycin in other forms of the disease make it the most promising choice for patients with disseminated infection, although its use in this rare situation has not yet been reported (37). He advocates initial daily therapy for a week followed by weekly dosing for 4-6 weeks.
Pregnancy
Donovanosis has a tendency to extend rapidly during pregnancy and to show a diminished responsiveness to antibiotic therapy. Many of the reported cases of haematogenous dissemination have been linked to tearing during delivery of an infected cervical lesion. Cordero has described such a patient who responded well to combination treatment with streptomycin and minocycline (14). Many first line antibiotics are contraindicated in pregnancy. Erythromycin is considered safe for use in pregnancy and satisfactory results among pregnant women have been reported with erythromycin alone (20) or in combination with lincomycin (3).
Donovanosis in Patients with HIV
Jardim has described two patients with HIV infection who failed to respond to extended treatment with combinations of co-trimoxazole, tetracycline and thiamphenicol (21). This would suggest that some patients may require vigorous treatment with high dose, parenteral, combination regimens. In a recent study from South Africa 18 pregnant women with HIV and donovanosis did not differ significantly in terms of outcome when compared with women without HIV (20).
Alternative Therapy
Second line drugs that may be considered for patients failing to respond to, or intolerant of the first line drugs listed above include ampicillin, chloramphenicol, thiamphenicol, lincomycin, streptomycin, co-trimoxazole and gentamicin. Prior to the introduction of antibiotics the following treatments were used with success for treatment of donovanosis: intravenous potassium antimony tartrate and other trivalent antimonials, surgical excision of lesions, diathermic fulguration, local treatment with podophyllin, ultra-violet radiation and radiotherapy (44).
ADJUNCTIVE THERAPY
Adjunctive surgical measures are required for patients with complications such as abscess formation, fistulae, strictures and elephantiasis (36). Surgery carries the risk of disseminating active infections if carried out without antibiotic cover.
Patients with extensive malodorous ulcers benefit from the addition of penicillin to treatment regimens and by bathing ulcers in solutions of dilute potassium permanganate.
ENDPOINTS FOR MONITORING THERAPY
Patients can be monitored clinically by observing the healing and re-epithelialization of ulcers. Repeat smears may be made from lesions to monitor the disappearance of Donovan bodies, though this is rarely undertaken outside the context of clinical trials. Follow-up should ideally be extended up to 18 months as late relapse may occur following healing. In long-standing cases a biopsy should be done to exclude malignant change.
PREVENTION
As donovanosis is sexually transmitted, management should always address the issues of partner management, health education and screening for other sexually transmitted infections, especially syphilis which often accompanies donovanosis. Exposed sexual partners should be offered examination and treated if lesions are found. Epidemiological treatment can be offered to asymptomatic exposed individuals who are concerned about becoming infected.
CONTROVERSIES, CAVEATS, COMMENTS
Debate still continues about the best nomenclature for the causative organism. Aragao and Vianna originally cultured a pleomorphic bacterium from ulcer lesions and identified it as C. granulomatis (2) but a number of studies suggested a link to Klebsiella species. After the advent of PCR, DNA sequencing of the 16SrRNA and phoE genes demonstrated that C. granulomatis had a greater than 99% similarity with Klebsiella pneumoniae and K. rhinoscleromatis and a proposal was put forward to reclassify the causative organism as K. granulomatis comb nov (4, 9). However, Kharsany et al performed a phylogenetic analysis of C. granulomatis based on 16S rRNA gene sequences and found that strains had similarities of only 95% and 94% respectively to the genera Klebsiella and Enterobacter (24).
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Table 1. Bactericidal Concentrations of Antibiotics Against C. granulomatis Reported by Chen (1951) (12).
| Antibiotic | Bactericidal concentration per ml of medium |
|---|---|
| Streptomycin | 0.2 mg |
| Penicillin G | 1 unit |
| Chlortetracycline | 5 mg |
| Chloramphenicol | 10 mg |
From Chen CH, Dienst RB, Greenblatt RB. Antibiotics versus Donovania granulomatis. Am J Syphilis 1951:35:383-392.
Table 2. Key Trials of Antibiotics for Treatment of Granuloma Inguinale
| Drug | Dose | Route | Duration | M:F | Total patients | Smear positive | Relapse | Days to smear negative | Days to heal | Ref |
|---|---|---|---|---|---|---|---|---|---|---|
| Ampicillin | 500 mg qid | O | 2-4wk | 31 | 67% | 8 | ||||
| Chloramphenicol | 500mg-1g 6h | O | 5-20d | 0/23 | 23 | 2 | 2-4 days | 18 | ||
| 2-4g every 3-4 days | IM | 8-12d | 20/23 | 43 | 43 | 5 | 1-7 days | 7-30d | 19 | |
| 500mg qid | O | 10-55d | 50 | 1 | av. 7 days | av.17d | 30 | |||
| Thiamphenicol | 2.5g stat, then 1Gram/day | O | 2 wk | 10/0 | 10 | 10 | 2 | 15 days | 15-30d | 5 |
| Co-trimoxazole | 160/800mg, bid | O | Mean 12.5d | 84/32 | 116 | 116 | 2 | 5 days | 7-22d | 26 |
| 160/800mg, bid | O | 20-49d | 19/1 | 20 | 16 | 2-5wk | 46 | |||
| 160/800mg, bid | O | 14d | 12/6 | 18 | 18 | 7-21d | 28 | |||
| Erythromycin | 1-300mg 6h | O | 16-37d | 5/4 | 9 | 9 | 1 | 9-30d | 45 | |
| Lincomycin | 500mg qid | O | 14d | 5 | 8 | |||||
| Streptomycin | 0.3-1g 4h | IM | 6-46d | 23 | 23 | 3 | 5-9 days | 17 | ||
| 0.3-4g/d | IM | 5-62d | 32/16 | 48 | 48 | 3 | 2-11 days | av. 3wk | 25 | |
| 1g bid | IM | 3-70d | 146/81 | 227 | 219 | 1 | av. 6 days | 41 | ||
| 1g bid | IM | av.12.5d | 83/39 | 122 | 27 | |||||
| Gentamicin | 1mg/kg tds | IM | mean 22d | 9 | mean 12 days | mean 22d | 30 | |||
| Tetracyclines | ||||||||||
| Minocycline | 200mg stat, then 100mg bid | O | 15-45d | 5/1 | 6 | 6 | 15-90d | 48 | ||
| Oxytetracycline | 2-3g/d | O | 2-29d | 32 | 32 | 2 | 4-5 days | 16 | ||
| Tetracycline hydrochloride | 1g/d | O | 20d | 14/6 | 20 | 20 | 5-7 days | 25-45d | 42 | |
| Norfloxacin | 400mg bid | O | 2-11d | 10/0 | 10 | 10 | 8 by 3 days | mean 7.3d | 43 | |
| Ceftriaxone | 1g od | IM/IV | 10d | 4/8 | 12 | 8 | 5 | 32 | ||
| Azithromycin | 1g per week or 500mg daily | O | 1-4 wk | 4/7 | 11 | 9 | 0 | 7 | ||
| Antibiotic Combinations | ||||||||||
| Streptomycin with | 1g/d | IM | 14d | 7/6 | 13 | 13 | 7-21d | 28 | ||
| tetracycline | 500mg 6h | O | 14d | |||||||
| Erythromycin with | 500mg qid | O | 10-14d | 0/4 | 4 | 4 | "rapid" | 3 | ||
| Lincomycin | 500mg qid | O | 10-14d | |||||||