Clinical Meetings at RH Year 2001

2001 - A Macau Patient

Dr Matthew Wong, Dr Bing Lam, Prof KY Yuen; Department of Medicine and Department of Microbiology, Queen Mary Hospital

A 27 years old lady was referred from Hospital Kiang Wu, Macau with a presumptive diagnosis of "antibiotic resistant" lung abscess. HVL was a non-smoker and enjoyed good past health. She was not on any regular medication and did not have history of allergy. She was married with a one-year old child. She was born and all along lived in Macau. Currently she worked for the Macau Government and had been stayed in Macau for the past one year.

She presented with symptoms of upper respiratory tract infection for two weeks followed by fever and dry cough for 10 days.

Investigations carried out in Macau had following findings:
• Mild hyponatriaemia and hypokalemia.
• Liver and renal function test were otherwise normal.
• Chest X-ray (CXR) revealed right lower lobe pneumonia and abscesses.
• Sputum culture grew Streptococcus pneumoniae.
• MTI was negative.
• Fibreoptic bronchoscopy did not find any endobronchial lesion but there was mucosal edema and copious amount of whitish mucoid secretion over the posterior segment of right lower lobe.



She received multiple courses of antibiotics including imipenem, metronidazole, Ampicillin/sulbactam, Ciprofloxacin, and even anti-TB medication for one week. However, there was no clinical or radiological improvement.

The lady was transferred to Hong Kong for further management.

On arriving to Queen Mary Hospital, the patient had low grade fever. Otherwise, she was reasonably stable with blood pressure of 108/65 mmHg, pulse 104 bpm. There was no palpable lymph node. Chest examination revealed pleural effusion and crepitation over the right lower zone. Examination of other systems was unremarkable. CXR showed multiple cavitations and fluid levels over the right lower lobe. There was also consolidation over the left middle zone as well.

Investigation
Complete blood picture revealed leukocytosis with neutrophil predominant, other differential counts were normal. Inflammatory markers including ESR and CRP were elevated. The clotting profile, arterial blood gas, random glucose, liver and renal funtion test were normal apart from mild hyponatraemia and hypokalaemia. Autoimmune markers were unremarkable.

The following investigation was all negative including: serum Aspergillus Ab, Serology of Influenza, adenovirus, Parainfluenza, mycoplasma, chlamydia, respiratory syncytial, enterovirus, cold agglutinins and blood culture.

However both the sputum and pleural fluid grew 'Pseudomonas aeruginosa'. Pseudomonas pseudomallei titre was 1:640. On further questioning, the patient had traveled to Thailand 2 years ago. The diagnosis of Melioidosis was made in the light of the serological study and a compatible clinical picture.

Treatment and Progress
Before the diagnostic serology came back, she was treated with Imipenem/cilastatin 500mg iv q6h for 5 days empirically and was switched to ceftazidime 2g iv q8h when the diagnosis was made. The serology titre dropped four-fold after one week of treatment. However, she developed leucopenia and skin rash. The diagnosis of drug allergy was confirmed with skin biopsy. Ceftazidime was discontinued, and rash subsided. Finally the patient was put on oral doxycycline and TMP-SMZ for maintenance.

The oral medication (doxycycline and TMP-SMZ) was maintained for 6 months. The ensuing CXR showed resolving cavitating pneumonia with residual right lower lobe haziness, see figure. The serial pseudomallei titer remained at 1:40 on subsequent follow up.



Discussion
Background
In 1911, Pseudomonas pseudomallei was first isolated by Captain A. Whitmore, a British pathologist at Rangoon General Hospital, Burma. In 1921, "Melioidosis" was described [Melis" Greek word = distemper of donkeys (actually asses)]. Later, it was renamed as Burkholderia pseudomallei.

Epidemiology
Burkholderia pseudomallei is widely distributed in water and soil in the tropics, between latitudes 20° north and 20° south. It is mainly caused by direct contact with contamined soil or water or through cutaneous inoculation. The latency period can range from two days to 26 years (1)

Diabetes mellitus, preexisting renal diseases, thalassemia, occupational exposure, classified by the soil and water risk assessment (2) and excessive alcohol intake (3) were confirmed to be significant risk factors for Melioidosis and bacteremic melioidosis.

The disease may be localized or disseminated and nearly all organs can be affected. Depending on whether the infection course is acute or chronic, it is sometimes difficult to differentiate from various infections, including septicemia from other common bacterial organisms, typhoid, malaria, tuberculosis etc.

Diagnosis
The definitive diagnosis of Melioidosis is by isolation of B pseudomallei from various speciments, eg blood, pus, sputum and pleural fluid, etc. B pseudomallei is an aerobic Gram negative rod on routine culture media. The most striking feature is that the old colonies often become sweet smell, wrinkled in appearance after incubation for two to three days. The bacteria shows bipolar staining and is oxidase positive. B pseudomallei shows resistance to aminoglycosides and older-generation penicillins and cephalosporins. The awareness and good communication between the physician and laboratory staff help to avoid the failure of identification.

In this patient, Pseudomonas aeruginosa was wrongly identified from the culture of the specimens. Without reassessing the colonies, technologists are unable to differentiate P aeruginosa from that of B pseudomallei. The characteristic old colonies and the resistance to aminoglycosides can help in making the right diagnosis.

Besides, Melioidosis can be diagnosed presumptively by using serologic testing. The indirect hemagglutination test use the lipopolysaccharides extracted from the bacteria as the antigen to coat the red cells. Serology of more than 1:40 is regarded as having had Melioidosis. However serology of 1:40 to 1:160 is common in endemic area without evidence of active infection. A high IHA titre, > 1 : 640 or four-fold increase, is decidedly suggestive of active disease. Enzyme-linked immunosorbent assays have been recently developed to replace the conventional IHA test.

Treatment
Treatment usually consisted of an intensive phase (at least 14 days) of iv antibiotics- primarily ceftazidime (4), but more recently, meropenam or imipenem has been used for critically ill patients. (5). This was followed by an eradication phase of oral antibiotics, which usually consisted of doxycycline (adult dosage, 200mg/day), TMP-SMX (adult dosage, 320 mg of TMP bd, and 1600mg of SMX bd), and Augmentine for at least 3 months. This regime would reduced the relapse rate to <10% (6, 7). Newer quinolones are only marginally active against B pseudomallei. The sensitivity may be falsely high when using the conventional disk susceptibility tests and should be interpreted with caution. The bacteria usually resist aminoglycosides and thus the initiation of these agents should be avoided.

Minimization of treatment failure and relapse in patients with Melioidosis depends on an adequate duration of initial intensive therapy and adherence to an adequate eradication phase (8)

Future
It is possible that the underlying predisposing disease relates primarily to impaired polymorphonuclear leukocytes (PMNL) and macrophages. Preliminary data on granulocyte colony-stimulating factor (G-CSF) in treating patients with melioidosis and strictly defined septic shock are very encouraging (9).

References

1. Mays EE, Ricketts EA, Melioidosis: recrudescence associated with bronchogenic carcinoma twenty-six years following initial geographic exposure. Chest 1975; 68:261-263.
2. Yupin Suputtamongkol, Wipada Chaowagul, Ploenchan Chetchotisakd. Nimit lertpatanasuwun. Clin Infect Dis 1999; 29:408-413.
3. Currie BJ, Fisher DA, Howard DM, Burrow JNC, Lo D, Selva-nayagam S. Endemicmelioidosis in tropical Northern Australia: A 10-year prospective study and review of the literature. Clinical Infectious Diseases 2000; 31:981-986.
4. White NJ, Chaowagul W, Dance DAB, et al. Halving of mortality of severe elioidosis by ceftazidime. The Lancet 1989; 8665:697-701.
5. Simpson AJH, Suputtamongkol Y, Smith MD, Angus BJ, Rajanuwong A, et al. Comparison of imipenem and ceftazidime as therapy for severe melioidosis. Clinical Infectious Diseases 1999; 29:381-387.
6. Chaowagul W, Simpson AJH, et al. A comparison of chloramphenicol, trimethoprim-sulfamethoxazole, and doxycycline with doxycycline alone as maintenance therapy for melioidosis. Clin Inf Disease 1999; 29:375-380.
7. Rajchanuvong A, Chaowagul W, Suputtamongkol Y, Smith MD, Dance DAB, White NJ. A prospective comparison of co-amoxiclav and the combination of chloramphenicol, doxycycline, and co-trimoxazole for the oral maintenance treatment of Melioidosis. Trans R Soc Trop Med Hyg 1995; 89:546-549.
8. Chaowagul W, Suputtamongkol Y, Dance DA, Rajchanuvong A, Pattaraaechachai J, White NJ. Relapse in melioidosis: incidence and risk factors. J Infect Dis 1993; 168: 1181-1185.
9. Nelson S, Belknap SM, Carlson RW, et al. A randomized controlled trial of filgrastim as an adjunct to antibiotics for treatment of hospitalized patients with community-acquired pneumonia. CAP Study Group. J Infect Dis 1998; 178:1075-1080.