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1.  Assessment of combination therapy in BALB/c mice injected with carbapenem-resistant Enterobacteriaceae strains 
Monotherapeutic options for carbapenem resistant infections are limited. Studies suggest that combination therapy may be associated with better outcomes than monotherapies. However, this is still controversial. This study assessed, the efficacy of combination therapy against carbapenem resistant Enterobacteriaceae harboring singly various extended spectrum beta lactamase or carbapenemase encoding genes. Thus, four isolates harboring either blaCTXM-15, blaCTXM-15 and blaOXA-48, blaNDM-1, or blaKPC-2 genes were selected for testing. Minimal inhibitory concentration was determined by broth dilution method. Gene transcript levels on single and combined treatments were done in vitro and in vivo by qRT-PCR. Assessment of treatments was done in BALB/c mice according to a specific protocol. As such, the qRT-PCR revealed a significant decrease of transcript levels in all isolates upon using rifampicin or tigecycline, singly or in combination with colistin. However, variable levels were obtained using colistin singly or in combination with meropenem or fosfomycin. In vivo assessment showed that all combinations used were effective against isolates harboring blaCTXM-15, blaOXA-48, and blaNDM-1. Conversely, the most significant combination against the isolate harboring blaKPC-2 gene was colistin with either carbapenem, fosfomycin, or kanamycin. As a conclusion, combination therapy selected based on the type of carbapenemase produced, appeared to be non-toxic and might be effective in BALB/c mice. Therefore, the use of a rationally optimized combination therapy might lead to better results than monotherapy, however, clinical trials are needed for human consumption.
PMCID: PMC4585037  PMID: 26441926
Enterobacteriaceae; carbapenem resistance; carbapenemase; in vivo; combination therapy; gene transcript
2.  Rotavirus Genotypes and Vaccine Effectiveness from a Sentinel, Hospital-Based, Surveillance Study for Three Consecutive Rotavirus Seasons in Lebanon 
PLoS ONE  2016;11(8):e0161345.
Globally, rotavirus (RV) is the leading cause of gastroenteritis (GE) in children. Longitudinal data about changes in RV genotype distribution and vaccine effectiveness (VE) are scarce. This study was conducted in Lebanon over 3 consecutive RV seasons to estimate the rate of RVGE hospitalization, identify RV genotypes, determine the seasonal and geographical variations, and calculate RV VE.
Materials and Methods
This prospective, multicenter, hospital-based surveillance study was conducted between 2011 and 2013 and enrolled children (<5 years) admitted for GE. Socio-demographic and clinical data about the current episode of GE at admission were collected. Genotypes were determined from stool samples testing positive for RV by PCR.
Of 1,414 cases included in the final analysis, 83% were <2 years old and 55.6% were boys. Median duration of hospitalization was 4 days and 91.6% of GE cases were severe (Vesikari score ≥11). PCR testing showed that 30.3% of subjects were RV-positive of which 62.1% had fever versus 71.1% of RV-negative subjects (P = 0.001). RV was predominantly detected in the cold season from November till March (69.9%). G and P genotype pairs for all RV-positive stool specimens showed a predominance of G1P[8] in 36% (n = 154) of specimens, G9P[8] in 26.4% (n = 113), and G2P[4] in 17.8% (n = 76). RV-negative subjects were more likely to be RV-vaccinated (21%) compared to the RV-positive subjects (11.3%) (P<0.001), with a vaccine breakthrough rate of 18.8%. The ratio of RV1-vaccinated for each RV5-vaccinated subject was 7.8 and VE against RV disease was 68.4% (95%CI, 49.6%-80.2%).
RV is a major cause of GE requiring hospitalization of children under 5 years of age in Lebanon. A few genotypes predominated over the three RV seasons studied. Mass RV vaccination will likely decrease the burden of hospitalization due to RV. VE is similar to what has been observed for other middle-income countries.
PMCID: PMC5003350  PMID: 27571515
3.  Escherichia coli O157:H7—Clinical aspects and novel treatment approaches 
Escherichia coli O157:H7 is a notorious pathogen often contracted by intake of contaminated water or food. Infection with this agent is associated with a broad spectrum of illness ranging from mild diarrhea and hemorrhagic colitis to the potentially fatal hemolytic uremic syndrome (HUS). Treating E. coli O157:H7 infection with antimicrobial agents is associated with an increased risk of severe sequelae such as HUS. The difficulty in treating this bacterium using conventional modalities of antimicrobial agent administration has sparked an interest in investigating new therapeutic approaches to this bacterium. These approaches have included the use of probiotic agents and natural products with variable success rates. In addition, novel modalities and regimen of antimicrobial agent administration have been assessed in an attempt at decreasing their association with aggravating infection outcomes.
PMCID: PMC3498739  PMID: 23162800
Escherichia coli O157:H7; hemolytic uremic syndrome; hemorrhagic colitis; shiga toxins; antimicrobial chemotherapy
4.  Correlation between Group B Streptococcal Genotypes, Their Antimicrobial Resistance Profiles, and Virulence Genes among Pregnant Women in Lebanon 
The antimicrobial susceptibility profiles of 76 Streptococcus agalactiae (Group B Streptococci [GBS]) isolates from vaginal specimens of pregnant women near term were correlated to their genotypes generated by Random Amplified Polymorphic DNA analysis and their virulence factors encoding genes cylE, lmb, scpB, rib, and bca by PCR. Based on the distribution of the susceptibility patterns, six profiles were generated. RAPD analysis detected 7 clusters of genotypes. The cylE gene was present in 99% of the isolates, the lmb in 96%, scpB in 94.7%, rib in 33%, and bca in 56.5% of isolates. The isolates demonstrated a significant correlation between antimicrobial resistance and genotype clusters denoting the distribution of particular clones with different antimicrobial resistance profiles, entailing the practice of caution in therapeutic options. All virulence factors encoding genes were detected in all seven genotypic clusters with rib and bca not coexisting in the same genome.
PMCID: PMC2817894  PMID: 20148175
6.  Escherichia coli Isolated from Urinary Tract Infections of Lebanese Patients between 2005 and 2012: Epidemiology and Profiles of Resistance 
The early treatment of urinary tract infections (UTIs) is directly related to decrease in morbidity, which makes the empirical treatment of great importance. Recently, beta lactamases of several types have emerged as significant mechanisms of resistance in Gram-negative bacilli, especially Escherichia coli. Our aim was to study the urinary E. coli isolated from Lebanese patients and to characterize their mechanisms of resistance. The study analyzed data between 2005 and 2012 of UTIs caused by E. coli. The mechanisms of resistance were characterized by phenotypic and genotypic methods and the pulsed-field gel electrophoresis (PFGE) was used to determine the different bacterial clusters. As expected, the highest incidence was observed with E. coli (60.53–73.98%) followed by K. pneumoniae (5.32–8.33%). ICU isolates were constantly associated with the lowest rates of susceptibility to extended-spectrum cephalosporins, ciprofloxacin, as well as most of the tested antibiotics. A 100% occurrence of CTX-M in extended-spectrum β-lactamase (ESBL)-producing isolates was recorded, followed by TEM, SHV, and OXA. In addition, 15.9% harbored 4 different ESBL enzymes and only 13 isolates (14.8%) harbored only one enzyme (CTX-M). Over the years, the simultaneous susceptibility of E. coli to ceftazidime and ciprofloxacin decreased from 62.5% in 2006 to 48.7% in 2012. PFGE results demonstrated that 10 clusters were 32 generated, denoting diversity among detected isolates. Understanding the epidemiology of resistance is 33 instrumental for the implementation of recommendations for the management of antimicrobials, infection 34 control measures, as well as active surveillance and antimicrobial stewardship.
PMCID: PMC4415468  PMID: 25984513
ESBL; carbapenemases; E. coli; urinary infections; bacterial resistance
7.  Approaches to treatment of emerging Shiga toxin-producing Escherichia coli infections highlighting the O104:H4 serotype 
Shiga toxin-producing Escherichia coli (STEC) are a group of diarrheagenic bacteria associated with foodborne outbreaks. Infection with these agents may result in grave sequelae that include fatality. A large number of STEC serotypes has been identified to date. E. coli serotype O104:H4 is an emerging pathogen responsible for a 2011 outbreak in Europe that resulted in over 4000 infections and 50 deaths. STEC pathogenicity is highly reliant on the production of one or more Shiga toxins that can inhibit protein synthesis in host cells resulting in a cytotoxicity that may affect various organ systems. Antimicrobials are usually avoided in the treatment of STEC infections since they are believed to induce bacterial cell lysis and the release of stored toxins. Some antimicrobials have also been reported to enhance toxin synthesis and production from these organisms. Various groups have attempted alternative treatment approaches including the administration of toxin-directed antibodies, toxin-adsorbing polymers, probiotic agents and natural remedies. The utility of antibiotics in treating STEC infections has also been reconsidered in recent years with certain modalities showing promise.
PMCID: PMC4364364  PMID: 25853096
Shiga toxin-producing Escherichia coli; hemorrhagic colitis; hemolytic uremic syndrome; antimicrobial agents; Shiga toxin 1; Shiga toxin 2
8.  Genotypes and serotype distribution of macrolide resistant invasive and non- invasive Streptococcus pneumoniae isolates from Lebanon 
This study determined macrolide resistance genotypes in clinical isolates of Streptococcus pneumoniae from multiple medical centers in Lebanon and assessed the serotype distribution in relation to these mechanism(s) of resistance and the source of isolate recovery.
Forty four macrolide resistant and 21 macrolide susceptible S. pneumoniae clinical isolates were tested for antimicrobial susceptibility according to CLSI guidelines (2008) and underwent molecular characterization. Serotyping of these isolates was performed by Multiplex PCR-based serotype deduction using CDC protocols. PCR amplification of macrolide resistant erm (encoding methylase) and mef (encoding macrolide efflux pump protein) genes was carried out.
Among 44 isolates resistant to erythromycin, 35 were resistant to penicillin and 18 to ceftriaxone. Examination of 44 macrolide resistant isolates by PCR showed that 16 isolates harbored the erm(B) gene, 8 isolates harbored the mef gene, and 14 isolates harbored both the erm(B) and mef genes. There was no amplification by PCR of the erm(B) or mef genes in 6 isolates. Seven different capsular serotypes 2, 9V/9A,12F, 14,19A, 19F, and 23, were detected by multiplex PCR serotype deduction in 35 of 44 macrolide resistant isolates, with 19F being the most prevalent serotype. With the exception of serotype 2, all serotypes were invasive. Isolates belonging to the invasive serotypes 14 and 19F harbored both erm(B) and mef genes. Nine of the 44 macrolide resistant isolates were non-serotypable by our protocols.
Macrolide resistance in S. pneumoniae in Lebanon is mainly through target site modification but is also mediated through efflux pumps, with serotype 19F having dual resistance and being the most prevalent and invasive.
PMCID: PMC3371826  PMID: 22248318
Antimicrobials; Macrolides; Resistance; Genes; Serotyping
9.  Decrease in Shiga toxin expression using a minimal inhibitory concentration of rifampicin followed by bactericidal gentamicin treatment enhances survival of Escherichia coli O157:H7-infected BALB/c mice 
Treatment of Escherichia coli O157:H7 infections with antimicrobial agents is controversial due to an association with potentially fatal sequelae. The production of Shiga toxins is believed to be central to the pathogenesis of this organism. Therefore, decreasing the expression of these toxins prior to bacterial eradication may provide a safer course of therapy.
The utility of decreasing Shiga toxin gene expression in E. coli O157:H7 with rifampicin prior to bacterial eradication with gentamicin was evaluated in vitro using real-time reverse-transcription polymerase chain reaction. Toxin release from treated bacterial cells was assayed for with reverse passive latex agglutination. The effect of this treatment on the survival of E. coli O157:H7-infected BALB/c mice was also monitored.
Transcription of Shiga toxin-encoding genes was considerably decreased as an effect of treating E. coli O157:H7 in vitro with the minimum inhibitory concentration (MIC) of rifampicin followed by the minimum bactericidal concentration (MBC) of gentamicin (> 99% decrease) compared to treatment with gentamicin alone (50-75% decrease). The release of Shiga toxins from E. coli O157:H7 incubated with the MIC of rifampicin followed by addition of the MBC of gentamicin was decreased as well. On the other hand, the highest survival rate in BALB/c mice infected with E. coli O157:H7 was observed in those treated with the in vivo MIC equivalent dose of rifampicin followed by the in vivo MBC equivalent dose of gentamicin compared to mice treated with gentamicin or rifampicin alone.
The use of non-lethal expression-inhibitory doses of antimicrobial agents prior to bactericidal ones in treating E. coli O157:H7 infection is effective and may be potentially useful in human infections with this agent in addition to other Shiga toxin producing E. coli strains.
PMCID: PMC3180354  PMID: 21906403
Escherichia coli O157:H7; rifampicin; gentamicin; Shiga toxins
10.  Frequency of conjugative transfer of plasmid-encoded ISEcp1 - blaCTX-M-15 and aac(6')-lb-cr genes in Enterobacteriaceae at a tertiary care center in Lebanon - role of transferases 
The frequency of transfer of genes encoding resistance to antimicrobial agents was determined by conjugation in ESBL-producing and/or fluoroquinolone or aminoglycoside resistant Enterobacteriaceae clinical isolates at a tertiary care center in Lebanon. In addition, the role of tra genes encoding transferases in mediating conjugation was assessed.
Conjugation experiments were done on 53 ESBL-producing and/or fluoroquinolone resistant E. coli and K. pneumoniae and ESBL-producing S. sonnei isolates. Antimicrobial susceptibility testing on parent and transconjugant isolates, and PCR amplifications on plasmid extracts of the resistance-encoding genes: blaCTX-M-15 with the ISEcp1 insertion sequence, the aac(6')-lb-cr and qnrS genes, as well as tra encoding transferases genes were done. Random amplified polymorphic DNA (RAPD) analysis was performed to demonstrate whether conjugative isolates are clonal and whether they are linked epidemiologically to a particular source.
Antimicrobial susceptibility testing on transconjugants revealed that 26 out of 53 (49%) ESBL-producing Enterobacteriaceae were able to transfer antimicrobial resistance to the recipients. Transfer of high-level resistance to the transconjugants encoded by the blaCTX-M-15 gene downstream the ISEcp1 insertion sequence against 3rd generation cephalosporins, and of low-level resistance against ciprofloxacin, and variable levels of resistance against aminoglycosides encoded by aac(6')-lb-cr gene, were observed in transconjugants. tra encoding transferase genes were detected exclusively in conjugative isolates.
In conclusion, the frequency of transfer of antimicrobial resistance in non clonal Enterobacteriaceae at the tertiary care center by conjugation was 49%. Conjugation occurred in isolates expressing the tra encoding transferase genes. Multiple conjugative strains harboring the plasmid encoded antimicrobial resistant genes were circulating in the medical center. Molecular epidemiology analysis showed that conjugative isolates are neither clonal nor linked to a particular site and transfer of antimicrobial resistance is by horizontal transfer of plasmids.
PMCID: PMC2919444  PMID: 20646305
11.  Evaluation of a Multilocus Variable-Number Tandem-Repeat Analysis Scheme for Typing Human Brucella Isolates in a Region of Brucellosis Endemicity▿ †  
Journal of Clinical Microbiology  2008;46(12):3935-3940.
Brucellosis remains an important anthropozoonosis worldwide. Brucella species are genetically homogeneous, and thus, the typing of Brucella species for epidemiological purposes by conventional molecular typing methods has remained elusive. Although many methods could segregate isolates into the phylogenetically recognized taxa, limited within-species genetic diversity has been identified. Recently, multilocus variable-number tandem-repeat analysis (MLVA) was found to have a high degree of resolution when it was applied to collections of Brucella isolates from geographically widespread locations, and an assay comprising 16 such loci (MLVA-16) was proposed. This scheme includes eight minisatellite loci (panel 1) and eight microsatellites (panel 2, which is subdivided into panels 2A and 2B). The utility of MLVA-16 for the subtyping of human Brucella isolates from geographically restricted regions needs to be further evaluated, and genotyping databases with worldwide coverage must be progressively established. In the present study, MLVA-16 was applied to the typing of 42 human Brucella isolates obtained from 41 patients recovered from 2002 to 2006 at a tertiary-care center in Lebanon. All isolates were identified as Brucella melitensis by MLVA-16 and were found to be closely related to B. melitensis isolates from neighboring countries in the Middle East when their genotypes were queried against those in the web-based Brucella2007 MLVA database ( Panel 2B, which comprised the most variable loci, displayed a very high discriminatory power, while panels 1 and 2A showed limited diversity. The most frequent genotype comprised seven isolates obtained over 7 weeks in 2002, demonstrating an outbreak from a common source. Two isolates obtained from one patient 5 months apart comprised another genotype, indicating relapsing disease. These findings confirm that MLVA-16 has a good discriminatory power for species determination, typing of B. melitensis isolates, and inferring their geographical origin. Abbreviated panel 2B could be used as a short-term epidemiological tool in a small region of endemicity.
PMCID: PMC2593282  PMID: 18923007
12.  Detection of a highly prevalent and potentially virulent strain of Pseudomonas aeruginosa from nosocomial infections in a medical center 
BMC Microbiology  2005;5:29.
We correlated genotypes, virulence factors and antimicrobial susceptibility patterns of nosocomially identified Pseudomonas aeruginosa isolates from clinical specimens to those of environmental isolates encountered in the same units of a medical center. Antibiotic susceptibility testing, RAPD analysis and detection of enzymatic activities of extracellular virulence factors, were done on these isolates.
Data showed that most of the clinical and environmental isolates were susceptible to tested antimicrobial agents. RAPD analysis determined the presence of 31 genotypes, with genotype 1 detected in 42% of the clinical isolates and 43% of the environmental isolates. Enzymatic activity testing showed that genotype 1 produced all virulence factors tested for.
In conclusion, our data demonstrated the predominant prevalence of a potentially virulent P. aeruginosa genotype, circulating in a number of units of the medical center and emphasize the need to reinforce infection control measures.
PMCID: PMC1168898  PMID: 15907204
13.  HLA Allele Associations and V-Beta T-Lymphocyte Expansions in Patients With Psoriasis, Harboring Toxin-Producing Staphylococcus aureus 
HLA alleles have been associated with psoriasis. Toxin-producing strains of Staphylococcus aureus behave as superantigens, and if present in patients, might play a role in the exacerbation of psoriatic lesions by activating certain V-beta (Vβ) T-lymphocyte subsets. Allele frequencies in 22 patients and 22 controls (alleles determined by DNA/SSP typing) were used to calculate a relative risk of 4.7 (P < .05) for HLA-Cw6. S aureus was isolated from the throat of 11 patients. Enterotoxins A and C were detected by agglutination in the culture filtrate of one isolate. The enterotoxin A and/or C genes were detected by PCR in 9 isolates, and transcripts were detected by RT-PCR in 7 of them. None of the isolates from controls harbored enterotoxin genes. Vβ expansions were detected by RT-PCR in all 22 patients. Low or no Vβ expansions were obtained in controls. The association of HLA-Cw6 with psoriasis in Lebanese concurs with that reported for other ethnic groups. Toxin-producing isolates that colonize patients might play a role in the exacerbation of psoriatic lesions.
PMCID: PMC1361490  PMID: 16489264
14.  PCR-Based Detection, Restriction Endonuclease Analysis, and Transcription of tonB in Haemophilus influenzae and Haemophilus parainfluenzae Isolates Obtained from Children Undergoing Tonsillectomy and Adenoidectomy 
We developed and evaluated a PCR-based-restriction endonuclease analysis method to detect and analyze the tonB gene of Haemophilus influenzae and Haemophilus parainfluenzae from pediatric patients undergoing tonsillectomy and adenoidectomy. Multiple sites from the same patient, including the surface of adenoids and tonsils, as well as the core of tonsils, were cultured on chocolate agar and identified using standard procedures and the API NH Kit. A total of 55 H. influenzae isolates were recovered from different sites of 20 patients, and 32 H. parainfluenzae isolates were recovered from various sites of 12 patients. DNA was extracted from American Type Culture Collection strains and test isolates by the PureGene kit. Two primers, G1 (21-mer) and G2 (23-mer), were designed by us to amplify by PCR the tonB gene that consists of an 813-bp fragment. A nested PCR using primers T1 (23-mer) and T2 (24-mer) that flank an internal sequence to the gene of the order of 257 bp and restriction endonuclease digestion using XhoI and BglII were done to detect whether heterogeneity within the gene exists between the two species. Reverse transcription-PCR (RT-PCR) was finally done to detect transcription of the gene in both species. Our data have shown that the tonB gene was detected in both species. It is known to encode a virulent protein, TonB, in H. influenzae; however, demonstration of its presence in H. parainfluenzae is novel. Nested-PCR and restriction endonuclease analysis have shown that the tonB gene is apparently structurally the same in both species, with possible differences that may exist in certain H. parainfluenzae isolates. RT-PCR done on selected numbers of H. influenzae and H. parainfluenzae have shown that the tonB gene was transcribed in both species. This shows that the TonB protein, if expressed, may play a different role in the virulence in H. parainfluenzae since it is not needed for heme or heme complexes uptake as with H. influenzae.
PMCID: PMC96040  PMID: 11238199
15.  Identification of Bartonella Species Directly in Clinical Specimens by PCR-Restriction Fragment Length Polymorphism Analysis of a 16S rRNA Gene Fragment 
Journal of Clinical Microbiology  1999;37(12):4045-4047.
It is now established that two species of Bartonella, namely, Bartonella henselae and B. quintana, cause bacillary angiomatosis in human immunodeficiency virus-infected patients. In addition, B. henselae causes cat scratch disease and B. quintana, B. henselae, and B. elizabethae can cause bacteremia and endocarditis in immunocompetent persons. We have developed a PCR-restriction fragment length polymorphism-based assay for direct detection and identification to species level of Bartonella in clinical specimens. This is accomplished by PCR amplification of Bartonella DNA using primers derived from conserved regions of the gene carrying the 16S ribosomal DNA, followed by restriction analysis using DdeI and MseI restriction endonucleases. We amplified a Bartonella genus-specific 296-bp fragment from 25 clinical samples obtained from 25 different individuals. Restriction analysis of amplicons showed that identical patterns were seen from digestion of B. henselae and B. quintana amplicons with DdeI, whereas a different unique pattern was seen by using the same enzyme with B. vinsonii and B. elizabethae. With MseI digestion, B. henselae and B. vinsonii gave nearly identical patterns while B. quintana and B. elizabethae gave a different pattern. By combining the restriction analysis data generated with MseI and DdeI, unique “signature” restriction patterns characteristic for each species were obtained. These patterns were useful in identifying the Bartonella species associated with each tissue specimen.
PMCID: PMC85877  PMID: 10565929
16.  Two-Step PCR-Based Assay for Identification of Bacterial Etiology of Otitis Media with Effusion in Infected Lebanese Children 
Journal of Clinical Microbiology  1998;36(5):1185-1188.
We developed and evaluated a two-step PCR-based assay with universal primers and genus- or species-specific primers for the detection of the most prevalent bacterial etiologies of otitis media with effusion (OME) in children from Lebanese hospitals. These etiologies included Haemophilus, Streptococcus, and Moraxella (Branhamella) catarrhalis, which were detected in middle-ear effusion (MEE) samples taken from children with OME. A total of 47 MEE samples were aspirated from 36 patients during insertion of a tympanostomy tube performed particularly for OME. The duration of effusion in all patients was ≥2 months. DNA was extracted from MEE samples, and PCR was initially done with DNA extracts by using the universal primers RW01 and DG74, which flank an ∼370-bp fragment found in the 16S rRNA gene of all bacterial species. For the identification of specific bacteria, we used in three separate reaction mixtures the following genus- or species-specific primers: (i) a Haemophilus-specific probe (probe RDR125) as a primer along with DG74, (ii) a Streptococcus-specific primer (primer STR1; designed by us) along with DG74, and (iii) an M. catarrhalis-specific primer pair (primer pair MCA1-MCA2). Thirty-five MEE samples (74.5%) gave the expected 370-bp band, indicating the presence of bacterial DNA in the tested samples. Of the 35 PCR-positive samples tested, 33 (94.3%) were positive for Haemophilus, 3 (8.6%) were positive for Streptococcus, and 10 (28.6%) were positive for M. catarrhalis. Ten samples (28.6%) exhibited a mixed infection and were positive for both Haemophilus and M. catarrhalis. Culture was simultaneously performed for all 47 MEE samples. Ten of the 47 MEE samples (21.3%) exhibited bacterial growth. These 10 were PCR positive for bacterial DNA. The remaining 25 PCR-positive samples were negative by culture, thus showing about 53% discordance between PCR results and those of culture. The PCR assay proved to be more sensitive than culture, more rapid, less cumbersome, and more cost-effective than the available PCR-Southern hybridization-based assays.
PMCID: PMC104796  PMID: 9574673

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