Emergence of Strepfococcus pneumoniae with high-level resistance to cefotaxime in Hong Kong
SSY Wong, PCY Woo, PL Ho, VCC Cheng, KY Yuen
We report on two cases of pneumococcal infection caused by strains demonstrating high-level cefotaxime resistance (minimal inhibitory concentration, 4 (ig/mL). One patient had acute community-acquired meningitis with hacteraemia and the other had bacteraemia probably as a result of nosocomial pneumo- nia. Both patients died despite treatment with third generation cephalosporins. This is the first report from Hong Kong of infection with Streptococcus pneumoniae with high-level cefotaxime resistance that resulted in death. The emergence of high-level resistance to third-generation cephalosporins will result in treatment failure when these agents or penicillin are used alone, especially in cases of severe infection, such as meningitis, in which drug penetration of the blood-brain harrier is critical. The treatment of severe infections due to these isolates is problematic. Indiscriminate use of life-saving third-generation cephalosporins as out-patient treatment of minor infections or as first-line therapy for uncomplicated community-acquired infections in the hospital and in the community should be discouraged.
HKMJ 1999:5:406-9
Key words' Cefot~~im~/dtfver~eeffeclf; Drug resistance, microbial; Microbial sensitivity tests; Pneumococcal infections/ drug therapy; Streptococcus pneumoniae/drug effect^
Introduction anti-pneumococcal activity (CAPA). We report on two fatal cases of poeumococcal infection in Hong Infection with Streptococcuspneumoniae is one of the Kong that demonstrated a high level of resistance to most common causes of community-acquired acute third-generation CAPA. This is the first report of the bacterial pneumonia and meningitis worldwide. The isolation of S pneumoniae isolates with such a high standard therapy with penicillin G (benzylpenicillin) level of CAPA resistance in Hong Kong. The thera- has been challenged in the past decade by the emer- peutic options for treating pneumococcal infections gence of strains that have moderate to high levels of in different clinical situations and their rationale are penicillin resistance. Penicillin-resistant Spneumoniae discussed. was first isolated in Hong Kong in 1989.' Since then, the prevalence of pneumococci demonstrating moder- Case reports ate to high levels of penicillin resistance has been increasing in Hong K~ng.~The treatment of choice Case 1 for severe infections that are caused by penicillin- A 47-year-old man was admitted to the Queen Mary resistant pneumococci has been to prescribe the Hospital because of a 1-week history of fever and cephalospotins ceftriaxone and cefotaxime. Of all prostration. The patient was mentally retarded owing cephalosporins, these two drugs possess the best ac- to an episode of paediatric meningitis and he was tivities against pneumococci.' In this article, they are living at home. He had a cough and was producing referred to as third-generation cephalosporins with mucopurulent sputum; he had been treated by a general practitioner for a chest infection. On the day of hospital admission, the patient's condition sud- Division of Infectious Diseases, Department of Microbiology, The University of Hong Kong, Queen Mary Hospital, Pokfulam, denly deteriorated and mental dullness increased. The Hong Kong oral temperature was 39'C and he was tachycardia SSY Wong. DipRCPath, DTM&H PCY Woo, MB, BS, DipRCPalh (pulse rate, 110 beats per minute). There was clinical PL Ho, MRCP FRCPA evidence of dehydration and marked neck stiffness. VCC Cheng, MB, BS, MRCP The score on the Glasgow coma scale was 9; com- KY Yuen. MD. MRCPath puted tomography of the brain showed evidence of Correspondence to: Dr KY Yuen bilateral hydrocephalus. External ventricular drainage
406 HKMJ Vol5 No 4 December 1999 Cefotaxime-resistant pneumococci
Year
Fig. Isolation of penicillin-resistant Streptococcus pneumoniae in Hong Kong of the cerebrospinal fluid (CSF) was performed 1 g every 12 hours was commenced Hypotension immediately. Gram smearing of the CSF showed developed on that evening, and the blood culture was numerous leukocytes and Gram-positive diplococci. found to positive for Spneumoniae the following day. The total cell count of the CSF was 520 x 106/L(97% The patient died on day 43 The isolate of Spneumomae neutrophils, 1% lymphocytes, 2% mononuclear cells); was subsequently found to have a penicillin MIC of the glucose concentration in the CSF was
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Table. Recommended treatment regimens for different diseases caused by Streptococcus pneumoniae3
Disease Treatment-if bacterial Isolate~~~~~ .~~~ is:~ ~.. Susceotible Moderately resistant Resistant to oenicillin - (250 mg three (500-750mg three (750-1000 mg three times daily) times daily) times daily) Pneumonia Penicillin G Penicillin G CAPA* (if susceptible or (1-2 megaunits (3-4megaumts moderately resistant to CAPA) or every 4-6 h) every 4 h) vancomycm (if resistant to CAPA, 500 mg every 6 h) Bacteraemia Penicillin G Penicillin G CAPA (if susceptible to CAPA) or (1 -2 M megaunits (3-4 megaunits vancomycin (if moderately every 4-6 h) every 4 h) resistant or resistant to CAPA; 500 mg every 6 h) Meningitis Penicillin G Ceftriaxone (2 g every 12 h) or cefotaxime (3-4 g every 4 h) (1-2 megaunits t vancomycin + rifampicin, specialist advice from clinical every 4-6 h) microbiologist is recommended Intravenous unless otherwise stated dosaaes as for a 70-ka adult with normal renal function
20.06 pg/rnL; moderately resistant, 0.12 to 1 ng/mL; than the penicillin MIC by two-fold. Oral amoxycillin and resistant, 22 pg/mL The corresponding MIC is preferable to ampicillin because the former has a values for the bacterium's susceptibility to ceftriaxone higher bioavailability (74%-90% versus 30%-50%, and cefotaxime are 20.15 pg/mL, 1 kg/mL, and respectively)! 22 ugImL. The MIC ot cefotaxime of 4 ug/mL in the two cases presented in this report show that The CAPA were initially very effective against S pneumuniae isolates that are highly resistant to penicillin-resistant pneumococci. Streptococcus cefotaxime have now been detected in Hong Kong. pneumoniae that was resistant to CAPA started to The MIC of Spneumon~ueto B-lactams carries more appear since the early 1990s.' Infections caused by than academic interest; it bears considerable clinical pneumococci with low-level CAPA resistance may significance in terms of the choice of antibiotics still be managed with high doses of these antibiotics, in different clinical situations with respect to the provided that the infections do not involve CNS. Treat- achievable antibiotic concentrations in blood and body ment failure has been noted, however, and is especially fluids. The choice of a rational regimen against multi- common in cases of meningitis owing to the relatively resistant pneumococcal infections depends on two lower levels of antibiotic in the CSF.37Vhepenetra- key considerations: the site of infection (eg central tion of most antibiotics through the normal meninges nervous system [CNS] or non-CNS infection) and is poor, and even in the presence of inflammation, the level of resistance to the 8-lactam antibiotics (in the CSF levels of penicillin G,ceftriaxone, cefotaxime, particular, penicillin, and CAPA). The recommended and vancomycin are only 8%' 16% to 32%, 27%, and regimens in different situations are listed in the Table.' 7% to 21 % of the serum levels, respe~tively.~The poor Owing to the different patterns of resistance to differ- penetration of most 8-lactam antibiotics into the CSF ent groups of antibiotics, it is important for clinicians is partly compensated by the use of higher doses of to communicate with clinical microbiologists in dif- antibiotics. Nevertheless, in the presence of moderate ficult cases, regarding the interpretation of the M1C to high levels of B-lactam resistance, the peak anti- data and the potential use of alternative agents. For biotic levels in the CSF may be marginally above the example, infections due to isolates that are fully sus- MIC, and may even drop below the MIC when trough ceptible to penicillin can be treated with penicillin G concentrations are reached. This effect probably if the infection is severe, or with oral amoxycillin in accounts for treatment failure of the cephalosporins uncomplicated respiratory tract infections such as acute or even vancomycin alone when meningitis is caused otitis media and sinusitis. For uncomplicated res- by multiresistant pneumococci. Hence, even when the piratory tract infections that are caused by penicillin- level of resistance to penicillins and cephalosporins resistant S pneumoniae, oral amoxycilhn given in is moderate by MIC criteria, meningitis caused by higher than usual doses is often effective. This is due these strains of S pneumomae must be treated very to the fact that the amoxycillin MIC is generally lower aggressively with antibiotic combinations (Table).
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Infections that do not involve the CNS are generally Streptococcus pneumoniae is one of the few, if not less problematic because most p-lactam antibiotics the only, multiresistant bacteria for which an effect- can be given inrelatively high doses, thereby ensuring ive vaccine is available for prophylaxis. The use of that drug concentrations in the blood are many times pneumococcal vaccine has not been common locally. greater than the MIC. However, in view of the recent emergence ot high- level penicillin and cephalosponn resistance, using Apart from p-lactams, other groups of antibiotics a vaccine should be seriously considered for the may be considered in the treatment of multiresistant high-risk population, such as patients who have func- pneumococcal infection^.^ In The only agents that tional or anatomical asplenia, or chronic respiratory S pneumoniae is universally sensitive teat least and cardiovascular diseases, or who are immuno- for the time being-are the glycopeptides such as compromised. Ultimately, the only effective means vancomycin. These drugs may he the only treat- of preventing further spread of multiresistant pneumo- ment in cases of severe infection that is caused by cocci is by the judicious use of antibiotics, because S pneumomae with high-level resistance to CAPA. previous use of broad-spectrum antibiotics is strongly Their use as fist-line agents in the treatment of un- associated with the appearance of multiresistant complicated pneumococcal infections that are caused bacteria. The inappropriate use of the third-generation by S pneumoniae with lower levels of p-lactam cephalosponns is therefore strongly discouraged. resistance is not recommended in view of the concern for the emergence of vancomycin-resistant Gram- References positive bacteria, the potential toxicity of the dings, and their poorer penetration into body fluids as 1. Yuen KY, Seto WH, Hui WT, Chau PY Multi-resistant compared with the p-lactams. The clinical efficacy Streptococcus piieumaiiiae in Hang Kong [letter] J Antunicrob of fourth-generation cephalosporins (eg cefepime Chemother 199025 721-3 2 Ho PL, Yuen KY, Y'IITIWC. Wong SS. Luk W Changing and cefpirome) and meropenem has not been estab- patterns of susceptibilities of blood, urinary and respiratory lished, although the in vitro activities of these agents pathogen;, in Hong Kong J Hosp Infect 1995,31 305.17 against local isolates are not superior to those of 3 Kaplan SL, Mason EO Jr Management of infections due to CAPA.' The other commonly used third-generation antibiotic-resistant Sireplocw'i ui pneumoniae Clin Miciobiol cephalosporins ceftazidime and cefoperazone- Rev 1998: 11'628-44. sulbactam are less effective than CAPA and are not 4 Song JH, Lee NY, Ichiyama S, et al Spread of drug-resistant Streptococ(.u$ pneumoniaem Asian countries: Asian Network recommended when pneumococcal infection is sus- for Surveillance of Resistant Pathogens (ANSORP) Study pected. The macrolides erythromycin, clarithromycin, Clin Infect Dis 1999,28 1206-1 1 and azithromycin may be useful in managing 5 Ho PL, Que TL. Tsang DN, Ng TK, Chow KH. Selo WH uncomplicated respiratory tract infections; the latter Einersen~e- of fluoioauinolone resistance amons" inultinlvc, two drugs are particularly valuable because they resistant strains of Strepfococcuspneumoniae in Hong Kong. achieve very high tissue levels Unfortunately, 78.5% Antimicrob Agents Chemother 1999;43:1310-3. 6. National Committee for Clinical Laboratory Standards. and 75.1% of local isolates are resistant to erythromy- cm and azithromycin, re~pectively.~And for clinda- . mycin, there is a 78.6% resistance rate l~cally.~ Report No.: ~100.~9.' The use of macrolides and clindamycin is limited by 7. John CC. Treatment failure with use of a third-generation their relatively low levels in the CSF. Similarly, the cephalosporin for penicillin-resistant pneumococcal meningi- tis: case report and review. Clin Infect Dis 1994;18:188-93. prevalence of quinolone resistance in local isolates 8. Amsden GW, Schentag JJ. Tables of antimicrobial agent precludes their use in the treatment of pneumococcal pharmacology. In: Mandell GL, Bennett JE, Dolin R, editors. infection^.^ Newer antibiotics that may he considered Mandell, Douglas and Bennett's principles and practice of include the streptogramins and oxazolidmones; how- infectious diseases. 4th ed. New York: Churchill Livingstone; ever, clinical efficacy data are scanty for these agents 1995:492-528. 9. Catalan MJ, Fernindez JM. Vazquez A. Varela de Seijas E, Suirez A, Bernaldo de Quir6s JC. Failure of cefotaxime in Inappropriate antibiotic usage, both in the com- the treatment of meningitis due to relatively resistant Stn-pin- munity and in the hospitals, has spawned a host of coccu.spneumoniae. Clin Infect Dis 1994;18:766-9. multiresistant bacteria in recent years. Prominent 10. Bradley JS, Scheld WM. The challenge of penicillin-resistanl
iI.i^-2213 extended-s~ectrump-lactamase-producing 11, ãonSs, Ho PL, Woo PC, Yuen KY Bacteremla caused bacteriaceae. The introduction of new antibiotics against by inducible vancomycin heternresistant ~taphy~ococciChn these organisms lags far behind their appearance. Infect DIS. In press 1999
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