(1)
Research TB Institute, Novosibirsk Medical University, Novosibirsk, Russia
Abstract
The first anti-tuberculosis drug streptomycin was created in 1945. Before this time the therapy for TB was based on diet and fresh air. Un-controlled using of antibiotics provoked development of drug resistant strains, so the history of urogenital TB can be divided into three periods: before antibiotics (AB), AB era and novo-days – MDR period. Mtb is drug-resistance, which may be: mono – Mtb are resistant to one of any antituberculous drugs; poly – Mtb are resistant to more than one of any drugs used for the treatment of the disease, excluding isoniazid and rifampicin simultaneously; multi-drug resistance (MDR) – Mtb are resistant to at least isoniazid and rifampicin, with or without resistance to other first-line drugs. Extensively drug-resistant TB (XDR-TB) refers to resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin and kanamycin). Persistence excluded an old specific for UGTB symptom – aseptic pyuria. Mtb hurts tissue and fades in persistence – for example, because the patient takes drugs for “UTI”. Damaged tissues are rapidly colonized by E.Coli – and now co-morbidity of UGTB and non-specific UTI enriches 75 %.
WHO notes that five drugs are currently regarded as essential in the management of TB – isoniazid, rifampicin, pyrazinamide, streptomycin and ethambutol. Thioacetaxone is also widely used to supplement isoniazid in many developing countries because of its low cost. Other drugs, including para-aminosalicylic acid (PAS), kanamycin, cycloserine, capreomycin, viomycin and ethionamide, can be of value in treating patients with MDR, but, in general, are more expensive and more toxic.
Possibilities of chemotherapy may be limited by different side effects. Usually a patient with TB has at least one more disease, and co-morbidity demands to take into account potential drug interaction, which may lead both to increasing and decreasing therapeutic effect.
Keywords
Urogenital tuberculosisTherapyAnti-tb drugsPersistenceResistenceSide effect4.1 History (Before Antibacterial Era)
The millennial flight against tuberculosis has been characterized by several defeats. Roman physicians advised TB patients to consume better nutrition, take sea voyages and fresh air; during the Middle Ages, the ‘royal touch’ was considered as an effective remedy for TB scrofula. In the following centuries, TB was cured using old herbal preparations and new chemical compounds, mainly aimed at soothing symptoms; in addition, harmful approaches (for example, bleeding and purging) were commonly accepted, according to medical theories of that time (Riva 2014).
Because antibiotics were unknown, the only means of controlling the spread of infection was to isolate patients in private sanatoria or hospitals limited to patients with TB (Fig. 4.1).
Fig. 4.1
Reproduction of color trade card, Paris, 1929 “Save the people with tuberculosis – romanticizing “consumption””. Association d’Hygiene Sociale et de Presentation Antituberculose du 1st Arr. Aon., Sauvons les Tuberculeux, color trade card
In that period only a sanatorium regimen based on aerotherapy, bed rest, better nutrition, sunbathing and moderate physical exercise appeared to provide first partial successes. Some invasive approaches were also employed, such as lung collapse surgical interventions (for example, phrenicotomy, thoracoplasty) and artificial pneumothorax. And only when infectious agent of TB was discovered by Koch, attempts to destroy Mtb were undertook, but by using ineffective and sometimes harmful, dangerous preparation (Riva 2014).
4.2 Antibacterial Era
In the second half of the past century a new antibacterial era started. The first anti-tuberculosis drug streptomycin was created by Selman Abraham Waksman in 1945. The development of anti-TB drugs (streptomycin, isoniazid, para-aminosalicylic acid, ethambutol and pyrazinamide) deeply revolutionized treatment for tuberculosis, allowing achievement of important successes. As an example I’d like to show the incidence rate of TB in the USSR and then in the Russian Federation (Fig. 4.2).
Fig. 4.2
Incidence of TB in the USSR (Russian Federation)
In the 1990’s the incidence of TB decreased dramatically in Russia. The main reasons were: BCG-vaccination of newborns and creation of such antituberculous drugs as isoniazid, rifampicin, pyrazinamid, PASA, ethambutol, protionamid. Later the incidence increased till about 1990 (mostly because of social and economic factors) and remained stable for decade.
4.2.1 MDR Period
The history of urogenital TB can be divided into three periods: before antibiotics (AB), AB era and novo-days – MDR period.
Before AB and in the beginning of the AB era, Mtb was calm and careless, it was confidents in her force, and it didn’t put on her armour. At that time Mtb did not allow urine to be in any other microflora simultaneously. Once began, it continued to destroy a tissue up to full destruction.
In MDR period antibiotics significantly have changed a character of Mtb. Mtb had to put down her visor and to defend. Mtb can defend itself by two ways: by persistence and by resistance.
4.2.2 Persistence of Mtb
In bad, poor conditions (cold, heat, presence of antibiotics, even in low doses, insufficient of air etc.) Mtb doesn’t multiply, hides in the cell and fades. Persistent Mtb is insensitive to the action of anti-bodies or antibiotic, which may kill her ONLY in a stage of her division. Normally Mtb replicates one time in 12–18 h, but in persistence it may rarely divide sporadically. A person infected with persistent Mtb has latent TB. In a stage of persistence, self-recovery is possible due to apoptosis of infected cells. Mycobacteria can sleep, can lie dormant any length of time. If the immunity of macroorganism is strong, Mtb can remain in persistence lifelong. Accordingly a person over a lifetime will be infected, but will not be ill and will not be contagious.
Once (after colds, stress, intercurrent disease etc.) Mtb wakes up. When it has emerged from the darkness of persistence, Mtb is very aggressive, and progression of TB begins rapidly.
Persistence excluded the old specific for UGTB symptom – aseptic pyuria. Mtb hurts tissue and fades in persistence – for example, because a patient takes drugs for “UTI”, masking UGTB – for example, fluoroquinolone, which inhibit Mtb, but doesn’t kill it during a short course of the therapy for UTI. Damaged tissues are rapidly colonized by E.Coli – and now co-morbidity of UGTB and non-specific UTI enriches 75 %.
4.2.3 Resistance of Mtb
The second way of the defense of Mtb is drug-resistance, which may be:
mono – Mtb are resistant to one of any antituberculous drugs;
poly – Mtb are resistant to more than one of any drugs used for the treatment of the disease, excluding isoniazid and rifampicin simultaneously;
multi-drug resistance (MDR) – Mtb are resistant to at least isoniazid and rifampicin, with or without resistance to other first-line drugs.
extensively drug-resistance (XDR). Extensively drug-resistant TB (XDR-TB) refers to resistance to at least isoniazid and rifampicin, and to any fluoroquinolone, and to any of the three second-line injectables (amikacin, capreomycin and kanamycin).
About 450 000 people developed MDR-TB in the world in 2012. More than half of these cases were in India, China and the Russian Federation. It is estimated that about 9.6 % of MDR-TB cases had XDR-TB (WHO 2014). MDR and XDR TB are associated both with a higher incidence of treatment failures and of disease recurrence, as well as with higher mortality, than forms of TB sensitive to first-line drugs.
Reasons for development of drug resistant M. tuberculosis in UGTB patient are:
Insufficient volume / duration of chemotherapy
Peculiarities of TB process
Condition of the patient and/or co-morbidity
Non-optimal previous AB therapy for UTI.
More often drug-resistant mycobacteria are revealed in pulmonary TB patients. Compared with PTB, EPTB is negatively associated with multidrug resistance (OR 0.6) (Peto et al. 2009). Drug resistant Mtb were found in 79 % in pulmonary TB patients and only in 52 % in extrapulmonary TB patients (Vishnevskyi and Steklova 2008). There is no reasonable explanation of this fact, we must take it for what it is worth.
4.2.4 How to Get Good Results in the Therapy for UGTB in MDR Period?
Since 1995, over 56 million patients with pulmonary TB have been successfully treated and an estimated 22 million lives saved through use of DOTS and the Stop TB Strategy (WHO 2014). But there are some conditions for this benefit scenario:
1.
The disease should be diagnosed on early stage (KTB 1–2);
2.
The patient should be primary infected with sensitive Mtb;
3.
The patient should be immunocompetent and shouldn’t have any serious co-morbidity;
4.
The regimen of the therapy should be optimal for good efficiency and prevention of the secondary drug resistance of Mtb;
5.
The adherence of the patient to the therapy should be high.
Widespread, often un-controlling use of antibiotics significantly changed clinical features of UGTB, which hid under masks of another disease during 5.6 years on average before a correct diagnosis was made. We analyzed 816 history cases of UGTB patients to estimate clinical features and evaluate masks under which TB was hidden for a long time.
Most common complaints were flank pain (68 %), dysuria (48 %) and renal colic (24 %); among laboratory signs – pyuria (78 %) and haematuria (34 %). Patients were treated by urologists or GPs with misdiagnoses of pyelonephritis (27 %), cystitis (43 %), cancer (8 %) or urolithiasis (22 %) during 5.6 years on average. Positive smear was in 17 % and positive culture of Mtb was in 44 %. Sixty four percent were diagnosed in late complicated cavernous stage, when surgery is necessary – and 90 % of operations were nephrectomy due to total involvement of kidney tissue.
Hence most common masks of UGTB are pyelonephritis, cystitis and urolithiasis. UGTB presents non-specific symptoms and laboratory findings, except for positive Mtb culture, but only about 44 % of cases are culture-positive. This is one of the main reasons for late and poor diagnosis of UGTB. The significance of UGTB may be considerable when the high prevalence of overall TB and the asymptomatic nature of UGTB are taken into account.
We analyzed the histories of 167 patients with renal TB. About 7 % of them had acute onset, were operated on in clinics of general urology and their previous therapy didn’t matter. Ninety three percent had chronic disease misdiagnosed as UTI, and for a long time they were treated with antibiotics, mostly for “cystitis”. Among them only in about 40 % were the so-called “small forms” of kidney TB diagnosed – TB of renal parenchyma and TB papillitis. Eighty percent of these patients received optimal antibiotics, which don’t inhibit Mtb (fosfomycin, gentamycin, nitrofurantoin, cephalosporins). Insufficient effect of the therapy allowed suspicion of TB, and a correct diagnosis was soon established. Then another 62 % of patients were revealed too late, with caverns – because in 75 % they were treated non-optimal, with antibiotics, which Mtb (fluoroquinolones, amycacin) and compels her to hide in persistence. And please let me remind the reader: if not treated, a person with TB infects an average of 10 to 15 new people each year, and TB is a sexually transmitted disease and one of the common reasons for both male and female infertility.
4.2.5 How to Improve an Adherence and Compliance
It is not secret – a poverty-ridden and asocial person is more liable to have any disease, including TB. These patients have a low motivation to undertake a long-time unpleasant treatment and put some limitation on fighting the disease. Poor adherence to Tb treatment is one of the main challenges for TB control, as it fosters TB transmission in the community and leads to drug resistance (Mirtskhulaya et al. 2013).
How can we improve the adherence? It was shown that additional food supplements improve adherences for care and treatment for TB patients, support treatment and minimize drug side effects together with results of the therapy (Kombe and Kapalata 2013; Kisonga et al. 2013). If rifampicin provokes an adverse effect, it can be replaced by rifabutin with the same efficiency but better tolerance (Chien et al. 2013).
One more reason for low adherence may be insufficient knowledge of both physicians and patients on fatal danger of TB for a patient, his family and society as a whole. It has resulted in interruption of the therapy and loss to follow-up – so called “default” (van der Werf et al 2013). TB treatment default rate remains above 10 % globally (Mirtskhulaya et al. 2013). Claasens et al (2013) reported, that in South Africa 25 % of new-revealed TB patients did not start treatment in a timely manner at primary healthcare facilities. These patients, defined as “initially lost to follow up” may transit Mtb within communities thereby contributing to the epidemic.
Mirtskhulaya et al. (2013) have found that the rate of defaulting was higher during the initial 3 months of chemotherapy. Multiple factors were attributed by defaulting patients as a cause for abandoning treatment, whereas different factors were independently associated with the TB therapy default. Authors believe that strengthening of outpatient treatment and enhanced psycho-social support to TB patients may reduce default rates.
Patients also used to interrupt the treatment because of side effects of anti-TB drugs (Chepuri Nagaraj et al. 2013).
4.2.6 How Can We Prevent Drug Resistance and Improve Results of the Therapy for UGTB?
TB is a treatable and curable disease. Active, drug-sensitive TB disease is treated with a standard 6-month course of four antimicrobial drugs that are provided with information, supervision and support to the patient by a health worker or trained volunteer. Without such supervision and support, treatment adherence can be difficult and the disease can spread. The vast majority of TB cases can be cured when medicines are provided and taken properly.
We prevent drug resistance and improve results of the therapy for UGTB by:
Early diagnostic.
Optimization chemotherapy.
Using pathogenetic therapy.
Poor knowledge of the doctors and the population, absence of the specific features, non-optimal antibacterial therapy for non-specific UTI resulted in late diagnosis of UGTB with polycavernous complicated forms typical picture is shown in Fig. 4.3.
Fig. 4.3
Late-diagnosed kidney TB 4th stage – polycavernous kidney TB – operational material
Late-diagnosed complicated form of cavernous UGTB (Fig. 4.4) can’t be cured by chemotherapy at all, surgery (often radical) is necessary.
Fig. 4.4
Slice –tomogram: late-diagnosed kidney TB 4th stage – polycavernous kidney TB
And KTB 1–2 stages without complications can be healed easyily and quickly.
4.2.7 Tuberculosis and Cancer
Even if the TB-patient is cured, he doesn’t become absolutely healthy; more or less sequels remain. Mor et al (2013) estimated long-term mortality and causes of death among patients who recovered from TB. Authors have found that these patients are at higher risk of mortality compared with the general population adjusted for age and sex, mainly in males and in the ages of 24–55. The overall most common diagnosis was malignancy.
Prostate cancer is one of the most common types of cancer and it is the second commonest cause of cancer-related death among men in the western world. Silberstein et al. (2013) have found microscopic prostate cancer in up to 30 % of men between 20–40 years old . In Japan, of 115,881 men attending the prostate cancer screening, 6099 men needed a second screening. Overall, 2320 of 6099 patients screened a second time underwent prostate biopsy, and 1073 men of them were diagnosed with prostate cancer (Koizumi et al. 2014).
Provocative factors for prostate cancer are unknown exactly. A recent study showed that chronic prostate inflammation accelerates prostate cancer progression (Simons et al. 2015), promotes initiation of diverse malignancies, enhances basal-to-luminal differentiation, and accelerates initiation of prostate cancer originating from basal cells (Kwon et al. 2014; Liu and Goldstein 2014; Sandhu 2008).
TB is a very chronic disease, so hyperchronic TB inflammation may provoke a malignization. Thus, TB may predispose a cancer, and prostate TB and prostate cancer have about the same clinical features, and the doctor has to have a highly suspicious index to recognize concomitant diseases. It is underlined by the following case history of our patient.
Case Report
A 72 years old man was presented to our Institute in March 2011 with complaints of frequency and urgency, weakening urine stream, night sweats, bladder and perineal pain. In 1987 the patient had had a pulmonary TB and had been treated during 10 months with three anti-TB drugs (isoniazid, rifampicin, and streptomycin) with good result. In 1990 the patient presented with hemospermia, strong perineal pain and was referred to a TB-urologist. Full examination revealed pyospermia, hemospermia and caverns of the prostate. Growth of Mtb was found both in ejaculate and prostate secretion. Mtb was sensitive to all anti-TB drugs. The pulmonary TB was not reactivated. The patient was treated during 10 months with four anti-TB drugs (isoniazid, rifampicin, streptomycin and pyrazinamide) again with good efficacy: pain and hemospermia disappeared and pyospermia decreased significantly. The prostate caverns, however, remained as complete healing of prostate tissue destructions is not possible. In 1993 the patient complained again of dysuria, perineal pain, and painful ejaculation. A relapse of prostate TB was finally diagnosed. Mtb did not grow, but could be detected in the ejaculate by polymerase chain reaction (PCR). The pulmonary TB remained inactive. The patient received isoniazid, rifampicin, streptomycin, PAS and pyrazinamid for 4 months, than isoniazid and rifampicin only for the rest of the year and in addition tocopherol, thiamin, phytotherapy, dimexid, and non-steroid inflammatory drugs. The patient also received rehabilitation courses annually for 5 years in a special anti-TB sanatorium. The patient was healed and remained well until March 2011, when pain and dysuria appeared again. Pyospermia with growth of Enterobacter sp. in prostatic secretion was found, but Mtb was not detected by any method. X-ray examination showed huge caverns of the prostate with calcification (Fig. 4.5).
Fig. 4.5
Urethrogram: cavern of the prostate with calcification
As the PSA level was 11 ng/ml, prostate biopsy was performed and a solid-glandular cancer was found by histological examination. There was, however, no active TB inflammation in the biopsies. The patient underwent radical prostatectomy. The section of the prostate gland revealed huge TB caverns filled with stones (actually calcified caseation) as demonstrated in Fig. 4.6.
Fig. 4.6
Cured cavernous prostate tuberculosis with calcified caseation and secondary prostate cancer
Histo-pathohistological investigations revealed a proliferation of the glandular prostate cancer with invasion of the capsule in the right and left lobes. The cavity walls of the caverns were lined with transitional epithelium with dense calcium salts in the lumen. In the seminal vesicles glandular tumor structures were growing into the muscle layer. Active TB inflammation was not found.
Although male genital TB seems to be a rare disease, 77 % of men who died from TB of all localizations had prostate TB, mostly overlooked during their lifetimes (Kulchavenya and Krasnov 2010). In a recent study 93 patients suspicious of prostate TB underwent ultrasound guided core prostate biopsy. Probes were investigated by PCR, pathomorphology and culture. Mtb was found by PCR in10.7 %, but Mtb culture was only positive in 6.9 %. Patho-histology revealed inflammation in 94.6 % of probes, fibrosis in 65.6 %, intraprostatic neoplasia in 9.7 %, cancer in 5.4 %, and TB in 24.7 % (Kulchavenya and Krasnov 2010).
Thus, prostate TB is rather often diseases, and all such patients have heightened risk of the development of prostate cancer.
UGTB is difficult to be diagnosed, and cancer is one of the most frequent diagnostic errors. Kho and Chan (2012) reported about a 20-year-old man who presented with a slow-growing painless scrotal tumor for 2 months, initially suspicious for a right paratesticular tumor. The patient underwent operation and pathohistology revealed TB.
Another case history was described by López Barón et al. (2009). A 65 year old man presented with symptoms of frequency, dysuria and weight loss within the last 6 months, without pulmonary symptoms and negative ELISA test for HIV. Digital rectal examination revealed a high volume, irregular and hard prostatic gland. Ultrasound investigation showed a prostatic volume of 39 cm3, without sign of malignancy. The prostate biopsy showed multiple granulomas and the Zhiel-Neelsen staining was positive for Mtb.
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