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| {{CMG}} | | {{CMG}} |
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| ==Overview== | | ==[[Multi-drug-resistant tuberculosis overview|Overview]]== |
| '''Multi-drug resistant [[tuberculosis]]''' ('''MDR-TB''') is defined as TB that is resistant at least to [[isoniazid|isoniazid (INH)]] and [[rifampicin|rifampicin (RMP)]]. Isolates that are multiply-resistant to any other combination of anti-TB drugs but not to INH and RMP are not classed as MDR-TB.
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| ==Epidemiology== | | ==[[Multi-drug-resistant tuberculosis historical perspective|Historical Perspective]]== |
| A 1997 survey of 35 countries found rates above 2% in about a third of the countries surveyed. The highest rates were in the former USSR, the Baltic states, Argentina, India and China, and was associated with poor or failing national Tuberculosis Control programmes. Likewise, the appearance of high rates of MDR-TB in New York city in the early 1990s was associated with the dismantling of public health programmes by the [[Ronald Reagan|Reagan]] administration.<ref>{{cite journal | author=Frieden TR, Sterling T, Pablos-Mendez A, ''et al.'' | title=The emergence of drug-resistant tuberculosis in New York City | journal=N Engl J Med | year=1993 | volume=328 | issue=8 | pages=521–56 | id=PMID 8381207 }}</ref><ref>{{cite book | author=Laurie Garrett | title=Betrayal of trust: the collapse of global public health | publisher=Hyperion | location=New York | year=2000 | pages=268ff | isbn=0786884407 }}</ref>
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| MDR-TB can develop in the course of the treatment of fully sensitive TB and this is always the result of patients missing doses or failing to complete a course of treatment.
| | ==[[Multi-drug-resistant tuberculosis classification|Classification]]== |
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| Thankfully, MDR-TB strains appear to be less fit and less transmissible. It has been known for many years that INH-resistant TB is less virulent in guinea pigs, and the epidemiological evidence is that MDR strains of TB do not dominate naturally. A study in Los Angeles found that only 6% of cases of MDR-TB were clustered. This should not be a cause for complacency: it must be remembered that MDR-TB has a mortality rate comparable to lung cancer. It must also be remembered that people who have weakened immune systems (because of diseases such as HIV or because of drugs) are more susceptible to catching TB.
| | ==[[Multi-drug-resistant tuberculosis pathophysiology|Pathophysiology]]== |
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| ==Risk Factors== | | ==[[Multi-drug-resistant tuberculosis causes|Causes]]== |
| In addition to the obvious risks (i.e., known exposure to a patient with MDR-TB), risk factors for MDR-TB include
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| *HIV infection,
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| *Previous incarceration,
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| *Failed TB treatment,
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| *Failure to respond to standard TB treatment,
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| *Relapse following standard TB treatment.
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| ==Treatment== | | ==[[Multi-drug-resistant tuberculosis differential diagnosis|Differentiating Multi-drug-resistant tuberculosis from other Diseases]]== |
| {{see also|Tuberculosis treatment}}
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| The treatment and prognosis of MDR-TB are much more akin to that for cancer than to that for infection. It has a mortality rate of up to 80%, which depends on a number of factors, including
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| #How many drugs the organism is resistant to (the fewer the better),
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| #How many drugs the patient is given (patients treated with five or more drugs do better),
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| #Whether an injectable drug is given or not (it should be given for the first three months at least),
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| #The expertise and experience of the physician responsible,
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| #How co-operative the patient is with treatment (treatment is arduous and long, and requires persistence and determination on the part of the patient),
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| #Whether the patient is HIV positive or not (HIV co-infection is associated with an increased mortality).
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| Treatment courses are generally measured in months to years; it may require surgery, and despite that, the death rates remain still high despite optimal treatment. That said, good outcomes are still possible.<!--
| | ==[[Multi-drug-resistant tuberculosis epidemiology and demographics|Epidemiology and Demographics]]== |
| --><ref name="Mitnick2003">{{cite journal
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| | author=Mitnick C ''et al.''
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| | title=Community-based therapy for multidrug-resistant tuberculosis in Lima, Peru
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| | journal=N Eng J Med
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| | volume=348
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| | issue=2
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| | year=2003
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| | pages=119-128
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| | URL=http://content.nejm.org/cgi/content/abstract/348/2/119
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| | id=PMID 12519922 }}</ref>
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| The treatment of MDR-TB must be undertaken by a physician experienced in the treatment of MDR-TB. Mortality and morbidity in patients treated in non-specialist centres is significantly inferior to those patients treated in specialist centres.
| | ==[[Multi-drug-resistant tuberculosis risk factors|Risk Factors]]== |
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| Treatment of MDR-TB must be done on the basis of sensitivity testing: it is impossible to treat such patients without this information. If treating a patient with suspected MDR-TB, the patient should be started on SHREZ ([[Streptomycin]]+[[INH|isonicotinyl Hydrazine]]+[[Rifampin]]+[[Ethambutol]]+[[pyrazinamide|pyraZinamide]])+[[moxifloxacin|MXF]]+[[cycloserine]] pending the result of laboratory sensitivity testing.
| | ==[[Multi-drug-resistant tuberculosis screening|Screening]]== |
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| A gene probe for ''[[rpoB]]'' is available in some countries and this serves as a useful marker for MDR-TB, because isolated RMP resistance is rare (except when patients have a history of being treated with rifampicin alone). If the results of a gene probe (''rpoB'') are known to be positive, then it is reasonable to omit RMP and to use SHEZ+[[moxifloxacin|MXF]]+[[cycloserine]]. The reason for maintaining the patient on INH is that INH is so potent in treating TB that it is foolish to omit it until there is microbiological proof that it is ineffective (even though isoniazid resistance so commonly occurs with rifampicin resistance).
| | ==[[Multi-drug-resistant tuberculosis natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
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| When sensitivities are known and the isolate is confirmed as resistant to both INH and RMP, five drugs should be chosen in the following order (based on known sensitivities):
| | ==Diagnosis== |
| * an [[aminoglycoside]] (e.g., [[amikacin]], [[kanamycin]]) or polypeptide antibiotic (e.g., [[capreomycin]])
| | [[Multi-drug-resistant tuberculosis staging|Staging]] | [[Multi-drug-resistant tuberculosis history and symptoms|History and Symptoms]] | [[Multi-drug-resistant tuberculosis physical examination|Physical Examination]] | [[Multi-drug-resistant tuberculosis laboratory findings|Laboratory Findings]] | [[Multi-drug-resistant tuberculosis chest x ray|Chest X Ray]] | [[Multi-drug-resistant tuberculosis CT|CT]] | [[Multi-drug-resistant tuberculosis MRI|MRI]] | [[Multi-drug-resistant tuberculosis other imaging findings|Other Imaging Findings]] | [[Multi-drug-resistant tuberculosis other diagnostic studies|Other Diagnostic Studies]] |
| * [[pyrazinamide|PZA]]
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| * [[ethambutol|EMB]]
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| * a [[fluoroquinolone]]s: [[moxifloxacin]] is preferred to [[ciprofloxacin]] or [[ofloxacin]];
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| * [[rifabutin]]
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| * [[cycloserine]]
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| * a [[thioamide]]: [[prothionamide]] or [[ethionamide]]
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| * [[Aminosalicylic acid|PAS]]
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| * a [[macrolide]]: e.g., [[clarithromycin]]
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| * [[linezolid]]
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| * high-dose [[isoniazid|INH]] (if low-level resistance)
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| * [[interferon-γ]]
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| * [[thioridazine]]
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| Drugs are placed nearer the top of the list because they are more effective and less toxic; drugs are placed nearer the bottom of the list because they are less effective or more toxic, or more difficult to obtain.
| | ==Treatment== |
| | [[Multi-drug-resistant tuberculosis medical therapy|Medical Therapy]] | [[Multi-drug-resistant tuberculosis surgery|Surgery]] | [[Multi-drug-resistant tuberculosis primary prevention|Primary Prevention]] | [[Multi-drug-resistant tuberculosis secondary prevention|Secondary Prevention]] | [[Multi-drug-resistant tuberculosis cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Multi-drug-resistant tuberculosis future or investigational therapies|Future or Investigational Therapies]] |
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| Resistance to one drug within a class generally means resistance to all drugs within that class, but a notable exception is rifabutin: rifampicin-resistance does not always mean rifabutin-resistance and the laboratory should be asked to test for it. It is only possible to use one drug within each drug class. If it is difficult finding five drugs to treat then the clinician can request that high level INH-resistance be looked for. If the strain has only low level INH-resistance (resistance at 1.0mg/l INH, but sensitive at 0.2mg/l INH), then high dose INH can be used as part of the regimen. When counting drugs, PZA and interferon count as zero; that is to say, when adding PZA to a four drug regimen, you must still choose another drug to make five. It is not possible to use more than one injectable (STM, capreomycin or amikacin), because the toxic effect of these drugs is additive: if possible, the aminoglycoside should be given daily for a minimum of three months (and perhaps thrice weekly thereafter). Ciprofloxacin should not be used in the treatment of tuberculosis if other fluoroquinolones are available.<ref>{{cite journal | author=Ziganshina LE, Vizel AA, Squire SB. | title=Fluoroquinolones for treating tuberculosis | journal=Cochrane Database Sys Rev | year=2005 | issue=3 | pages=CD004795 | doi=10.1002/14651858.CD004795.pub2 }}</ref>
| | ==Case Studies== |
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| There is no intermittent regimen validated for use in MDR-TB, but clinical experience is that giving injectable drugs for five days a week (because there is no-one available to give the drug at weekends) does not seem to result in inferior results. Directly observed therapy certainly helps to improve outcomes in MDR-TB and should be considered an integral part of the treatment of MDR-TB.<!--
| | [[Multi-drug-resistant tuberculosis case study one|Case #1]] |
| --><ref name="Leimane2005">{{cite journal
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| | author=Leimane V., ''et al.''
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| | title=Clinical outcome of individualised treatment of multidrug-resistant tuberculosis in Latvia: a retrospective cohort study
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| | journal=Lancet
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| | volume=365
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| | issue=9456
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| | year=2005
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| | pages=318-26
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| | URL=http://linkinghub.elsevier.com/retrieve/pii/S0140673605177861
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| | id=PMID 15664227}}</ref>
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| Response to treatment must be obtained by repeated sputum cultures (monthly if possible). Treatment for MDR-TB must be given for a minimum of 18 months and cannot be stopped until the patient has been culture-negative for a minimum of nine months. It is not unusual for patients with MDR-TB to be on treatment for two years or more.
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| Patients with MDR-TB should be isolated in negative-pressure rooms, if possible. Patients with MDR-TB should not be accommodated on the same ward as immunosuppressed patients (HIV infected patients, or patients on immunosuppressive drugs). Careful monitoring of compliance with treatment is crucial to the management of MDR-TB (and some physicians insist on hospitalisation if only for this reason). Some physicians will insist that these patients are isolated until their sputum is smear negative, or even culture negative (which may take many months, or even years). Keeping these patients in hospital for weeks (or months) on end may be a practical or physical impossibility and the final decision depends on the clinical judgement of the physician treating that patient. The attending physician should make full use of therapeutic drug monitoring (particularly of the aminoglycosides) both to monitor compliance and to avoid toxic effects.
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| Some supplements may be useful as adjuncts in the treatment of tuberculosis, but the for the purposes of counting drugs for MDR-TB, they count as zero (if you already have four drugs in the regimen, it may be beneficial to add arginine or vitamin D or both, but you still need another drug to make five).
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| * [[arginine]]<ref>{{cite journal | journal=Eur Respir J | year=2003 | volume=21 | pages=483–88 | title=Arginine as an adjuvant to chemotherapy improves clinical outcome in active tuberculosis | author=Schön T, Elias D, Moges F, ''et al.'' | url=http://erj.ersjournals.com/cgi/content/abstract/21/3/483 }}</ref> (peanuts are a good source)
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| * [[Vitamin D]]<ref>{{cite journal | journal=Infect Immunity | year=1998 | pages=5314–21 | volume=66 | issue=11 | author=Rockett KA, Brookes R, Udalova I, ''et al.'' | title=1,25-Dihydroxyvitamin D3 induces nitric oxide synthase and suppresses growth of ''Mycobacterium tuberculosis'' in a human macrophage-like cell line | url=http://iai.asm.org/cgi/content/abstract/66/11/5314 }}</ref>
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| The drugs listed below have been used in desperation and it is uncertain whether they are effective at all. They are used when it is not possible to find five drugs from the list above.
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| * [[imipenem]]<ref>{{cite journal | journal=Antimicrob Agents Chemother | year=2005 | volume=49 | issue=7 | pages=2816–21 | title=Imipenem for treatment of tuberculosis in mice and humans | author=Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC. | id=PMID 15980354 }}</ref>
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| * [[co-amoxiclav]]<ref>{{cite journal | journal=Clin Infect Dis | year=1998 | volume=26 | issue=4 | pages=874–7 | title=Activity of amoxicillin/clavulanate in patients with tuberculosis | author=Chambers HF, Kocagoz T, Sipit T, Turner J, Hopewell PC. | id=PMID 9564467 }}</ref><ref>{{cite journal | journal=Scand J Infect Dis | year=2001 | volume=33 | issue=6 | pages=466–9 | title=Early bactericidal activity of amoxicillin in combination with clavulanic acid in patients with sputum smear-positive pulmonary tuberculosis | author=Donald PR, Sirgel FA, Venter A, ''et al.'' | id=PMID 11450868 }}</ref>
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| * [[clofazimine]]<ref>{{cite journal | journal=Am J Respir Crit Care Med | volume=151 | issue=4 | year=1995 | pages=1083–86 | title=Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and ''in vivo'' studies. | author=Jagannath C, Reddy MV, Kailasam S, O'Sullivan JF, Gangadharam PR. | url=http://ajrccm.atsjournals.org/cgi/content/abstract/151/4/1083 }}</ref><ref>{{cite journal | journal=Antimicrob Agents Chemother | year=1999 | pages=1638–43 | volume=43 | issue=7 | title=Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine | author=Adams LM, Sinha I, Franzblau SG, ''et al.'' | url=http://aac.asm.org/cgi/reprint/43/7/1638.pdf }}</ref><ref>{{cite journal | journal=Antimicrob Agents Chemother | year=2004 | pages=3133–35 | volume=48 | issue=8 | title=Lack of activity of orally administered clofazimine against intracellular ''Mycobacterium tuberculosis'' in whole-blood culture | url=http://aac.asm.org/cgi/reprint/48/8/3133.pdf }}</ref>
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| * [[prochlorperazine]]<ref>{{cite journal | journal=Antibiotic Med Clin Ther. | year=1958 | volume=5 | issue=5 | pages=305–9 | title=Prochlorperazine (compazine) as an aid in the treatment of pulmonary tuberculosis | author=Shubin H, Sherson J, Pennes E, Glaskin A, Sokmensuer A.
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| | id=PMID 13521769 }}</ref>
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| * [[metronidazole]]<ref>{{cite journal | journal=Antimicrob Agents Chemother | year=1994 | volume=38 | issue=9 | pages=2054–58 | title=Metronidazole is bactericidal to dormant cells of ''Mycobacterium tuberculosis'' | author=Wayne LG, Sramek HA | url=http://aac.asm.org/cgi/content/abstract/38/9/2054 }}</ref>
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| The follow drugs are experimental compounds that are not commercially available, but which may be obtained from the manufacturer as part of a clinical trial or on a compassionate basis. Their efficacy and safety are unknown:
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| * [[PA-824]]<ref name="Stover2000">{{cite journal | journal=Nature | year=2000 | volume=405| issue=6789 | pages=962–6 | title=A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis | author=Stover CK, Warrener P, VanDevanter DR, ''et al.'' | id=PMID 10879539}}</ref> (manufactured by [[PathoGenesis Corporation]], Seattle, Washington)
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| * [[R207910]]<ref name="Andries2005">{{cite journal | title=A diarylquinoline drug active on the ATP-synthase of ''Mycobacterium tuberculosis'' | author=Andries K, Verhasselt P, Guillemont J, ''et al.'' | journal=Science | year=2005 | volume=307 | issue=5707 | pages=223–27 | DOI=10.1126/science.1106753 }}</ref> ([[Koen Andries]] et al., under development by [[Johnson & Johnson]])
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| ===Surgery===
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| In extremely resistant disease, surgery is sometimes the last port of call. The centre with the largest experience in this is the [[National Jewish Medical and Research Center]] in Denver, Colorado. In 17 years of experience, they have performed 180 operations; of these, 98 were lobectomies, 82 were pneumonectomies. There is a 3.3% operative mortality, with an additional 6.8% dying following the operation; 12% experienced significant morbidity (particularly extreme breathlessness). Of 91 patients who were culture positive before surgery, only 4 were culture positive after surgery.
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| ==See also== | | ==See also== |
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| *[[MRSA]] | | *[[MRSA]] |
| *[[Vancomycin-resistant enterococcus]] (VRE) | | *[[Vancomycin-resistant enterococcus]] (VRE) |
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| ==References==
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| {{reflist|2}}
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| [[Category:Bacterial diseases]] | | [[Category:Bacterial diseases]] |