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Linezolid for tympanostomy tube otorrhea caused by methicillin-resistant Staphylococcus aureus and multiple drug-resistant Streptococcus pneumoniae
International Journal of Pediatric Otorhinolaryngology (2008) 72, 647—651
www.elsevier.com/locate/ijporl
Linezolid for tympanostomy tube otorrhea caused by methicillin-resistant Staphylococcus aureus and multiple drug-resistant Streptococcus pneumoniae Glenn Isaacson a,b,*, Stephen C. Aronoff b a
Departments of Otolaryngology–—Head & Neck Surgery, Temple University School of Medicine, First floor Kresge West, 3400 North Broad Street, Philadelphia, PA 19140, United States b Departments of Otolaryngology–—Pediatrics, Temple University School of Medicine, United States Received 13 December 2007; received in revised form 15 January 2008; accepted 18 January 2008 Available online 5 March 2008
KEYWORDS Antibiotic resistance; Linezolid; MRSA; Otorrhea; Ototopical drops; Resistant Streptococcus pneumoniae; Tympanostomy tube
Summary Objective: To describe a consecutive series of children with refractory tympanostomy tube otorrhea treated with linezolid and document its clinical effectiveness and adverse effects. Design: Retrospective, single institution case series. Methods: The records of children treated with linezolid for refractory gram-positive otorrhea from 2003 to 2007 were analyzed for causative organisms, antimicrobial sensitivities, history of prior medical treatments, time to cessation of otorrhea, adverse effects of linezolid and recurrence of infection. Results: Ten episodes of refractory gram-positive otorrhea treated with linezolid were documented among eight children during the study period. Seven were caused by methicillin-resistant Staphylococcus aureus and three by multiple-drug resistant Streptococcus pneumoniae. Prior treatment regimes included clindamycin, trimethoprim-sulfamethoxazole/rifampin, amoxicillin-clavulanate, and/or a third-generation cephalosporin. Seven of eight children had failed extended courses of fluoroquinolone ear drops. All children were free of otorrhea by the 14th day of twice-daily treatment with oral linezolid at 20 mg/kg/day. One child developed two additional episodes of S. aureus otorrhea three and 10 months after initial treatment. Each was successfully controlled with linezolid. There were no adverse effects from linezolid treatment. Conclusion: Oral linezolid is highly effective in the treatment of refractory otorrhea caused by methicillin-resistant S. aureus and multiple drug-resistant S. pneumoniae. It has a low risk of serious side effects. It is one of only a few oral agents with activity against these organisms and is very expensive. Linezolid should be used only when
* Corresponding author. Tel.: +215 707 3665. E-mail address: [email protected] (G. Isaacson). 0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.01.019
648
G. Isaacson, S.C. Aronoff otorrhea cannot be treated with conventional agents or when complications of otitis media pose a risk to life or function. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gram-positive organisms, particularly Streptococcus pneumoniae, beta-hemolytic streptococci, and Staphylococcus aureus, are the major cause of serious otologic infections [1]. With the development of antibiotics in the 1940s, otolaryngologists enjoyed several decades a safe, effective therapy for otitis media and its complications. Over the last 10 years, resistant strains of S. pneumoniae [2,3] (MDR-SP) and methicillin-resistant S. aureus (MRSA) [4] have emerged as important pathogens. The widespread use of antimicrobials in the pediatric population has contributed to a substantial increasing in resistant gram-positive infections in otherwise healthy children [5]. Fortunately, most gram-positive organisms remain susceptible to one or more of the common oral antibiotics [6]. Linezolid (ZyvoxTM) received food and drug administration approval in April 2000 for the treatment infections caused by vancomycin-resistant Enterococcus faecium, for nosocomial pneumonia, and complicated skin infections caused by MSRA. It was approved for pediatric indications two years later. Linezolid (an oxazolidinone) is a synthetic antimicrobial with a unique site of action and no pre-existing resistance in nature. It is 100% bioavailable when administered orally [7]. Over the last four years, we have care for several children whose post-tympanostomy tube otorrhea proved refractory to commonly available oral antibiotics and ototopical drops. We describe our experience with oral linezolid in the treatment of these infections.
2. Methods and materials Following a protocol approval by the Temple University office for human subjects protection (IRB), we searched our pediatric otolaryngology departments computerized database to find children treated with linezolid during the period January 2003— August 2007. The complete medical records of all identified children with refractory otorrhea were reviewed. Duration of otorrhea, prior medical treatments, causative organisms and their antibiotic sensitivities were recorded. ‘‘Methicillin’’ resistance for S. aureus was defined by a minimum inhibitory concentration (MIC) of >2 mg/mL for oxa-
cillin (Microscan1 breakpoint micro-well dilution technique, Dade Behring, Inc, West Sacramento, CA.). Drug resistances of S. pneumoniae were defined according to an MIC interpretive breakpoint panel (Clinical and Laboratory Standards Institute) [8]. Treatment success was defined as cessation of otorrhea by 2 weeks follow up. Treatment failure, delayed recurrence and retreatments were noted.
3. Results Ten episodes of refractory gram-positive otorrhea treated with linezolid were documented in eight children during the study period. Seven were caused by methicillin-resistant S. aureus (MRSA) and three by multiple-drug resistant S. pneumoniae (MDR-SP). All patients were followed clinically for at least 6 months following treatment (range 6 months— 4 years, median 27 months). Seven had undergone tympanostomy tube placement and one had persistent otorrhea following spontaneous tympanic membrane perforation. Ages ranged from 8 months to 10 years (median 2 years). Two girls and six boys were treated. One child was diabetic and one had trisomy 21. Prior treatment regimes included clindamycin, trimethoprim-sulfamethoxazole/rifampin, amoxicillin-clavulanate, and/or a thirdgeneration cephalosporin. Seven of eight children had failed extended courses of fluoroquinolone ear drops. All children were free of otorrhea by the 14th day of twice-daily treatment with oral linezolid at 20 mg/kg/day. One child developed two additional episodes of MRSA otorrhea 3 and 10 months after initial treatment. Each was successfully controlled with linezolid. There were no adverse effects from linezolid treatment. During the study period an additional 18 children with post-tympanostomy tube MRSA otorrhea were successfully treated with agents other than linezolid. Based on their organisms’ sensitivities, they were received trimethoprim-sulfasoxazole, clindamycin and/or rifampin +/ an ototopical drop.
4. Discussion Gram-positive organisms are the most common cause of bacterial otitis media and its complications. Capsule and cell wall components promote
Linezolid for tympanostomy tube otorrhea caused by MRSA and MSDR adhesion and secrete toxins and hyaluronidase that facilitate penetration into deep tissues and spread along fascial planes. S. pneumoniae and S. aureus are both are capable of causing mastoiditis and intracranial complications [1,9]. These organisms frequently cause otorrhea complicating tympanostomy tube insertion [10,11]. An increasing proportion of Staphylococcus aureus infections are methicillin-resistant. In some tertiary pediatric facilities, MRSA accounted for 35—50% of community-acquired S. aureus [12]. Most community-associated MRSA isolates remain susceptible to clindamycin and trimethoprim-sulfamethoxazole, unlike most nosocomial MRSA isolates. This difference probably reflects differences in genotype between community-acquired and nosocomial MRSA isolates [5]. Post-tympanostomy tube otorrhea caused by MRSA has been reported with increasing frequency [13]. In 2000, Hartnick et al. [14] described eight children with community-acquired MRSA otorrhea. Three of the eight had been treated empirically with fluoroquinolone ototopical drops and did not respond. The authors recommend systemic and topical therapy guided by culture and sensitivities. Coticchia and Dohar [15] describe 17 children with MRSA otorrhea. They compared this group with 10 age and sex matched boys and girls with methicillin-sensitive S. aureus otorrhea. Children with MRSA otorrhea averaged 14.4 antibiotic courses in their lives — more than twice the number in children with methicillin-sensitive infections. They advocate culture guided treatment for MRSA otorrhea — usually with intravenous vancomycin. From the beginning of the antibiotic era to the mid-1970s, S. pneumoniae remained uniformly susceptible to all classes of antibiotics. This changed in the mid-1970 when outbreaks of resistant S. pneumoniae occurred in South Africa [16]. Although, they were originally called penicillin-resistant pneumococci, these organisms appeared to have acquired genetic material that encodes resistance both to penicillin and to other commonly used antibiotics. Based on their relative resistance to beta lactam antibiotics, S. pneumoniae are categorized as susceptible — MIC 0.06 mg/mL; intermediately resistant — MIC 0.12 to 1 mg/mL; or resistant — MIC 2 mg/mL. By these definitions, approximately 60% of S. pneumoniae are currently susceptible to penicillin in the United States; 20% are intermediately resistant; and 20% are resistant. These figures have remained stable throughout the last 5 years [17]. Widespread use of heptavalent pneumococcal immunization has resulted in a shift in S. pneumoniae populations to serotypes that favor multiple
649
drug resistance [18,19]. Resistance to other common antimicrobials including macrolides, tetracycline, folate inhibitors and quinolones has risen [20]. Almost one third of world-wide isolates display macrolide insensitivity. Moreover, S. pneumoniae species with resistance to several drug classes (MDR-SP) are found commonly, especially in patients previously treated with several of these agents [20]. Several studies have addressing the increase prevalence of otitis media caused by resistant S. pneumoniae. A recent survey of nasopharyngeal carriage at the time of tympanostomy tube placement found 42% of S. pneumoniae were non-susceptible to penicillin, and 34.8% were resistant to macrolides [21]. Linezolid, the first member of the oxazolidinones class of antibiotics licensed by the United States Food and Drug Administration inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. It is approved for use in adults and children for serious infections caused by E. faecium or Enterococcus fecalis including vancomycin-resistant strains (VRE), S. aureus including methicillin resistant strains, coagulate negative Staphylococci and Streptococci including penicillin-resistant S. pneumoniae. Linezolid is bacteriostatic for S. aureus isolates; the linezolid MIC90 for MRSA is 4 m/mL. Virtually 100% of an oral dose of linezolid is bioavailable. The most common side effects of linezolid are rash, nausea, and vomiting. Thrombocytopenia is more common in adults who receive linezolid for more than 14 days [22]. The pharmacokinetics of linezolid has been studied in children, and the dose in children is different from that recommended in adults. Linezolid clearance in children younger than 11 years old is greater than in those 12 and older. Thus, more frequent dosing is required in the younger children. The recommended pediatric doses for linezolid are 10 mg/kg every 8 h intravenously or orally for children <12 years of age and every 12 h for those 12 years and older [7]. The results of a study in which linezolid was compared with vancomycin for treating invasive infections in children, including those caused by MRSA, has shown that linezolid is as effective and better tolerated than is vancomycin. In the pediatric trials, side effects similar to those in adults have been observed except thrombocytopenia has not been a problem [23]. The appropriate roles of ototopical drops and oral antibiotics for the treatment of post-tympanostomy tube otorrhea remain a topic of vigorous debate [24—26]. Consensus conferences have advocated fluoroquinolone drops as the first line for empiric treatment of otorrhea [27]. The utility of these
650 drops in treating organisms insensitive to antimicrobials at normal tissue concentrations is more controversial. Some authors argue that ototopical drops achieve such high local levels that in vitro sensitivity studies are irrelevant [15]. This was not the case in our patients. Those who failed ototopical drops when their organisms were resistant responded promptly when they were treated with agents that were effective in vitro. We examined the role of linezolid in the treatment of refractory otorrhea caused by MSRA and MDR-SP. It proved safe and highly effective in our population. Linezolid is expensive–—a 14-day course for a 30 kg child costs $1186 at a discount pharmacy (September 2007) [28]. As important, linezolid remains one of only few well-absorbed oral antibiotics available for treating serious resistant grampositive infections. As such, we do not advocate its use for empiric therapy of otorrhea or when MRSA or MDR-SP is sensitive to common antimicrobials. In our series, fluoroquinolone ear drops were not effective when culture and sensitivity predicted resistance.
References [1] A. Katz, E. Leibovitz, D. Greenberg, S. Raiz, M. GreenwaldMaimon, A. Leiberman, R. Dagan, Acute mastoiditis in Southern Israel: a twelve-year retrospective study (1990 through 2001), Pediatr. Infect. Dis. J. 22 (10) (2003) 878—882. [2] S.L. Block, J. Hedrick, C.J. Harrison, R. Tyler, A. Smith, R. Findlay, E. Keegan, Pneumococcal serotypes from acute otitis media in rural Kentucky, Pediatr. Infect. Dis. J. 21 (9) (2002) 859—865. [3] E.R. Wald, E.O. Mason Jr., J.S. Bradley, W.J. Barson, Kaplan SL, US pediatric multicenter pneumococcal surveillance group, acute otitis media caused by S. pneumoniae in children’s hospitals between 1994 and 1997, Pediatr. Infect. Dis. J. 20 (1) (2001) 34—39. [4] L.D. Saravolatz, D.J. Pohlod, L.M. Arking, Communityacquired methicillin resistant Staphylococcus aureus infections: a new source for nosocomial outbreaks, Ann. Inter. Med. 97 (1982) 325—329. [5] M.C. Enright, D.A. Robinson, G. Randle, et al., The evolutionary history of methicillin-resistant Staphylococcus aureus (MRSA), Proc. Natl. Acad. Sci. USA 99 (2002) 7687. [6] J.E. Fergie, K. Purcell, Community-acquired methicillinresistant Staphylococcus aureus infections in south Texas children, Pediatr. Infect. Dis. J. 20 (2001) 860. [7] G.L. Jungbluth, I.R. Welshman, N.K. Hopkins, Linezolid pharmacokinetics in pediatric patients: an overview, Pediatr. Infect. Dis. J. 22 (2003) S153—S157. [8] Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing. Sixteenth Informational Supplement, Document M100eS16, Wayne, PA, 2006. [9] K. Sichizya, G. Fieggen, A. Taylor, J. Peter, Brain abscesses–— the Groote Schuur experience, 1993—2003, S. Afr. J. Surg. 43 (3) (2005) 79—82.
G. Isaacson, S.C. Aronoff [10] E.M. Mandel, M.L. Casselbrant, M. Kurs-Lasky, Acute otorrhea: bacteriology of a common complication of tympanostomy tubes, Ann. Otol. Rhinol. Laryngol. 103 (1994) 713—718. [11] P.S. Roland, D.A.M.D. Parry, D.W. Stroman, Microbiology of acute otitis media with tympanostomy tubes, Otolaryngol. Head Neck Surg. 133 (2005) 585—595. [12] K.G. Hulten, S.L. Kaplan, B.E. Gonzalez, W.A. Hammerman, L.B. Lamberth, J. Versalovic, E.O. Mason Jr., Three-year surveillance of community onset health care-associated Staphylococcus aureus infections in children, Pediatr. Infect. Dis. J. 25 (4) (2006) 349—353. [13] F. Santos, L.A. Mankarious, R.D. Eavey, Methicillin-resistant Staphylococcus aureus: pediatric otitis, Arch. Otolaryngol. Head Neck Surg. 126 (11) (2000) 1383—1385. [14] C.J. Hartnick, S. Shott, J.P. Willging, C.M. Myer III, Methicillin-resistant Staphylococcus aureus otorrhea after tympanostomy tube placement: an emerging concern, Arch. Otolaryngol. Head Neck Surg. 126 (2000) 1440—1443. [15] J.M. Coticchia, J.E. Dohar, Methicillin-resistant Staphylococcus aureus Otorrhea. After tympanostomy tube placement, Arch. Otolaryngol. Head Neck Surg. 131 (2005) 868— 873. [16] CDC. Geographic Variation in Penicillin Resistance in S. pneumoniae: Selected Sites, United States, 1997. MMWR (1999) 48, 656—61. [17] D.F. Sahm, M.S. Benninger, A.T. Evangelista, Y.C. Yee, C. Thornsberry, N.P. Brown, Antimicrobial resistance trends among sinus isolates of S. pneumoniae in the United States (2001—2005), Otolaryngol. Head Neck Surg. 136 (3) (2007) 385—389. [18] W.P. Hanage, S.S. Huang, M. Lipsitch, C.J. Bishop, D. Godoy, S.I. Pelton, R. Goldstein, H. Huot, J.A. Finkelstein, Diversity and antibiotic resistance among nonvaccine serotypes of S. pneumoniae carriage isolates in the post-heptavalent conjugate vaccine era, J. Infect. Dis. 195 (Feb 1 (3)) (2007) 347— 352 (Epub 2006 Dec 27). [19] D.J. Farrell, K.P. Klugman, M. Pichichero, Increased antimicrobial resistance among nonvaccine serotypes of S. pneumoniae in the pediatric population after the introduction of 7-valent pneumococcal vaccine in the United States, Pediatr. Infect. Dis. J. 26 (2) (2007) 123—128. [20] D. Felmingham, R. Canto, S.G. Jenkins, Regional trends in blactam, macrolide, fluoroquinolone and telithromycin resistance among Streptococcus pneumoniae isolates 2001— 2004, J. Infect. 55 (2007) 111e118. [21] M.R. Jacobs, C.E. Good, T. Sellner, S. Bajaksouzian, A. Windau, J.B. Anon, Nasopharyngeal carriage of respiratory pathogens in children undergoing pressure equalization tube placement in the era of pneumococcal protein conjugate vaccine use, Laryngoscope 117 (Feb (2)) (2007) 295—298. [22] T.Q. Tan, Update on the use of linezolid a pediatric perspective, Pediatr. Infect. Dis. J. 23 (2004) 955—956. [23] L. Saiman, et al., Safety and tolerability of linezolid in children, Pediatr. Infect. Dis. J. 22 (2003) S193—S200. [24] G. Isaacson, Why do not those ear drops work for my patients? Pediatrics 118 (2006) 1252—1253. [25] J. Dohar, W. Giles, P. Roland, N. Bikhazi, S. Carroll, R. Moe, B. Reese, S. Dupre, M. Wall, D. Stroman, C. McLean, K. Crenshaw, Topical ciprofloxacin/dexamethasone superior to oral amoxicillin/clavulanic acid in acute otitis media with otorrhea through tympanostomy tubes, Pediatrics 118 (3) (2006) e561—e569 (Epub 2006 Jul 31). [26] S.J. Daniel, F.K. Kozak, M.C. Fabian, R. Hekkenberg, L.E. Hruby, K.S. Harjee, R. Rana, R.F. Lubell, Hawke M., Expert round table of pediatric and general otolaryngologists, pediatricians, and family physicians. Guidelines for the
Linezolid for tympanostomy tube otorrhea caused by MRSA and MSDR treatment of tympanostomy tube otorrhea, J. Otolaryngol. (2005) S60—S63, Review 34 (Suppl 2). [27] L. Vaile, T. Williamson, A. Waddell, G. Taylor, Interventions for ear discharge associated with grommets (ventilation
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tubes), Cochrane Database Syst. Rev. 19 (2) (2006) CD001933. [28] http://www.walgreens.com/library/finddrug/druginfo1. jsp?particularDrug=Zyvox&id=18047.
Available online at www.sciencedirect.com
www.elsevier.com/locate/ijporl
Linezolid for tympanostomy tube otorrhea caused by methicillin-resistant Staphylococcus aureus and multiple drug-resistant Streptococcus pneumoniae Glenn Isaacson a,b,*, Stephen C. Aronoff b a
Departments of Otolaryngology–—Head & Neck Surgery, Temple University School of Medicine, First floor Kresge West, 3400 North Broad Street, Philadelphia, PA 19140, United States b Departments of Otolaryngology–—Pediatrics, Temple University School of Medicine, United States Received 13 December 2007; received in revised form 15 January 2008; accepted 18 January 2008 Available online 5 March 2008
KEYWORDS Antibiotic resistance; Linezolid; MRSA; Otorrhea; Ototopical drops; Resistant Streptococcus pneumoniae; Tympanostomy tube
Summary Objective: To describe a consecutive series of children with refractory tympanostomy tube otorrhea treated with linezolid and document its clinical effectiveness and adverse effects. Design: Retrospective, single institution case series. Methods: The records of children treated with linezolid for refractory gram-positive otorrhea from 2003 to 2007 were analyzed for causative organisms, antimicrobial sensitivities, history of prior medical treatments, time to cessation of otorrhea, adverse effects of linezolid and recurrence of infection. Results: Ten episodes of refractory gram-positive otorrhea treated with linezolid were documented among eight children during the study period. Seven were caused by methicillin-resistant Staphylococcus aureus and three by multiple-drug resistant Streptococcus pneumoniae. Prior treatment regimes included clindamycin, trimethoprim-sulfamethoxazole/rifampin, amoxicillin-clavulanate, and/or a third-generation cephalosporin. Seven of eight children had failed extended courses of fluoroquinolone ear drops. All children were free of otorrhea by the 14th day of twice-daily treatment with oral linezolid at 20 mg/kg/day. One child developed two additional episodes of S. aureus otorrhea three and 10 months after initial treatment. Each was successfully controlled with linezolid. There were no adverse effects from linezolid treatment. Conclusion: Oral linezolid is highly effective in the treatment of refractory otorrhea caused by methicillin-resistant S. aureus and multiple drug-resistant S. pneumoniae. It has a low risk of serious side effects. It is one of only a few oral agents with activity against these organisms and is very expensive. Linezolid should be used only when
* Corresponding author. Tel.: +215 707 3665. E-mail address: [email protected] (G. Isaacson). 0165-5876/$ — see front matter # 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2008.01.019
648
G. Isaacson, S.C. Aronoff otorrhea cannot be treated with conventional agents or when complications of otitis media pose a risk to life or function. # 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Gram-positive organisms, particularly Streptococcus pneumoniae, beta-hemolytic streptococci, and Staphylococcus aureus, are the major cause of serious otologic infections [1]. With the development of antibiotics in the 1940s, otolaryngologists enjoyed several decades a safe, effective therapy for otitis media and its complications. Over the last 10 years, resistant strains of S. pneumoniae [2,3] (MDR-SP) and methicillin-resistant S. aureus (MRSA) [4] have emerged as important pathogens. The widespread use of antimicrobials in the pediatric population has contributed to a substantial increasing in resistant gram-positive infections in otherwise healthy children [5]. Fortunately, most gram-positive organisms remain susceptible to one or more of the common oral antibiotics [6]. Linezolid (ZyvoxTM) received food and drug administration approval in April 2000 for the treatment infections caused by vancomycin-resistant Enterococcus faecium, for nosocomial pneumonia, and complicated skin infections caused by MSRA. It was approved for pediatric indications two years later. Linezolid (an oxazolidinone) is a synthetic antimicrobial with a unique site of action and no pre-existing resistance in nature. It is 100% bioavailable when administered orally [7]. Over the last four years, we have care for several children whose post-tympanostomy tube otorrhea proved refractory to commonly available oral antibiotics and ototopical drops. We describe our experience with oral linezolid in the treatment of these infections.
2. Methods and materials Following a protocol approval by the Temple University office for human subjects protection (IRB), we searched our pediatric otolaryngology departments computerized database to find children treated with linezolid during the period January 2003— August 2007. The complete medical records of all identified children with refractory otorrhea were reviewed. Duration of otorrhea, prior medical treatments, causative organisms and their antibiotic sensitivities were recorded. ‘‘Methicillin’’ resistance for S. aureus was defined by a minimum inhibitory concentration (MIC) of >2 mg/mL for oxa-
cillin (Microscan1 breakpoint micro-well dilution technique, Dade Behring, Inc, West Sacramento, CA.). Drug resistances of S. pneumoniae were defined according to an MIC interpretive breakpoint panel (Clinical and Laboratory Standards Institute) [8]. Treatment success was defined as cessation of otorrhea by 2 weeks follow up. Treatment failure, delayed recurrence and retreatments were noted.
3. Results Ten episodes of refractory gram-positive otorrhea treated with linezolid were documented in eight children during the study period. Seven were caused by methicillin-resistant S. aureus (MRSA) and three by multiple-drug resistant S. pneumoniae (MDR-SP). All patients were followed clinically for at least 6 months following treatment (range 6 months— 4 years, median 27 months). Seven had undergone tympanostomy tube placement and one had persistent otorrhea following spontaneous tympanic membrane perforation. Ages ranged from 8 months to 10 years (median 2 years). Two girls and six boys were treated. One child was diabetic and one had trisomy 21. Prior treatment regimes included clindamycin, trimethoprim-sulfamethoxazole/rifampin, amoxicillin-clavulanate, and/or a thirdgeneration cephalosporin. Seven of eight children had failed extended courses of fluoroquinolone ear drops. All children were free of otorrhea by the 14th day of twice-daily treatment with oral linezolid at 20 mg/kg/day. One child developed two additional episodes of MRSA otorrhea 3 and 10 months after initial treatment. Each was successfully controlled with linezolid. There were no adverse effects from linezolid treatment. During the study period an additional 18 children with post-tympanostomy tube MRSA otorrhea were successfully treated with agents other than linezolid. Based on their organisms’ sensitivities, they were received trimethoprim-sulfasoxazole, clindamycin and/or rifampin +/ an ototopical drop.
4. Discussion Gram-positive organisms are the most common cause of bacterial otitis media and its complications. Capsule and cell wall components promote
Linezolid for tympanostomy tube otorrhea caused by MRSA and MSDR adhesion and secrete toxins and hyaluronidase that facilitate penetration into deep tissues and spread along fascial planes. S. pneumoniae and S. aureus are both are capable of causing mastoiditis and intracranial complications [1,9]. These organisms frequently cause otorrhea complicating tympanostomy tube insertion [10,11]. An increasing proportion of Staphylococcus aureus infections are methicillin-resistant. In some tertiary pediatric facilities, MRSA accounted for 35—50% of community-acquired S. aureus [12]. Most community-associated MRSA isolates remain susceptible to clindamycin and trimethoprim-sulfamethoxazole, unlike most nosocomial MRSA isolates. This difference probably reflects differences in genotype between community-acquired and nosocomial MRSA isolates [5]. Post-tympanostomy tube otorrhea caused by MRSA has been reported with increasing frequency [13]. In 2000, Hartnick et al. [14] described eight children with community-acquired MRSA otorrhea. Three of the eight had been treated empirically with fluoroquinolone ototopical drops and did not respond. The authors recommend systemic and topical therapy guided by culture and sensitivities. Coticchia and Dohar [15] describe 17 children with MRSA otorrhea. They compared this group with 10 age and sex matched boys and girls with methicillin-sensitive S. aureus otorrhea. Children with MRSA otorrhea averaged 14.4 antibiotic courses in their lives — more than twice the number in children with methicillin-sensitive infections. They advocate culture guided treatment for MRSA otorrhea — usually with intravenous vancomycin. From the beginning of the antibiotic era to the mid-1970s, S. pneumoniae remained uniformly susceptible to all classes of antibiotics. This changed in the mid-1970 when outbreaks of resistant S. pneumoniae occurred in South Africa [16]. Although, they were originally called penicillin-resistant pneumococci, these organisms appeared to have acquired genetic material that encodes resistance both to penicillin and to other commonly used antibiotics. Based on their relative resistance to beta lactam antibiotics, S. pneumoniae are categorized as susceptible — MIC 0.06 mg/mL; intermediately resistant — MIC 0.12 to 1 mg/mL; or resistant — MIC 2 mg/mL. By these definitions, approximately 60% of S. pneumoniae are currently susceptible to penicillin in the United States; 20% are intermediately resistant; and 20% are resistant. These figures have remained stable throughout the last 5 years [17]. Widespread use of heptavalent pneumococcal immunization has resulted in a shift in S. pneumoniae populations to serotypes that favor multiple
649
drug resistance [18,19]. Resistance to other common antimicrobials including macrolides, tetracycline, folate inhibitors and quinolones has risen [20]. Almost one third of world-wide isolates display macrolide insensitivity. Moreover, S. pneumoniae species with resistance to several drug classes (MDR-SP) are found commonly, especially in patients previously treated with several of these agents [20]. Several studies have addressing the increase prevalence of otitis media caused by resistant S. pneumoniae. A recent survey of nasopharyngeal carriage at the time of tympanostomy tube placement found 42% of S. pneumoniae were non-susceptible to penicillin, and 34.8% were resistant to macrolides [21]. Linezolid, the first member of the oxazolidinones class of antibiotics licensed by the United States Food and Drug Administration inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit. It is approved for use in adults and children for serious infections caused by E. faecium or Enterococcus fecalis including vancomycin-resistant strains (VRE), S. aureus including methicillin resistant strains, coagulate negative Staphylococci and Streptococci including penicillin-resistant S. pneumoniae. Linezolid is bacteriostatic for S. aureus isolates; the linezolid MIC90 for MRSA is 4 m/mL. Virtually 100% of an oral dose of linezolid is bioavailable. The most common side effects of linezolid are rash, nausea, and vomiting. Thrombocytopenia is more common in adults who receive linezolid for more than 14 days [22]. The pharmacokinetics of linezolid has been studied in children, and the dose in children is different from that recommended in adults. Linezolid clearance in children younger than 11 years old is greater than in those 12 and older. Thus, more frequent dosing is required in the younger children. The recommended pediatric doses for linezolid are 10 mg/kg every 8 h intravenously or orally for children <12 years of age and every 12 h for those 12 years and older [7]. The results of a study in which linezolid was compared with vancomycin for treating invasive infections in children, including those caused by MRSA, has shown that linezolid is as effective and better tolerated than is vancomycin. In the pediatric trials, side effects similar to those in adults have been observed except thrombocytopenia has not been a problem [23]. The appropriate roles of ototopical drops and oral antibiotics for the treatment of post-tympanostomy tube otorrhea remain a topic of vigorous debate [24—26]. Consensus conferences have advocated fluoroquinolone drops as the first line for empiric treatment of otorrhea [27]. The utility of these
650 drops in treating organisms insensitive to antimicrobials at normal tissue concentrations is more controversial. Some authors argue that ototopical drops achieve such high local levels that in vitro sensitivity studies are irrelevant [15]. This was not the case in our patients. Those who failed ototopical drops when their organisms were resistant responded promptly when they were treated with agents that were effective in vitro. We examined the role of linezolid in the treatment of refractory otorrhea caused by MSRA and MDR-SP. It proved safe and highly effective in our population. Linezolid is expensive–—a 14-day course for a 30 kg child costs $1186 at a discount pharmacy (September 2007) [28]. As important, linezolid remains one of only few well-absorbed oral antibiotics available for treating serious resistant grampositive infections. As such, we do not advocate its use for empiric therapy of otorrhea or when MRSA or MDR-SP is sensitive to common antimicrobials. In our series, fluoroquinolone ear drops were not effective when culture and sensitivity predicted resistance.
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