# Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment.

Rammaert Blandine, Goyet Sophie, Beauté Julien, Hem Sopheak, Te Vantha, Try Patrich Lorn, Mayaud Charles, Borand Laurence, Buchy Philippe, Guillard Bertrand, et al.

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## To cite this version:

Rammaert Blandine, Goyet Sophie, Beauté Julien, Hem Sopheak, Te Vantha, et al., Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment. BMC Infectious Diseases, 2012, 12 (3), 10.1186/1471-2334-12-3. pasteur-00853147

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Submitted on 22 Aug 2013

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# Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: Clinical characteristics and treatment

Blandine Rammaert<fnref n="1" />, Sophie Goyet<fnref n="1" />, Julien Beauté<fnref n="1" />, Sopheak Hem<fnref n="1" />, Vantha Te², Patrich Lorn Try³, Charles Mayaud⁴, Laurence Borand<fnref n="1" />, Philippe Buchy<fnref n="1" />, Bertrand Guillard<fnref n="1" /> and Sirenda Vong<fnref n="1" />*

## Abstract

**Background:** In many Asian countries, Klebsiella pneumoniae (KP) is the second pathogen responsible for community-acquired pneumonia. Yet, very little is known about KP etiology in ALRI in Cambodia, a country that has one of the weakest medical infrastructures in the region. We present here the first clinico-radiological description of KP community-acquired ALRI in hospitalized Cambodian patients.

**Methods:** Through ALRI surveillance in two provincial hospitals, KP was isolated from sputum and blood cultures, and identified by API20E gallery from patients ≥ 5 years-old with fever and respiratory symptoms onset ≤14 days. Antibiotics susceptibility testing was provided systematically to clinicians when bacteria were isolated. We collected patients' clinical, radiological and microbiological data and their outcome 3 months after discharge. We also compared KP-related with other bacteria-related ALRI to determine risk factors for KP infection.

**Results:** From April 2007 to December 2009, 2315 ALRI patients ≥ 5 years-old were enrolled including 587 whose bacterial etiology could be assigned. Of these, 47 (8.0%) had KP infection; their median age was 55 years and 68.1% were females. Reported prior medication was high (42.5%). Patients' chest radiographs showed pneumonia (61.3% including 39% that were necrotizing), preexisting parenchyma lesions (29.5%) and pleural effusions alone (4.5%) and normal parenchyma (4.5%). Five patients had severe conditions on admission and one patient died during hospitalization. Of the 39 patients that were hospital discharged, 14 died including 12 within 1 month after discharge. Only 13 patients (28%) received an appropriate antibiotherapy. Extended-spectrum beta-lactamases (ESBL) - producing strains were found in 8 (17.0%) patients. Female gender (Odds ratio (OR) 2.1; *p* = 0.04) and diabetes mellitus (OR 3.1; *p* = 0.03) were independent risk factors for KP-related ALRI.

**Conclusions:** KP ALRI in Cambodia has high fatality rate, are more frequently found in women, and should be considered in diabetic patients. The extremely high frequency of ESBL-producing strains in the study is alarming in the context of uncontrolled antibiotic consumption and in absence of microbiology capacity in most public-sector hospitals.

**Keywords:** Klebsiella pneumoniae, Community-acquired, Pneumonia, Extended-spectrum betalactamases, Diabetes mellitus

## Background

Klebsiella pneumoniae (KP) is a Gram negative bacillus often involved in severe community-acquired and nosocomial infections [1]. It has been proven to be an independent risk factor for mortality in severe community-

acquired pneumonia (CAP) [2]. Its distribution as a CAP pathogen is uneven across the world with a highest incidence in developing countries and in Asia [3-5]. To explain these geographical patterns, hypotheses include differences in virulence of strains, host defences and the importance of antibiotic consumption in self-medication [6,7]. KP is naturally resistant aminopenicillins (i.e. ampicillin or amoxicillin), an antibiotic that is commonly used as the first line antibiotherapy in CAP in

<footnote>* Correspondence: Sirenda.vong@gmail.com</footnote>

<footnote n="1">¹Institut Pasteur in Cambodia, Réseau International des Instituts Pasteur, Phnom Penh, Cambodia</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
many developing countries. This raises serious concerns since a recent multicenter prospective study conducted in several Asian countries (not including Cambodia) showed *KP* accounted for 15.4% of the pathogens responsible for hospitalized CAP, just after *Streptococcus pneumoniae* [8]. Last, emerging resistances among Gram-negative bacilli such as extended-spectrum beta-lactamases (ESBL) are increasingly recognized as a major public health issue in both developed and developing countries [9,10].

In Cambodia - one of the poorest countries in the region with ill-equipped health care facilities - microbial identification is a challenge and antimicrobial resistance detection is poorly documented. This study aimed at better characterizing hospitalized patients with *KP*-related acute lower respiratory infections (ALRI) in Cambodia collecting clinical, radiological and microbiological data.

## Methods

Beginning in April 2007, we conducted surveillance of ALRI in two Cambodian provincial hospitals. Eligible patients (≥5 years-old) included those with ALRI defined by onset symptoms ≤14 days, a fever of ≥ 38°C (axillary temperature using digital thermometers) or a history of fever within the previous 3 days, recent cough, plus at least one respiratory symptom (i.e. dyspnea, chest pain or crackles on lung auscultation). Patients with known tuberculosis (TB) or known acquired immunodeficiency were not included. For each participant, hospital physicians filled out a standardized case report form including information on patient's medical history, clinical features, treatment, laboratory and radiological findings and status at discharge. Medical records and chest X-rays were retrospectively reviewed by an expert pulmonologist. A home visit was conducted at least 3 months following hospital discharge to determine the outcome of the *KP*-infected patients. The surveillance project was approved by the National Ethical Committee. All patients and parents of <18 year-old patients who participated provided written informed consent.

## Specimens' collection and microbiology

Blood, non-induced sputum, and nasopharyngeal swabs were collected in each participant once within 48 h after hospital presentation for direct examination, cultures and molecular diagnostic. Sputum and blood (10 mL in Hemoline Diphasic Performance bottle (bioMérieux, Marcy l'Etoile, France) for adult and Isolator 1.5 (Oxoid, Basingstoke, England) (1.5 mL for children) were sent to Institut Pasteur in Cambodia to perform Gram stain and culture. Only good-quality sputum specimens were submitted for bacterial cultures using Murray-Washington's score (>25 polynuclear leukocytes and <25

squamous epithelial cells per low-power field) [11]. Sputum specimens were inoculated on colistin-nalidixic acid agar, cystine-lactose-electrolyte-deficient agar, chocolate polyvitex agar with bacitracin and Ashdown agar. Bacterial isolates were identified by API gallery (BioMérieux). Antibiotic susceptibility testing was performed by disk-diffusion method on Mueller-Hinton agar plates (Bio-Rad, Marnes-la-Coquette, France). ESBL production was detected by using the double-disk synergy test (clavulanic acid and cefotaxime, ceftazidime, cefepime and aztreonam) performed on Mueller-Hinton media.

Complete microbiology results were returned to the patient's hospital clinicians as soon as they were available. Microscopy for acid fast bacilli detection was systematically performed at the hospital laboratory, and TB culture where indicated in the guidelines of the national TB program.

## Definitions

*KP*-infected cases were defined by identification of *KP* in either blood or sputum culture. A significant growth of *KP* was defined as greater than 10⁷ organisms per mL of original sputum.

A severe case was defined by the presence of at least two of the following criteria: systolic blood pressure (BP) < 90 mmHg, cardiac frequency ≥120 bpm, respiratory rate ≥30/mn, oxygen saturation <90%, temperature <35°C or ≥40°C. Severity definition was adapted to the Cambodian setting from PSI and CRB65 scores [12]. Since no patient was taking anti-diabetic drug and fasting plasma glucose was not always available, we defined as diabetic every patient with glycemia >7.8 µmol/L or with a medical history of diabetes mellitus [13].

Renal impairment was defined as a serum creatinine >150 µmol/L and liver disease by a history of chronic liver involvement. Cardiovascular disease was defined by a history of high blood pressure or cardiomegaly on chest X-ray or known cardiopathy. Having TB was defined by a positive AFB smear, as 97% of them were linked to a positive culture for *Mycobacterium tuberculosis* in Cambodian hospitalized patients (unpublished data). A necrotizing pneumonia was defined by the presence of either cavity or abscess, unique or multiple. We created a separate preexisting lung lesions diagnostic group as these lesions may alter or disguise the appearance of a pneumonic infiltrate. The ALRI with normal radiography group consisted of patients presenting with symptoms of acute bronchitis and normal lung parenchyma radiographs [14,15]. Expert pulmonologists retrospectively interpreted radiographs unware of the microbiology diagnosis.

## Statistical analyses

We analyzed variables associated with mortality among patients with *KP* infection. In addition, we compared
KP-infected cases with ALRI cases infected with Haemo-
philus influenzae and Streptococcus pneumoniae (H&S),
the two main pyogenic bacteria identified in patients in
both hospitals to determine clinical/radiological charac-
teristics associated with KP infection. Variables that
were tested by univariate analysis included age, gender,
comorbidities, prior treatment to admission, hemoptysis,
chest pain, severity on admission, pneumonia, necrotiz-
ing pneumonia, uncomplicated pneumonia, pleurisy,
preexisting pulmonary lesions and TB co-infection. For
mortality-associated risk factors, the variable "receiving
an appropriate antibiotherapy" was added into the ana-
lyses. Variables for which a *p*-value in stratified analysis
was ≤0.2, were further analyzed using a stepwise forward
logistic regression model. Statistical analyses were per-
formed using STATA version 9.2 (Statacorp, College
Station, TX, USA). Odds ratio (OR) and 95% confidence
interval (CI) were calculated for all variables significantly
associated with KP infection or mortality.

Continuous variables were presented with their med-
ian and inter quartile range (IQR) or mean and mini-
mum/maximum ranges. Variables were compared across
groups using Wilcoxon-Mann-Whitney test for continu-
ous variables, and the Chi-square or Fisher's exact test
for categorical variables. For all analyses, statistical sig-
nificance was defined at *P* < 0.05.

**Results**

Patients characteristics

From April 2007 to December 2009, 2315 ALRI patients
≥5 years-old were enrolled including 587 whose bacter-
ial etiology could be assigned. Of these, 47 (8.0%) had
*KP* infection. The median age of *KP*-infected cases was
55 years (range 25-79). Women were predominant (n =
32; 68.1%); of which 72% aged >45 years. Main comor-
bidities or known risk factors included chronic lung dis-
ease (n = 13), smoker (n = 10), cardiovascular disease (n
= 7), diabetes mellitus (n = 7), alcoholism (n = 6), renal
impairment (n = 3), liver disease (n = 1). Treatment
prior to hospitalization was reported in 20 patients
(42.5%), of which 5 reported the use of antibiotics.
Reports of cigarette smoking and excessive alcohol
drinking (≥1 glass of rice wine or few beer cans per day)
were significantly more frequent in males than females
(6/14 versus 0/29; *p* < 0.001). Distribution of other
comorbidities did not significantly differ between gen-
ders or age groups.

Clinical, biological and radiological features on admission

Onset of symptoms occurred on average within 9 days
before presentation (range 1-14 days).

On admission, patients presented with fever >38°C (n = 30; 63.8%), chest pain (n = 28; 59.6%), cough (n = 26; 55.3%), and/or hemoptysis (n = 11; 23.4%). Five (10.6%)

patients had at least 2 severity criteria of which none
had hemoptysis. Interpretation of the 44 chest radio-
graphs that were available yielded 27 (61.3%) pneumonia
(i.e. 2 associated with pleural effusion and 14 with cavi-
tations), 13 (29.5%) preexisting pulmonary lesions
(bronchiectasis and/or infectious sequelae with cavita-
tion, fibrosis, retraction, pleural thickening), 2 (4.5%)
pleural effusion and 2 with normal parenchyma. For the
latter group, both radiographies showed a thoracic
hyperinflation, suggestive of a chronic obstructive pul-
monary disease. Of the 10 patients who had hemoptysis
and available chest X-rays, 4 had preexisting lung
lesions and 6 had pneumonia including 5 with cavita-
tions. Of note, AFB were found on direct sputum exam-
ination in only 2 cases. Among the 5 severe cases, 3 had
pneumonia without cavities, 1 had pleural effusion and
1 had preexisting lung lesions. Females had significantly
more radiological evidence of pneumonia than males
(55.6% vs. 44.4% respectively; *p* = 0.02).

**Microbiological data**

KP grew from 46 (97.8%) sputum cultures and 1 blood cul-
ture. No patients had both positive sputum and blood cul-
tures. In 5 cases, other bacteria (S. pneumoniae, n = 3; H
influenza, n = 1, Staphylococcus aureus, n = 1) grew
together with KP. AFB was also identified in six (12.8%)
patients. Viruses (respiratory syncytial virus, n = 7; influ-
enza B virus, n = 2; human rhinovirus, n = 2, including one
rhinovirus and respiratory syncytial virus co-infection) was
found in 21.3% (n = 10/47) of the patients. Bacterial or viral
coinfections were not associated with severity. Resistance to
cotrimoxazole was present in 32.3% (n = 10) of the strains
and resistance to ciprofloxacin was detected in only one
strain. ESBL production was detected in 17.0% (n = 8) of
the strains cultured from sputum specimens. All patients
infected with ESBL-producing strains were women. One
patient had a medical history of diabetes mellitus, one had
a cardiopathy and another one had pulmonary TB sequelae.
Comorbidities distribution was not significantly different in
patients with and without ESBL-producing KP. ESBL pro-
duction was frequently associated with gentamicin resis-
tance (50%; n = 4/8) and in most cases with susceptibility
to ciprofloxacin (n = 7/8) and fosfomycine (n = 8). Suscept-
ibility testing of the 39 non-ESBL producing KP strains
were as follows: amoxicillin/clavulanic acid, 94.7% (37/39),
cefotaxime, 97.4% (38/39), cefepime, 96.7% (29/30), ceftazi-
dime, 97.4% (38/39), ticarcilline, 2.5% (1/39), imipenem
97.4% (38/39), nalidixic acid, 83.3% (25/30), ciprofloxacine,
92.3 (36/39), gentamicin, 89.7% (35/39), amikacin, 97.4%
(38/39), cotrimoxazole, 61.3% (19/31).

Comparison between KP and H&S infected patients

As 4 patients were co-infected with *KP* and *H&S*, we
compared the 43 *KP* to the 160 *H&S* infected patients
(122 *H. influenzae* and 58 *S. pneumoniae*) (Table 1). There was a significantly higher proportion of females (67.4 vs. 50.0%; *p* = 0.04) in the *KP* group compared with the *H&S* group. Of all reported co-morbidities, only diabetes mellitus was more frequently associated with *KP*-infected patients than *H&S*-infected patients (16.3% vs. 6.0%; *p* = 0.02). Biological results did not differ between *KP* and *H&S* infected patients (Table 1).

There was no difference between radiological findings in both groups as shown in Table 2. Based on multivariate analysis, female gender (OR = 2.1; 95%CI [1.0-4.5]; *p* = 0.04) and diabetes mellitus (OR = 3.1; 95%CI [1.1-9.1]; *p* = 0.03) were independent risk factors for *KP*-related ALRI.

## Treatment and outcome

In the *KP* group, 47 received antibiotics during their hospital stay, two patients were transferred to another ward or hospital and one left the hospital before being treated, probably because the family could not afford the hospitalization costs. Appropriate first line antimicrobial therapy (ceftriaxone, amoxicillin/clavulanic acid, cotrimoxazole or ciprofloxacin) was prescribed to only four patients (9.0%). In the remaining 40 patients,

penicillin A was given (n = 39/40; 97.5%), in combination with gentamicin in 13 patients (33%) while one patient only received macrolides. This antimicrobial therapy was appropriately modified in nine (22.5%). Only 2 of 8 patients with ESBL-producing *KP* received an appropriate treatment and were considered as cured. For these patients, the treatment was adapted following antibiotic susceptibility. The overall length of stay at the hospital was on average 10.7 days (range 1-35) and longer for patients appropriately treated compared with that of patients without appropriate treatment (13.3 (range 3-21) vs 9.7 days (range 1-35); *p* = 0.01). On discharge, 59.6% (n = 28/47) of the patients were considered as cured by clinicians, one patient died during hospitalization and the outcome was unknown for 18 (38.3%) patients (14 were transferred to another ward or hospital and 4 escaped). Thirty-nine patients could be located for home visit. Of these, 14 (35.9%) died including 12 and two within 1 month and 6 weeks after discharge, respectively; none received an appropriate treatment. Twenty five (64.1%) were considered having recovered of which 13 received an appropriate treatment. Among the eight patients infected by ESBL-producing strains, three died within 1 month, two were not

<table><caption>Table 1 Characteristics on admission of *K. pneumoniae* infected patients compared to patients with *H. influenzae/S. pneumoniae* ALRI aged ≥5 years in univariate analysis</caption><thead><tr><th></th><th>Patients with <i>K. pneumoniae</i><br>ALRI<br>(n = 43)</th><th>Patients with <i>H. influenzae</i> and <i>S. pneumoniae</i><br>ALRI<br>(n = 160)</th><th>P-value</th></tr></thead><tbody><tr><td>Age, median years (Inter Quartile Range<br>[IQR])</td><td>55 (45-72)</td><td>57 (42-65)</td><td>0.8</td></tr><tr><td>Male gender (%)</td><td>14 (32.6)</td><td>80 (50.0)</td><td>0.04</td></tr><tr><td>Co-morbidities (%)</td><td></td><td></td><td></td></tr><tr><td>Smoking history</td><td>10 (23.3)</td><td>50 (31.2)</td><td>0.3</td></tr><tr><td>Cardiovascular disease</td><td>6 (13.9)</td><td>17 (10.6)</td><td>0.5</td></tr><tr><td>Diabetes mellitus</td><td>7 (16.3)</td><td>10 (6.2)</td><td>0.03</td></tr><tr><td>Alcoholism</td><td>6 (13.9)</td><td>35 (21.9)</td><td>0.2</td></tr><tr><td>Renal impairment</td><td>3 (7.0)</td><td>10 (6.2)</td><td>0.8</td></tr><tr><td>Liver disease</td><td>1 (2.3)</td><td>1 (0.6)</td><td>0.3</td></tr><tr><td>Prior treatment</td><td>19 (44.2)</td><td>92 (57.5)</td><td>0.08</td></tr><tr><td>Prior antibiotic</td><td>5 (11.6)</td><td>7 (4.4)</td><td>0.08</td></tr><tr><td>Clinical data</td><td></td><td></td><td></td></tr><tr><td>Chest pain</td><td>24 (55.8)</td><td>106 (66.2)</td><td>0.1</td></tr><tr><td>Hemoptysis</td><td>10 (23.2)</td><td>23 (14.4)</td><td>0.1</td></tr><tr><td>Severity criteria</td><td>5 (11.6)</td><td>8 (5.0)</td><td>0.1</td></tr><tr><td>Laboratory results</td><td></td><td></td><td></td></tr><tr><td>Leucocytes, median 10<sup>9</sup>/L (IQR)</td><td>8.5 (6.7 - 10.8)</td><td>8.3 (6.2 - 10.6)</td><td>0.6</td></tr><tr><td>AST*, median U/L (IQR)</td><td>29 (25-42)</td><td>27.5 (21-38)</td><td>0.1</td></tr><tr><td>ALT*, median U/L (IQR)</td><td>30 (21-32)</td><td>26 (20-34)</td><td>0.4</td></tr><tr><td>Blood creatinine µmol/L (IQR)</td><td>88.4 (77.8 - 108.7)</td><td>88.4 (76.0 - 99.0)</td><td>0.6</td></tr></tbody></table>

NOTE. Liver enzymes: AST (Aspartate transaminase) and ALT (Alanine transaminase)
<table><caption>Table 2 Radiological data on admission for 40 *K. pneumoniae* compared to 146 *H. influenzae* & *S.pneumoniae* infected patients aged ≥5 years in univariate analysis</caption><thead><tr><th></th><th>Patients with <i>K. pneumoniae</i> ALRI<br>N = 40 (%)</th><th>Patients with <i>H. influenzae</i> and <i>S. pneumoniae</i> ALRI<br>N = 146 (%)</th><th>P-value</th></tr></thead><tbody><tr><td>Pneumonia</td><td>25 (62.5)</td><td>68 (46.6)</td><td>0.05</td></tr><tr><td>Consolidation</td><td>16 (40.0)</td><td>51 (34.9)</td><td>0.3</td></tr><tr><td>Consolidation with cavitation</td><td>9 (22.5)</td><td>17 (11.6)</td><td>0.07</td></tr><tr><td>Consolidation with pleural effusion</td><td>2 (5.0)</td><td>6 (4.1)</td><td>0.5</td></tr><tr><td>Pleural effusion alone</td><td>1 (2.5)</td><td>0 (0.0)</td><td>0.2</td></tr><tr><td>Preexisting lung diseases</td><td>12 (30.0)</td><td>62 (42.5)</td><td>0.1</td></tr><tr><td>Normal parenchyma<sup>a</sup></td><td>2 (5.0)</td><td>16 (10.9)</td><td>0.2</td></tr></tbody></table>

NOTE. Data are no. (%) of patients

found and three were cured including two who received an appropriate antimicrobial therapy. As a result, the overall case fatality rate was 37.5% (15/40). Receiving an incorrect antimicrobial therapy was not a risk factor for mortality, although comorbidities, clinical and radiological features were not significantly different between survivors and non survivors (p = 0.12). Of the 12 patients who received at discharge incorrect treatment, none were considered severe. At the follow-up visit, 43.3% (13/30) of the patients who did not receive an appropriate treatment were alive.

Discussion

This is the first clinico-radiological description of a substantial number of community-acquired *KP* ALRI in hospitalized patients in Cambodia. Our findings confirmed that *KP*-related respiratory infections carried poor prognosis with high fatality rates, longer hospital stays and was associated with older ages and co-morbidities. More importantly, *KP* pneumonia was frequently unsuspected and the initial antimicrobial treatment was often inappropriate. Yet, we found from this surveillance project that *KP* was the second pyogenic bacterium found among severe CAP in patients aged 5 years and older, and the 4th in infections on preexisting pulmonary lesions in Cambodia (Institut Pasteur's unpublished data). Moreover, the high frequency of ESBL-producing strains in *KP* infection was particularly worrisome. The ESBL resistance among community-acquired infections varied from 0% (Taiwan, South Korea, Malaysia) to 36.4% (India), but the incidence is not well studied in Cambodia or neighboring countries [16]. In a multicenter study in Asian countries determining CAP etiologies, antibiotic susceptibility testing was done for 36 strains of *KP* [8]. All but one were susceptible to ceftriaxone. Another international multicenter study conducted in Taiwan, Argentina, South Africa, Europe, United States, and Australia, showed an incidence of community-acquired ESBL-producing *KP* was of 3.5% (n = 7/202),

all patients but one had a history of prior hospitalization [6]. In contrast, none of our patients with ESBL-producing strain reported previous hospitalization within the month prior to admission. In our cohort, 42.5% of the patients reported having taken treatment prior to hospitalization although the proportion of actual intake of antimicrobial drugs was not known. In the Cambodian context, it is believed however that this proportion may be high as patients have access to antibiotics and corticosteroids without medical prescription, through formal, informal and unregulated private health sectors [17]. Overuse and misuse (e.g. incorrect dosage) of antibiotics is a known risk factor for developing ESBL-producing strains [18]. Interestingly, a Cambodian study recently conducted in the capital city showed that up to 37% of the *E. coli* strains isolated from community acquired urinary tract infections carried ESBLs, of which all were CTX-M type [19].

Female gender and diabetes mellitus are independent risks factors associated with *KP* ALRI in Cambodia. Surprisingly, women accounted for more than two thirds (68.1%) of all cases. Published data report that community-acquired *KP* are associated with male gender, women accounting for 20% to 42% of the studied populations [1,6,20,21]. There was a trend to a higher antibiotic intake prior to hospitalization in women, whereas no data informed about health seeking behavior among women in Cambodia to confirm this tendency. Whereas age was not statistically different between men and women, 72% of women in our study were postmenopausal. Postmenopausal women are at risk to develop certain infections such as atypical mycobacterial infections [22]. In animals' models, the role of sex hormones in susceptibility to lung infections has been well demonstrated [23]. Higher frequency of diabetes mellitus in *KP* CAP patients was consistent with commonly reported association between diabetes condition and community-acquired *KP* bacteremia or community-acquired pleural effusion [24,25].

<footnote>ªA chronic pulmonary disease cannot be excluded as chest computed tomography scan and pulmonary function tests were not available</footnote>
Hemoptysis is a clinical sign of interest in a TB endemic country. Hemoptysis is known to be associated with *KP* necrotizing pneumonia but is rarely described in the literature [26]. In our series, ~20% of the patients infected by *KP* had hemoptysis on admission. We failed to demonstrate an association between *KP* and hemoptysis as the frequency of TB and bronchiectasis—known as confounding factors—was high in our cohort *KP* accounted for 4.5% of documented pleural effusion. This number is lower than proportions found (12 to 23.6%) in other Asian countries [18,27,28]. As bacteriological analysis of pleural fluids was not available in our study, the proportion of *KP* pleural effusion might be underestimated.

Our finding also pointed to the fact many patients did
not receive an appropriate antimicrobial treatment
although the causal agent bundled with antibiotics sus-
ceptibility testing results was made available as soon as
possible. Several reasons may explain this: (i) antibiotics
susceptibility results were sent to the hospital while
patients were already discharged (families usually request
discharge when no hope of cure is expected), (ii) treat-
ments may have been too expensive for some patients
and their relatives, (iii) the prescription of penicillin A as
a first line antibiotic in ALRI was the rule in these 2 hos-
pitals but is known to be inefficient against *KP*. Another
point is, the high prevalence of pulmonary sequelae, par-
ticularly TB sequelae in a highly endemic country, may
be the cause of *KP* bronchiectasis colonization. In 50
Thai patients diagnosed with bronchiectasis, *KP* was the
second isolated bacterium (14%). Unfortunately, the
authors did not report as whether this pathogen was
found during an acute exacerbation or not [29].

Some limitations have to be underlined. The project
was implemented for surveillance of ALRI related etiolo-
gies in settings where microbiology capacity was inexis-
tent, although we were able to capture about all the
patients who were admitted with acute respiratory
symptoms, the frequency and the quality of specimens'
collection for diagnosis was insufficient. Only ~50% of
all included patients had available sputum (unpublished
data). Capacity for more refined diagnosis was also lim-
ited by the absence of computed tomographic scan or
capacity for aspiration by bronchial fibroscopy. Addi-
tionally, no colony forming unit/mL threshold was vali-
dated in patients with preexisting pulmonary lesions. In
the context of surveillance, we did not request systema-
tic verification of bacterial eradication at the end of the
treatment, which made it difficult to confirm the causal
implication of *KP* in the respiratory infection.

Conclusions

Nevertheless, despite these limitations, our first docu-
mented series of *KP*-infected cases in Cambodia have

shown particularly relevant information for Cambo-
dian clinicians. As a result, we recommend a change
of the current national approach in managing ALRI at
the hospital level in the country. Antibiotics which
include *KP* in their spectrum (i.e. amoxicillin/clavula-
nic acid, ceftriaxone) should be used when the first
line antimicrobial therapy (mainly penicillin A in
national Cambodian guidelines) fails or in case of
necrotizing pneumonia. In any case, it is crucial for
Cambodia to be able to acquire adequate microbiolo-
gical capacity (i.e. culture) in public hospitals. Finally,
the emergence or the rise of ESBL-producing strains
causing community-acquired infections in Cambodia
should draw the attention of the Cambodian health
authorities as well as the international public health
community.

Acknowledgements

We specifically acknowledge the patients for their participation to this study. We are grateful to Dr Phat, Dr Mam, Dr Me, Dr Ya, Dr Koy, Dr Teav, Dr Ke, Dr Phea, Dr Chroeng, Dr Kim, Dr Iv, Dr Kheang, Dr Phe, Dr Chhav, Dr Ean, Dr Leang for their contribution to this study and for patients care. We are also grateful to Drs. Cecile Toper, Nomonde Mafuna, Mélanie Courouble and Guy Letellier for participating in the interpretation of chest radiographs and the reviews of some of the CRF.

Funding

The present study was part of the Surveillance and Investigation of epidemic situations in South-East Asia (SISEA) project, which was funded by the French Agency for Development (Agence Française de Développement, AFD). This surveillance project also received financial support from the US Department of Human and Health Services (US DHHS). BR received a grant from the Fondation Pierre Ledoux Jeunesse Internationale and from the Société de Pathologie Infectieuse de Langue Française.

Author details

Authors' contributions

Conceived and designed the study: SV, BR, CM; Performed the study: BR, VT, PLT. Analyzed the data: BR, JB, SG. Contributed reagents/materials/analysis tools: BR, BG, SH, VT, PLT, CM, LB, PB, JB. Wrote the paper: BR, JB, SV. Critical review of the paper: All. Found funding: SV, PB. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Received: 22 July 2011 Accepted: 10 January 2012
Published: 10 January 2012

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## Pre-publication history

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doi:10.1186/1471-2334-12-3

Cite this article as: Rammaert et al.: Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: Clinical characteristics and treatment. *BMC Infectious Diseases* 2012 **12**:3.

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