Glossary: A Quick Guide to the MathematicalI just found this here : www.math.ucdavis.edu/, couldn’t resist sharing. • absolute maximum. The all-time, one-and-only, single, absolute andtotal maximum value of a function over a specified domain of the function. (Although it is the unique maximum value, it could occur at more thanone point, as when you have two mountain peaks of exactly the sam
Emergence of fluoroquinolone-resistant streptococcus pneumoniae in lebanon: a report of three casesARTICLE IN PRESS
Emergence of ﬂuoroquinolone-resistant
Streptococcus pneumoniae in Lebanon:
A report of three cases
Mazen R. Naba , George F. Araj , Tania A. Baban ,
Zuhayr A. Tabbarah , Ghassan N. Awar , Souha S. Kanj
a Division of Infectious Diseases, Department of Internal Medicine, American University of BeirutMedical Center, Beirut, Lebanonb Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center,P.O. Box 11-0236, Beirut, Lebanon Received 6 January 2010 ; received in revised form 24 June 2010; accepted 2 July 2010 KEYWORDS
The global emergence of Streptococcus pneumoniae resistance to ﬂu- oroquinolones is alarming and has grown to be a cause for signiﬁcant concern worldwide. We report the ﬁrst three cases of levoﬂoxacin resistant S. pneumoniae isolates in a tertiary medical center in Beirut, Lebanon. Judicious use of antimicro-bial agents is imperative to limit the spread of such resistant strains.
2010 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz Universityfor Health Sciences. All rights reserved.
tory ﬂuoroquinolones (FQ), as one of the treatmentoptions Streptococcus pneumoniae remains a predomi- Although the emergence of S. pneumoniae nant identiﬁable bacterial pathogen in community strains that are resistant to ␤-lactams, macrolides, acquired pneumonia (CAP) and is associated with and other antibiotics including FQ, have been signiﬁcant morbidity and mortality Treatment reported from several countries around the world, success has been limited by the increasing preva- levels of resistance to the latter remain low lence of antimicrobial resistance Current In 2002, The Centers for Disease Control and Pre- CAP-inpatient management guidelines of the Infec- vention (CDC) estimated that of 37,000 cases of tious Diseases Society of America (IDSA) and the invasive disease due to S. pneumoniae, 34% were American Thoracic Society (ATS), include respira- resistant to at least one antibiotic, while 17% wereresistant to three or more antibiotics How- ever, S. pneumoniae has remained, for the most Corresponding author. Tel.: +961 1 350000x5215; part, highly susceptible to FQ. Annual surveillance data from the US and Italy have shown that S. 1876-0341/$ — see front matter 2010 Published by Elsevier Limited on behalf of King Saud Bin Abdulaziz University for Health Sciences. All rights reserved.
Please cite this article in press as: Naba MR, et al. Emergence of ﬂuoroquinolone-resistant Streptococcus pneumoniaein Lebanon: A report of three cases. J Infect Public Health (2010), doi: ARTICLE IN PRESS
pneumoniae resistance to respiratory FQ, includ- ing levoﬂoxacin and moxiﬂoxacin, were less than the last of which being 10 days prior to his 1—3% with minimal yearly increase Further- current presentation. Findings upon admission more, S. pneumoniae levoﬂoxacin resistance rates included: a blood pressure of 115/88 mm Hg, have been reported to be less than 1% in the United temperature of 40 ◦C, pulse of 128 min−1 and a States in 2005—2006 (0.6% resistance and 0.2% respiratory rate of 35 min−1. Chest auscultation intermediate resistance) On the other hand, revealed decreased breath sounds with diffuse during 2000—2001, Turkey reported a rise in resis- rhonchi. Laboratory data showed a white cell tance rates to FQ among invasive S. pneumoniae count of 75,000 cells/mm3 with 94% lympho- cytes, and a creatinine of 1.5 mg/dl. CT-scan of In Lebanon, S. pneumoniae isolates have shown the chest showed bilateral consolidations. The increasing resistance to penicillin, macrolides, and patient was started empirically on intravenous other antimicrobial agents, but to our knowledge, cefepime (2 g every 8 h) and oral clarithromycin none so far have been reported against FQ (500 mg tablets twice daily) after blood and spu- This is consistent with data published from other tum cultures were taken. Subsequently, blood countries in the Middle East, including Saudi Arabia cultures grew S. pneumoniae which showed inter- mediate resistance to penicillin based on oral identiﬁed the ﬁrst levoﬂoxacin resistant S. pneu- CSLI breakpoint guidelines (MIC = 0.5 g/ml) and moniae at our institution. Since then, and over the was resistant to levoﬂoxacin (MIC > 32 g/ml), past 5 years, a total of three cases of FQ resistant S. but susceptible to clindamycin, erythromycin, pneumoniae have been identiﬁed, warranting their after 72 h of initiating therapy and the sameantibiotic regimen was continued for 10 days withno complications.
Isolates of S. pneumoniae were obtained fromfresh clinical samples taken from the concerned A 66-year-old male with multiple co-morbidities, three patients with clinical evidence of respiratory presented to AUBMC with cough and dyspnea.
tract infections using routine collection methods.
The patient had a history of recurrent aspiration Minimum inhibitory concentrations (MICs) of the pneumonia and had received multiple courses isolates were determined by E-test susceptibility of oral levoﬂoxacin and amoxicillin/clavulanate.
testing method according to the manufacturer’s His most recent hospitalization with pneumonia instructions (AB, Biodisk, Solna, Sweden). Disc was 3 weeks prior to the current presenta- diffusion susceptibility testing was performed tion, at which time he received intravenous against a range of antimicrobial agents accord- piperacillin/tazobactam (4.5 g every 8 h) and was ing to the Clinical and Laboratory Standards later discharged on oral amoxicillin/clavulanate Institute (CLSI) interpretive guidelines. Also the (1 g tablets twice daily). Physical examination CLSI breakpoint MICs (g/ml) for S. pneumoniae showed: a temperature of 37 ◦C, blood pressure against penicillin was used as follows: susceptible of 120/80 mm Hg, pulse of 88 min−1 and a respi- (≤2), intermediate (4), resistant (≥8) for par- ratory rate of 30 min−1, with bilateral decreased enteral (non-meningitis); and susceptible (≤0.06), breath sounds on lung auscultation. His white cell intermediate (0.12—1), resistant (≥2) for oral for- count was 11,700 cell/mm3, with 77% neutrophils and his creatinine was 0.3 mg/dl. A CT-scan ofthe chest showed left lobe consolidation and a Patient A
mediastinal mass. Blood and sputum cultureswere taken and the patient was given intra- A 78-year-old male with a history of chronic venous amoxicillin/clavulanate (1.2 g every 8 h).
obstructive pulmonary disease (COPD) and chronic Subsequently, sputum culture grew extended spec- lymphocytic leukemia was admitted to the Amer- trum beta-lactamase (ESBL) producing Klebsiella ican University of Beirut Medical Center (AUBMC) pneumoniae, and a multidrug-resistant (MDR) S. with fever, productive cough, and dyspnea. He pneumoniae with the following susceptibility pro- had been treated as out-patient in another hos- ﬁle: fully resistant to penicillin based on oral CSLI pital, with numerous courses of oral levoﬂoxacin breakpoint guidelines (MIC = 3 g/ml), ceftriaxone and ciproﬂoxacin of undocumented doses, for Please cite this article in press as: Naba MR, et al. Emergence of ﬂuoroquinolone-resistant Streptococcus pneumoniaein Lebanon: A report of three cases. J Infect Public Health (2010), ARTICLE IN PRESS
Levoﬂoxacin-resistant Streptococcus pneumoniae Discussion
ble to rifampin, vancomycin, and teicoplanin.
Due to the time required to establish the iden- Despite negative blood cultures, the patient tity and susceptibility of bacterial pathogens was treated with intravenous vancomycin (1 g from patients with CAP, therapeutic choices are every 12 h) and imipenem (500 mg every 6 h) frequently empirical. There is increasing evi- for a clinical picture that was consistent with dence that inappropriate empirical therapy results pneumonia and showed marked improvement.
in increased rates of morbidity and mortality He was soon after diagnosed to have poorly among patients with serious bacterial infections differentiated lung carcinoma, followed by a Therefore, in immunocompromised patients, complicated hospital course, and died 3 months patients with a history of FQ therapy in the past 3—4 months, and in patients with other risk fac-tors for FQ resistance, it may not be prudent to use Patient C
FQ monotherapy empirically to treat suspected orproven pneumococcal infection until susceptibility A 78-year-old male admitted to AUBMC with a data become available To evaluate the con- recent history of watery diarrhea, with no associ- sistency of medical management at our institution ated abdominal pain, nausea, nor fever. The patient with IDSA guidelines for CAP, a study enrolled a total had a history of cellulitis, treated with antibiotics of 65 adult patients diagnosed with CAP between 2 months earlier, and non-small cell lung cancer, for which he received radiotherapy and chemother- that all 65 patients had received empirical ther- apy. On admission he reported dyspnea and a apy, with levoﬂoxacin being the most commonly productive cough with blood tinged sputum. Find- prescribed monotherapy (51%). Although generally ings included: a blood pressure of 130/70 mm Hg, administered in the recommended doses, 12 of 22 temperature of 36.6 ◦C, pulse of 85 min−1 and a patients received an inappropriate dosage of lev- respiratory rate of 16 min−1. When examined, the oﬂoxacin (500 mg twice daily). The authors argue patient had decreased breath sounds on ausculta- that, while the overall medical practice was con- tion. Laboratory data showed a white cell count sistent with IDSA CAP guidelines; the majority of of 6100 cells/mm3 with 89% neutrophils. His cre- patients treated with levoﬂoxacin were classiﬁed atinine value was 0.5 mg/dl and his O2 saturation as low risk according to the Pneumonia Patient 91% on room air. Chest X-ray revealed new inﬁl- Outcomes Research Team (PORT) criteria, and thus trates in the right lobe. Therapy was initiated with could have been managed with alternative antimi- oral rifaximin (400 mg tablets every 12 h) and mox- crobials to avoid losing the FQ efﬁcacy to resistance iﬂoxacin (400 mg every 24 h). Subsequently, stool cultures grew Salmonella spp. group C resistant to Although low incidences have been reported quinolones and susceptible to cephalosporins and from the USA, there have been reports of an alarm- trimethoprim/sulfamethoxazole (TMP/SMX). Fur- ing increase in resistance to FQ in S. pneumoniae thermore, the patient had a drop of his absolute from different parts of the world with rates rang- neutrophil count to 220. Thus, treatment was ing from 5.3% in Spain, 12.1% in Hong Kong, to 15.2% shifted to cefdinir (300 mg every 12 h).
in Ireland In Lebanon, and up to this current During his hospitalization, the patient under- report, no FQ S. pneumoniae resistant isolates have went bronchoscopy, and was found to have an been reported, although the ﬁrst penicillin resistant endobronchial mass. BAL cultures taken during strain was reported in 1996 Based on disc the procedure grew Stenotrophomonas maltophilia diffusion testing, an annually circulated brochure and S. pneumoniae which was fully resistant to on antimicrobial susceptibility patterns of bacte- penicillin based on oral CSLI breakpoint guide- rial isolates collected at AUBMC since 2006 show lines (MIC = 2 g/ml), levoﬂoxacin (MIC > 32 g/ml) penicillin resistant S. pneumoniae strains to range and TMP/SMX, but susceptible to ceftriaxone from 64 to 72%. MIC data from the latter have (MIC = 1 g/ml), vancomycin, teicoplanin and tetra- shown the fully penicillin resistant strains to range cycline. The patient was started on intravenous between 12% and 15% (based on oral penicillin CLSI ceftazidime (2 g every 8 h) and vancomycin (1 g MIC breakpoints). (AUBMC, Clinical Microbiology, every 12 h) with no clinical improvement and thus Department of Pathology and Laboratory Medicine, was shifted to intravenous ceftriaxone (2 g every 24 h) and TMP/SMX double strength every 12 h.
Resistance is a stepwise process, and is deter- Despite efforts, the patient clinically deteriorated mined by efﬂux mechanisms and/or mutations and died 21 days after hospitalization.
in the quinolone resistance-determining regions Please cite this article in press as: Naba MR, et al. Emergence of ﬂuoroquinolone-resistant Streptococcus pneumoniaein Lebanon: A report of three cases. J Infect Public Health (2010), doi: ARTICLE IN PRESS
(QRDRs) of parC and parE genes coding for topoi- inﬂuenzae in Turkey, 2004—2005. J Antimicrob Chemother somerase IV, and/or gyrA and gyrB genes coding for DNA gyrase Although not studied in our  Araj GF, Bey HA, Itani LY, Kanj SS. Drug-resistant Streptococ- cus pneumoniae in the Lebanon: implications for presump- isolates, due to the retrospective nature of our tive therapy. Int J Antimicrob Agents 1999;12:349—54.
data collection, the molecular basis of resistance in  File TM. The science of selecting antimicrobials for S. pneumoniae worldwide is a combined mutation community-acquired pneumonia (CAP). J Manag Care Pharm of both gyrA and parC genes For exam- ple, among 1817 screened S. pneumoniae isolates  Centers for Disease Control and Prevention. Drug-resistant Streptococcus pneumoniae disease. in 44 US hospitals, 21% of the isolates were found to have mutations in the QRDRs of parC and/or gyrA that resulted in diminished quinolone activ-  De Vecchi E, Nicola L, Ossola F, Drago L. In vitro selec- tion of resistance in Streptococcus pneumoniae at in vivo become resistant to older quinolones but remain ﬂuoroquinolone concentrations. J Antimicrob Chemother2009;63:721—7.
susceptible to the newer members of the quinolone  Morrissey I, Colclough A, Northwood J. TARGETed surveil- class Therefore, assessment of the frequency lance: susceptibility of Streptococcus pneumoniae isolated with which resistance mutations take place, may from community acquired respiratory tract infections in represent a reﬁned means for tracking changes 2003 to ﬂuoroquinolones and other agents. Int J Antimicrob in FQ resistance patterns The proportion of  Kanj SS, El-Dbouni O, Kanafani ZA, Araj GF. Antimicro- resistant isolates are encountered more frequently bial susceptibility of respiratory pathogens at the American among older subjects and patients with chronic University of Beirut Medical Center. Int J Infect Dis lung disease A prospective cohort study of 3339 patients with invasive pneumococcal infection  Uwaydah M, Mokhbat JE, Karam-Sarkis D, Baroud-Nassif R, between 1995 and 2002 showed that previous FQ Rohban T. Penicillin-resistant Streptococcus pneumoniae inLebanon: the ﬁrst nationwide study. Int J Antimicrob Agents use (odds ratio [OR] = 12.1), current residence in a nursing home (OR = 12.9), and nosocomial acquisi-  Memish ZA, Balkhy HH, Shibl AM, Barrozo CP, Gray GC.
tion of infection (OR = 9.9) were all signiﬁcant risk Streptococcus pneumoniae in Saudi Arabia: antibiotic resis- factors for infection with a FQ resistant S. pneu- tance and serotypes of recent clinical isolates. Int J moniae strain Other risk factors included the  Elshaﬁe SS, Al-Kuwari J. In vitro activity of moxiﬂoxacin presence of COPD and immunosuppressive condi- against community respiratory pathogens in Qatar. Int J tions All three of our patients had several  Scheld WM. Maintaining ﬂuoroquinolone class efﬁcacy: The emergence of FQ resistant S. pneumoniae in review of inﬂuencing factors. Emerg Infect Dis 2003;9:1— Lebanon constitutes a serious threat to the treat-  Anderson KB, Tan JS, File Jr TM, DiPersio JR, Willey BM, Low ment of potentially life-threatening pneumococcal DE. Emergence of levoﬂoxacin-resistant pneumococci in infections. Although our ﬁndings in the presented immunocompromised adults after therapy for community- cases cannot be generalized and are not neces- sarily representative of local medical practice, efﬁcient patient management should be based on  Cherfan AJ, Bizri AR, Steitieh SW, Moukhachen OE. Man- agement of community-acquired pneumonia at a tertiary local resistance patterns in selecting proper antimi- care medical center in Lebanon. Am J Health Syst Pharm crobial therapy. At this point, further prospective surveillance studies are crucial in clarifying the  Fine MJ, Auble TE, Yealy DM, Hanusa BH, Weissfeld LA, extent of the local patterns of resistance and Singer DE, et al. A prediction rule to identify low-risk in guiding judicious antimicrobial therapy to help patients with community-acquired pneumonia. N Engl J Med1997;336:243—50.
prevent the possible emergence of new resistant  Brueggemann AB, Coffman SL, Rhomberg P, Huynh H, Almer L, Nilius A<ET-EL>. Fluoroquinolone resistancein Streptococcus pneumoniae in United States since 1994—1995. Antimicrob Agents Chemother 2002;46:680— Competing interest: None declared.
Ethical approval: Not required.
 Doern GV, Richter SS, Miller A, Miller N, Rice C, Heilmann K, et al. Antimicrobial resistance among Streptococcus pneu- References
moniae in the United States: have we begun to turn thecorner on resistance to certain antimicrobial classes? Clin ¸kanat F, Ulusoy S, Tünger A, Söyletir glu L, et al. A survey of antibiotic resis-  Pletz MW, McGee L, Jorgensen J, Beall B, Facklam RR, tance in Streptococcus pneumoniae and Haemophilus Whitney CG, et al. Levoﬂoxacin-resistant invasive Strepto- Please cite this article in press as: Naba MR, et al. Emergence of ﬂuoroquinolone-resistant Streptococcus pneumoniaein Lebanon: A report of three cases. J Infect Public Health (2010), ARTICLE IN PRESS
Levoﬂoxacin-resistant Streptococcus pneumoniae coccus pneumoniae in the United States: evidence for clonal spread and the impact of conjugate pneumococcal vaccine.
characteristics of quinolone-nonsusceptible Streptococcus Antimicrob Agents Chemother 2004;48:3491—7.
pneumoniae in Croatia. Antimicrob Agents Chemother  Pankuch GA, Bozdogan B, Nagai K, Tambi´ Available online at www.sciencedirect.com Please cite this article in press as: Naba MR, et al. Emergence of ﬂuoroquinolone-resistant Streptococcus pneumoniaein Lebanon: A report of three cases. J Infect Public Health (2010), doi:
On October 12, 2012, the Italian Supreme Court, namely the “Corte di Cassazione” (3rd level of judgment), confirmed a previous decision by the Civil Court of Appeals of Brescia (Sentence December 22 2009 no 614) that ruled the Insurance Body for Work (INAIL) must compensate worker Innocente Marcolini who developed a tumor in the head due to long-term, heavy use of mobile phones on the job.