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ANTIMICROBIAL RESISTANCE IN STREPTOCOCCUS PNEUMONIAE
Antimicrobial Resistance in Streptococcus pneumoniae: An Overview Peter C. Appelbaum
From the Department of Pathology. Hershey Medical Center. Hershey, Pennsylvania
History of Pneumococcal Resistance to Antimicrobial Agents Although mutants of Streptococcus pneumoniae resistant to penicillin G were selected soon after this drug was introduced [I], clinical resistance to penicillin was not reported until 20 years later, when investigators in Boston noted penicillin MICs in the intermediate-resistance range (0, 1-0.2 Jig/ mL) for two of 200 strains but failed to recognize the significance of that resistance [2]. Hansman and co-workers were the first both to report and to realize the significance of penicillin resistance in S. pneumoniae. Their first resistant strain, with a penicillin MIC of0.6 Jig/mL, was isolated in Australia from the sputum of a patient with hypogammaglobulinemia [3]. Subsequently, resistant strains were identified in New Guinea and Australia [4-6], where the proportion of strains resistant rose from 12% of 521 in 1970 to 33% of 57 in 1980 [6, 7]. After the initial reports by Hansman and colleagues, anecdotal descriptions of meningitis due to penicillin-resistant pneumococci began to appear in the literature; most strains showed intermediate resistance. All patients were ~5
Received 21 October 1991; revised 26 December 1991. This article is part ofa series of papers presented at a symposium entitled "Antimicrobial Resistance in Streptococcus pneumoniae" at the 5th European Congress of Clinical Microbiology and Infectious Diseases in Oslo in September 1991. Reprints or correspondence: Dr. Peter C. Appelbaum. Department of Pathology, Division ofClinical Microbiology, Hershey Medical Center, P.O. Box 850, Hershey, Pennsylvania 17033.
Clinical Infectious Diseases
1992;15:77-83
© 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1501-0007$02.00
years of age, and most were debilitated by a concomitant systemic disease [8-13]. In 1977 pneumococci resistant to penicillin began to appear in Durban, South Africa, among patients with meningitis, bacteremia, pneumonia, and empyema. All isolates were highly resistant to penicillin (MIC, 4-8 Jig/mL) and were also resistant to chloramphenicol; they exhibited differing degrees of resistance to other penicillins and cephalosporins [14]. In 1978 Jacobs and co-workers reported on the prevalence of penicillin resistance in Johannesburg, South Africa [15]. Both intermediately resistant and fully resistant strains were encountered. Strains resistant to ,B-Iactam antibiotics, erythromycin, clindamycin, tetracycline, and chloramphenicol were isolated from 128 carriers and were responsible for bacteremia. Strains from 40 other carriers were resistant to penicillin alone; to penicillin and chloramphenicol; or to penicillin, chloramphenicol, and tetracycline. Strains were divided into six groups on the basis of serotypes and resistance patterns. One group was resistant to all antimicrobial agents tested except for rifampin, fusidic acid, vancomycin, bacitracin, and novobiocin [15]. The problem of penicillinresistant pneumococci in South Africa continues. In the United States the first infection due to penicillin-resistant pneumococci (MIC, 0.25 Jig/mL) was reported in 1974. This infection-a case of meningitis-developed in a patient with sickle cell anemia [8]. Soon after 1974, penicillin-resistant pneumococci were reported worldwide. At first, these strains were especially prom-
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Clinical resistance to penicillin in Streptococcus pneumoniae was first reported by researchers in Boston in 1965; subsequently, this phenomenon was reported from Australia (1967) and South Africa (1977). Since these early reports, penicillin resistance has been encountered with increasing frequency in strains of S. pneumoniae from around the world. In South Africa strains resistant to penicillin and chloramphenicol as well as multiresistant strains have been isolated. Similar patterns of resistance have been reported from Spain. Preliminary evidence points to a high prevalence of resistant pneumococci in Hungary, other countries of Eastern Europe, and some countries in other areas of Europe, notably France. In the United States most reports of resistant pneumococci come from Alaska and the South, but resistance is increasing in other states and in Canada. Pneumococcal resistance has also been described in Zambia, Japan, Malaysia, Pakistan, Bangladesh, Chile, and Brazil; information from other African, Asian, and South American countries is not available. The rising prevalence of penicillin-resistant pneumococci worldwide mandates selective susceptibility testing and epidemiological investigations during outbreaks.
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Table 1. Surveys of resistance to penicillin among isolates of S. pneumoniae. Location. year(s)
Source of isolates
Reference
Clinical Not given
[6] [16]
65/521 (12.5) 7/49(14.3) 181/1,016 (17.8) 19/57 (33.3) 3/233 (1.3)
Clinical. carriers Carriers Not given Clinical Clinical
[6] [5] [16] [7] [17]
28/318 (8.8) 20/200 (10.0) 51/100 (51.0) 57/159 (35.8) 21/147 (14.3) 48/91 (52.7) 231/521 (44.3)
Clinical Clinical Clinical Carriers Clinical Clinical Clinical
[18] [19] [20] [21] [22] [23] [24]
3/100 (3.0) 3/133 (2.3) 14/206 (6.8)
Clinical Clinical Clinical, carriers
[25] [26] [27]
4/1,266 (0.3) 203/3,847 (5.3) 166/1,329 (12.5) 28/1,933 (1.5)
Clinical Clinical, carriers Clinical, carriers Clinical
[28] [29] [29] [30]
4/100 (4.0) 8/30 (26.7) 78/135 (57.8) 4/16 (25.0)
Clinical, carriers Clinical Clinical, carriers Carriers
[3 I] [32] [33] [34]
1/866 2/150 4/100 6/431 12/484 4/488
Clinical Clinical Clinical Clinical, carriers Clinical, carriers Clinical
[35] [36] [37] [38] [38] [39]
22/880 (2.5) 25/676 (3.7) 39/406 (9.6) 65/229 (28.4)
Clinical Clinical Clinical Clinical
[40] [40] [40] [41]
168/270 (62.2) 110/1,316 (8.4) 21/178 (11.8) 249/3.568 (7.0) 73/302 (24.2) 156/1,100(14.2) 1/39 (2.6)
Carriers Carriers Carriers Clinical Carriers Clinical Carriers
[15] [42] [43] [44] [45] [46] [47]
1/100(1.0) 4/461 (0.9) 106/1,809 (5.9) 49/176 (27.8)
Clinical Clinical Clinical, carriers Clinical
[48] [49] [50] [51]
4/1,098 (0.4) 27/2,427(1.1)
(0.1) (1.3) (4.0) (1.4) (2.5) (0.8)
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Australasia Australia 1967-1970 1971-1976 New Guinea 1969-1970 1970 1971-1974 1978 New Zealand. 1981-1986 Europe/Middle East Spain 1979-1981 1978-1981 1983-1984 1987 1984-1986 1984-1986 1989 Switzerland 1976-1977 1984-1985 West Germany, 1979-1980 France 1980-1986 1987-1989 1990 Belgium. 1983-1988 Poland 1969-1970 1975 Hungary. 1988-1989 Romania. I991 England 1977t 1981 1987 1987-1988 1988-1989 Northern Ireland, 1986 Iceland 1989 1990 1991 Israel. 1981-1982 Africa South Africa 1977 1977-1978 1981 1983-1986 1986 1990 Zambia. 1986 Asia Japan 1974-1975 1979-1982 1984-1989 1991
No. of isolates resistant*/no. tested (% resistant)
79
Pneumococcal Drug Resistance: Overview
ClD 1992: 15 (July)
Table 1. (Continued) Location. year(s)
Source of isolates
Reference
5/249 (2.0)
Clinical
[52]
7/79 (8.9) 8/87 (9.2) 6/51(11.8)
Clinical Clinical Clinical
[53] [54] [55]
39/178 (21.9) 25/150 ( 16.7)
Clinical Clinical. carriers
[56] [57]
2/200 (1.0) 19/131 (14.5) 6/50 (12.0) 1/50 (2.0) 3j169 (1.8) 1/98 ( 1.0) 6/243 (2.5) 16/103 (15.5) 16/523 (3.1) 9/62(14.5) 13/222 (5.9) 9/215 (4.2) 5/200 (2.5) 21/258 (8.1)
Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Carriers Clinical Clinical Clinical Clinical
[2] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70]
10/294 (3.4) 17/139 (12.2) 22/197 {I 1.2) 15/284 (5.3) 40/155 (25.8) 280/5,479 (5. I) 20/487 (4.1)
Clinical, carriers Clinical Clinical Clinical Carriers Clinical Clinical
[71 ] [72] [73] [74] [74] [75] [76]
143/6.000 (2.4) 4/117 (3.4) 6/468 (1.3)
Clinical Not given Clinical
[77] [16]
[78]
* MIC, ~O.I /oLg/mL. : Includes Scotland as well.
inent in New Guinea, Israel, Poland, Spain, and South Africa as well as in the U.S. states of New Mexico, Oklahoma, Massachusetts, Colorado, and Alaska [16-78]. Published surveys of pneumococcal resistance to penicillin are summarized in table 1 and figure 1. Reports of penicillin-resistant pneumococci from African countries other than South Africa (e.g., Nigeria, Kenya, and Zambia) are scanty [47, 79, 80, 82], and more data are required before prevalence and distribution can be accurately defined. In Japan the incidence of penicillin-resistant pneumococci increased from ~l.o% during 1974-1982 to 5.9%27.8% during 1984-1991 [48-51]. Resistance to penicillin in S. pneumoniae has also been described in Malaysia, Pakistan, and Bangladesh [52-55]. Data from other Asian countries are inadequate. In Europe, Spain is the focus of penicillin-resistant pneu-
mococcal strains, with patterns mirroring those in South Africa [18-24]. The incidence of penicillin-resistant pneumococci in Spain rose from 6%in 1979 to 44% in 1989 [24]. A similar increase in the rate of resistance-from 0.3% in 1980-1986 to 5.3% in 1987-1989 and 12.5%in 1990-was observed in France [28, 29]. Moreover, the incidence of penicillin-resistant pneumococci in Iceland rose from 2.5% in 1989 to 9.6% in 1991 [40]. Recent reports of penicillin resistance in more than 50% of pneumococcal strains from Hungary [33] and in 25%of strains from Romania [34] may indicate foci of resistance in those countries and possibly in other countries of Eastern Europe and the former Soviet Union. Early anecdotal reports of penicillin resistance from Poland and Romania [31, 32, 81] support the existence of such foci. The first published report of penicillin-resistant pneumococci in South America came from Chile in 1987 [56]; a
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Asia (Continuedy Malaysia. 1984-1985 Pakistan 1989 1986-1989 Bangladesh. 1989-1991 South America Chile. 1983-1985 Brazil. 1989-1990 United States Boston. 1964-1965 New Mexico. 1972 Boston. 1972-1973 U.S.. 1976-1977 Pittsburgh, 1978 Denve~ 1975-1979 Madison. WI. 1978 Oklahoma City. 1977-1978 Detroit. 1978-1980 Denver. 1980 Houston. 1981 Denver. 1981 Atlanta. 1981 Dallas. 1981-1983 Veterans Administration hospitals. 1981-1984 Denver. 1984 Alaska. 1980-1984 Alaska. 1980-1986 Alaska. 1987 U.S .. 1979-1987 U.S.. 1987-1988 Canada Alberta. 1974-1976 Montreal, 1977-1978 Canad~ 1984-1986
No. of isolates resistant* /no. tested (% resistant)
80
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subsequent report from Brazil [57] documented a similarly high rate of penicillin resistance in that country. The prevalence of antibiotic-resistant pneumococci in other South American countries is unknown at present. The level of resistance to penicillin among pneumococcal strains in Canada remains low [16, 77, 78]. In the United States, nationwide rates of penicillin resistance were reported as 4.1%-5.1% for 1987-1988 [75, 76]. Of all U.S. states, Alaska has had the highest rate of pneumococcal resistance to penicillin (25.8%) [73. 74]. It is extremely important in the examination of data from surveillance reports such as those detailed above to realize that strains have been isolated from different sources, different hospitals, and different cities in the same country. Thus the data are representative only of a specific population group.
Pneumococcal Resistance to Multiple Drugs Pneumococcal resistance to penicillin may occur either on its own or in combination with resistance to other antimicrobial agents. Resistance to antibiotics of at least three different groups has been defined as multiple resistance [15, 82]. In South Africa multiple resistance soon followed the original description of resistance to penicillin and chlorampheni-
col in 1977 [14, 15]. The first multiresistant strain-isolated from the sputum ofa patient with pneumonia-was resistant to penicillin, tetracycline, erythromycin, clindarnycin, trimethoprim-sulfamethoxazole, and chloramphenicol [15, 83]. In an investigation at six Johannesburg hospitals, 56% of 315 pneumococci isolated from carriers were multiresistant, as were 15% of 180 strains from carriers in Durban [42]. Although the prevalence of multiple resistance among pneumococcal isolates from hospitalized carriers in South Africa remains high, infections caused by these isolates are relatively uncommon [44, 82]. After the emergence of multiresistant pneumococci in South Africa, a high prevalence of these organisms was documented in Spain (table 1). The epidemiological pattern of multiresistant pneumococci in South Africa and Spain was initially similar (i.e., occurrence among hospitalized children receiving antibiotics); however, disease caused by multiresistant S. pneumoniae is now a significant problem in both children and adults in Spain [84]. Strains resistant to penicillin, tetracycline, and chloramphenicol have been described in Britain, and strains whose multiple resistance includes trirnethoprim-sulfamethoxazole and erythromycin have been isolated from carriers as well as from patients in that country [38, 85-87]. Multiresistant strains have been reported to the Central Public Health Labo-
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Figure 1. Worldwide prevalence and distribution of penicillin-resistant S. pneurnoniae. White areas represent countries in which prevalence is unknown. Information on countries not listed in table I and most other data are from [82].
CID 1992; 15 (July)
Pneumococcal Drug Resistance: Overview
Africa, Asia, Eastern Europe, the former Soviet Union, and South America.
COCCI III
References I. Eriksen KR. Studies on induced resistance to penicillin in a pneumococcus type I. Acta Pathol Microbiol Scand 1945;22:398-405. 2. Kislak JW. Razavi LMB, Daly AK, Finland M. Susceptibility ofpneumococci to nine antibiotics. Am J Med Sci 1965;250:261-8. 3. Hansman D. Bullen MM. A resistant pneumococcus [letter]. Lancet
1967;2:264-5. 4. Hansman D. Glasgow H. Sturt J. Devitt HL. Douglas R. Increased resistance to penicillin of pneumococci isolated from man. N Engl J Med 1971;284: 175-7. 5. Hansman D. Type distribution and antibiotic sensitivity of pneumococci from carriers in Kiriwina, Trobriand Islands (New Guinea). Med J Aust 1972;2:771-3. 6. Hansman D. Devitt L. Miles H. Riley I. Pneumococci relatively insensitive to penicillin in Australia and New Guinea. Med J Aust
1974;2:353-6. 7. Gratten M. Naraqi S. Hansman D. High prevalence of penicillin-insensitive pneumococci in Port Moresby. Papua New Guinea. Lancet
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Serotypes of Resistant Pneumococcal Strains The three countries with the highest reported incidence of penicillin-resistant pneumococci are South Africa, Spain, and Hungary. South African isolates belong predominantly to serotypes 6, 14, 19, and 23 [46]. In Spain serotypes 6,9, 19, and 23 are the commonest isolates from blood cultures; resistant isolates from the CSF are mainly of serotypes 6, 9, and 23; and isolates from the lungs are most often of serotypes 6,9, 14, 19, and 23 [96]. In Hungary resistant isolates belong to serotypes 19A, 6B, and 23F [97]. In France, where the problem of penicillin-resistant pneumococci has become severe during the past few years, serotypes 19, 23, 14, and 6 predominate [29]. Molecular studies have shown that the resistant serotype 23F probably spread from Spain to France and the United States [29, 98].
Conclusions Resistance to penicillin among strains of S. pneumoniae is now widespread and is rapidly increasing all over the world. Serotyping and analyses of other epidemiological markers reveal that a specific strain of resistant S. pneumoniae may spread from country to country and even from one continent to another. Recognition of this problem mandates susceptibility testing of pneumococcal isolates from blood, CSF, and other normally sterile body fluids; isolates from the ears and eyes may also need to be tested. Epidemiological investigations and measures designed to lower rates of carriage are necessary in areas with high rates of pneumococcal resistance to penicillin. The optimal choice of therapy for infections caused by penicillin-resistant pneumococci depends on the strain's specific susceptibility pattern. More information is necessary on the prevalence of penicillin-resistant pneumo-
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ratory in London from 14 of 15 health regions in England, Wales, Scotland, and Ireland [87]. The number ofpneumococcal strains resistant to three or more antimicrobial agents increased from two in 1984to 40 in 1987 [87]. The predominant group in whom multiresistant pneumococci are found in the United Kingdom consists of elderly hospitalized patients receiving multiple antibiotics for acute exacerbations of chronic bronchitis [86, 88]. Four of 200 pneumococcal strains isolated in Italy during 1982 were resistant to three different antibiotic groups [89]. Multiresistant strains have also been isolated in France [28, 29, 90-92] and Belgium [30]. Recent findings suggest a problem with multiple antibiotic resistance in Hungary [33], Romania [34], and Pakistan [53, 54]. In the United States multiresistant pneumococci were responsible for an outbreak of community-acquired pneumonia in Denver in 1981 [66]. Subsequently, multiresistant strains were isolated in Ohio [93], Vermont [94], and New York [71]. The first multiresistant Canadian isolate was described in 1983 [95].
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patterns of Streptococcus pneumoniae. Antimicrob Agents Chemother 1978; 13:645-8. Gartner JC, Michaels RH. Meningitis from a pneumococcus moderately resistant to penicillin. JAMA 1979;241: 1707-9. Lauer BA. Reller LB. Serotypes and penicillin susceptibility of pneumococci isolated from blood. J Clin Microbiol 1980; II :242-4. Maki DG, Helstad AG. Kimball JL. Penicillin susceptibility of Streptococcus pneumoniae in 1978: screening for resistance by disk testing. Am J Clin Pathol 1980;73: 177-82. Saah AJ, Mallonee JP, Tarpay M, Thornsberry CT. Roberts MA. Rhoades ER. Relative resistance to penicillin in the pneumococcus: a prevalence and case-control study. J AMA 1980;243: 1824-7. Anderson KC, Maurer MJ. Dajani AS. Pneumococci relatively resistant to penicillin: a prevalence survey in children. J Pediatr 1980;97:93941. Radetsky MS, Istre GR, Johansen TL, et al. Multiply resistant pneumococcus causing meningitis: its epidemiology within a day-care centre. Lancet 1981;2:771-3. Krause KL, Stager C, Gentry La. Prevalence of penicillin-resistant pneumococci in Houston. Texas. Am J Clin PathoI1982;77:21O-3. Istre GR, Humphreys JT, Albrecht KD, Thornsberry C, Swenson JM, Hopkins RS. Chloramphenicol and penicillin resistance in pneumococci isolated from blood and cerebrospinal fluid: a prevalence study in metropolitan Denver. J Clin Microbiol 1983; 17:472-5. Perlino CA. Lichtenberger CJ. Antibiotic susceptibility and serotype distribution of Streptococcuspneunioniae: stable incidence of antibiotic-resistant isolates and common serotypes. Am Rev Respir Dis 1984; 129: 1018-20. Jackson MA. Shelton S, Nelson JD, McCracken GH Jr. Relatively penicillin-resistant pneumococcal infections in pediatric patients. Pediatr Infect Dis 1984;3: 129-32. SimberkoffMS, Lukaszewski M, Cross A, et al. Antibiotic-resistant isolates of Streptococcuspneunioniae from clinical specimens: a cluster of serotype 19A organisms in Brooklyn, New York. J Infect Dis 1986; 153:78-82. Istre GR, Tarpay M, Anderson M. Pryor A. Welch D. and the Pneumococcus Study Group. Invasive disease due to Streptococcus pneumoniae in an area with a high rate of relative penicillin resistance. J Infect Dis 1987; 156:732-5. Parkinson AJ. Heyward WL, Facklam RR. Oxtoby MJ. Partial penicillin resistance of Streptococcus pneumoniae isolates recovered from Alaskan Eskimos [abstract no 710]. In: Program and abstracts of the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology. 1986:227. Arctic Investigations Laboratory. Centers for Disease Control. Partial penicillin resistance (PPR) pneumococcal isolates recovered from Alaskan patients. Alaska Med 1987;29:186-7. Spika JS. Facklam RR. Plikaytis BD, Oxtoby MJ, and the Pneumococcal Surveillance Working Group. Antimicrobial resistance of Streptococcus pneumoniae in the United States, 1979-1987. J Infect Dis 1991; 163: 1273-8. Jorgensen JH. Maher LA. Howell AW, Redding JS, Doern GY. National surveillance ofantimicrobial resistance among respiratory isolates of Haeniophilus influenzae and Streptococcus pneumoniae [abstract no 1286]. In: Program and abstracts of the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington. DC: American Society for Microbiology, 1989:319. Dixon JMS. Lipinski AE, Graham MEP. Detection and prevalence of pneumococci with increased resistance to penicillin. Can Med Assoc J 1977;117:1159-61.
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78. Jette LP, Lamothe F. and the Pneumococcus Study Group. Surveillance of invasive Streptococcus pneumoniae infection in Quebec. Canada. from 1984 to 1986: serotype distribution. antimicrobial susceptibility, and clinical characteristics. J C1in MicrobioI1989;27: 1-
5. 79. Hansman D. Chloramphenicol-resistant pneumococci in West Africa [letter]. Lancet 1978;1:1102-3. 80. Wamola IA. Mirza NB. Nsnazumuhire H. Penicillin-resistant pneumococcal meningitis in Kenyatta National Hospital, Nairobi. Kenya. East Afr Med J 1981;58: 12-7. 81. Yatii A, Turcu T. Mihul Y, et al. Penicillin-resistant Streptococcuspneumoniae. Arch Roum Pathol Exp Microbiol 1977;36:277-83. 82. Klugman KP. Pneumococcal resistance to antibiotics. Clin Microbiol Rev 1990;3: 171-96. 83. Appelbaum PC, KoornhofHJ. Jacobs M, et al. Multiple-antibiotic resistance of pneumococci-South Africa. MMWR 1977;26:285-6. 84. Pallares R. Gudiol F, Linares J, et al. Risk factors and response to antibiotic therapy in adults with bacteremic pneumonia caused by penicillin-resistant pneumococci. N Engl J Med 1987;317: 18-22. 85. Paton JH. Reeves DS. First multiresistant pneumococcus in Britain. BMJ 1987;295:810-1. 86. Gould FK. Magee JG, Ingham HR. A hospital outbreak of antibioticresistant Streptococcuspneumoniae. J Infection 1987; 15:77-9. 87. George RC, Cooper PG, Erdman YJ. Not the first multiresistant pneumococcus in Britain [letter]. BMJ 1987;295: 1208. 88. Moore EP, Williams EW. Hospital transmission of multiply antibioticresistant Streptococcus pneumoniae [letter]. J Infect 1988: 16:199200. 89. Figura N, Rossolini A. Tagliaferri L. Saletti M. Prevalence of chemoresistance in recent clinical isolates of 'Streptococcuspneumoniae,' Ann Sclavo 1982;24:93-100. 90. Buu-Hoi' AY, Goldstein FW. Acar JF. A seventeen-year epidemiological survey of antimicrobial resistance in pneumococci in two hospitals. J Antimicrob Chemother 1988;22(suppl B):41-52. 91. Dublanchet A. Durieux R. Isolement d'une souche de Streptococcus pneuntoniae rnultiresistante aux antibiotiques. Presse Med 1979;8:872. 92. Nguyen J. Bismuth R. Gallinari C, Grosset J. Geslin P. Multiply resistant type 23 Streptococcus pneumoniae: an outbreak among elderly institutionalized patients [abstract no 513]. In: Program and abstracts of the 30th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology. 1990: 171. 93. O'Donnell ED, Alter KE, Frenkel LD. Postoperative infection caused by an unusual serotype of Streptococcus pneumoniae associated with multiple drug resistance. J Clin Microbiol 1982; 15:967-8. 94. Ramsay A. Meningitis secondary to multiply resistant Streptococcus pneumoniae. J Fam Pract 1982: 14:1041-4. 95. Lapointe JR. Joncas JH. Meningitis in a Canadian infant due to pneumococcus resistant to penicillin and chloramphenicol. J Pediatr 1983; 103:580-2. 96. Pallares R. Pneumococcal antimicrobial resistance: the problem in Spain [abstract no 311]. In: Program and abstracts of the 5th European Congress of Clinical Microbiology and Infectious Diseases. 1991:56. 97. Marton A. Pneumococcal antimicrobial resistance: the problem in Hungary [abstract no 312]. In: Program and abstracts of the 5th European Congress of Clinical Microbiology and Infectious Diseases. 1991:56. 98. Tomasz A. Antimicrobial resistance in Streptococcus pneumoniae [abstract no 313]. In: Program and abstracts of the 5th European Congress of Clinical Microbiology and Infectious Diseases. 1991:57.
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67.
Pneumococcal Drug Resistance: Overview
ANTIMICROBIAL RESISTANCE IN STREPTOCOCCUS PNEUMONIAE
Antimicrobial Resistance in Streptococcus pneumoniae: An Overview Peter C. Appelbaum
From the Department of Pathology. Hershey Medical Center. Hershey, Pennsylvania
History of Pneumococcal Resistance to Antimicrobial Agents Although mutants of Streptococcus pneumoniae resistant to penicillin G were selected soon after this drug was introduced [I], clinical resistance to penicillin was not reported until 20 years later, when investigators in Boston noted penicillin MICs in the intermediate-resistance range (0, 1-0.2 Jig/ mL) for two of 200 strains but failed to recognize the significance of that resistance [2]. Hansman and co-workers were the first both to report and to realize the significance of penicillin resistance in S. pneumoniae. Their first resistant strain, with a penicillin MIC of0.6 Jig/mL, was isolated in Australia from the sputum of a patient with hypogammaglobulinemia [3]. Subsequently, resistant strains were identified in New Guinea and Australia [4-6], where the proportion of strains resistant rose from 12% of 521 in 1970 to 33% of 57 in 1980 [6, 7]. After the initial reports by Hansman and colleagues, anecdotal descriptions of meningitis due to penicillin-resistant pneumococci began to appear in the literature; most strains showed intermediate resistance. All patients were ~5
Received 21 October 1991; revised 26 December 1991. This article is part ofa series of papers presented at a symposium entitled "Antimicrobial Resistance in Streptococcus pneumoniae" at the 5th European Congress of Clinical Microbiology and Infectious Diseases in Oslo in September 1991. Reprints or correspondence: Dr. Peter C. Appelbaum. Department of Pathology, Division ofClinical Microbiology, Hershey Medical Center, P.O. Box 850, Hershey, Pennsylvania 17033.
Clinical Infectious Diseases
1992;15:77-83
© 1992 by The University of Chicago. All rights reserved.
1058-4838/92/1501-0007$02.00
years of age, and most were debilitated by a concomitant systemic disease [8-13]. In 1977 pneumococci resistant to penicillin began to appear in Durban, South Africa, among patients with meningitis, bacteremia, pneumonia, and empyema. All isolates were highly resistant to penicillin (MIC, 4-8 Jig/mL) and were also resistant to chloramphenicol; they exhibited differing degrees of resistance to other penicillins and cephalosporins [14]. In 1978 Jacobs and co-workers reported on the prevalence of penicillin resistance in Johannesburg, South Africa [15]. Both intermediately resistant and fully resistant strains were encountered. Strains resistant to ,B-Iactam antibiotics, erythromycin, clindamycin, tetracycline, and chloramphenicol were isolated from 128 carriers and were responsible for bacteremia. Strains from 40 other carriers were resistant to penicillin alone; to penicillin and chloramphenicol; or to penicillin, chloramphenicol, and tetracycline. Strains were divided into six groups on the basis of serotypes and resistance patterns. One group was resistant to all antimicrobial agents tested except for rifampin, fusidic acid, vancomycin, bacitracin, and novobiocin [15]. The problem of penicillinresistant pneumococci in South Africa continues. In the United States the first infection due to penicillin-resistant pneumococci (MIC, 0.25 Jig/mL) was reported in 1974. This infection-a case of meningitis-developed in a patient with sickle cell anemia [8]. Soon after 1974, penicillin-resistant pneumococci were reported worldwide. At first, these strains were especially prom-
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Clinical resistance to penicillin in Streptococcus pneumoniae was first reported by researchers in Boston in 1965; subsequently, this phenomenon was reported from Australia (1967) and South Africa (1977). Since these early reports, penicillin resistance has been encountered with increasing frequency in strains of S. pneumoniae from around the world. In South Africa strains resistant to penicillin and chloramphenicol as well as multiresistant strains have been isolated. Similar patterns of resistance have been reported from Spain. Preliminary evidence points to a high prevalence of resistant pneumococci in Hungary, other countries of Eastern Europe, and some countries in other areas of Europe, notably France. In the United States most reports of resistant pneumococci come from Alaska and the South, but resistance is increasing in other states and in Canada. Pneumococcal resistance has also been described in Zambia, Japan, Malaysia, Pakistan, Bangladesh, Chile, and Brazil; information from other African, Asian, and South American countries is not available. The rising prevalence of penicillin-resistant pneumococci worldwide mandates selective susceptibility testing and epidemiological investigations during outbreaks.
Appelbaum
78
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Table 1. Surveys of resistance to penicillin among isolates of S. pneumoniae. Location. year(s)
Source of isolates
Reference
Clinical Not given
[6] [16]
65/521 (12.5) 7/49(14.3) 181/1,016 (17.8) 19/57 (33.3) 3/233 (1.3)
Clinical. carriers Carriers Not given Clinical Clinical
[6] [5] [16] [7] [17]
28/318 (8.8) 20/200 (10.0) 51/100 (51.0) 57/159 (35.8) 21/147 (14.3) 48/91 (52.7) 231/521 (44.3)
Clinical Clinical Clinical Carriers Clinical Clinical Clinical
[18] [19] [20] [21] [22] [23] [24]
3/100 (3.0) 3/133 (2.3) 14/206 (6.8)
Clinical Clinical Clinical, carriers
[25] [26] [27]
4/1,266 (0.3) 203/3,847 (5.3) 166/1,329 (12.5) 28/1,933 (1.5)
Clinical Clinical, carriers Clinical, carriers Clinical
[28] [29] [29] [30]
4/100 (4.0) 8/30 (26.7) 78/135 (57.8) 4/16 (25.0)
Clinical, carriers Clinical Clinical, carriers Carriers
[3 I] [32] [33] [34]
1/866 2/150 4/100 6/431 12/484 4/488
Clinical Clinical Clinical Clinical, carriers Clinical, carriers Clinical
[35] [36] [37] [38] [38] [39]
22/880 (2.5) 25/676 (3.7) 39/406 (9.6) 65/229 (28.4)
Clinical Clinical Clinical Clinical
[40] [40] [40] [41]
168/270 (62.2) 110/1,316 (8.4) 21/178 (11.8) 249/3.568 (7.0) 73/302 (24.2) 156/1,100(14.2) 1/39 (2.6)
Carriers Carriers Carriers Clinical Carriers Clinical Carriers
[15] [42] [43] [44] [45] [46] [47]
1/100(1.0) 4/461 (0.9) 106/1,809 (5.9) 49/176 (27.8)
Clinical Clinical Clinical, carriers Clinical
[48] [49] [50] [51]
4/1,098 (0.4) 27/2,427(1.1)
(0.1) (1.3) (4.0) (1.4) (2.5) (0.8)
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Australasia Australia 1967-1970 1971-1976 New Guinea 1969-1970 1970 1971-1974 1978 New Zealand. 1981-1986 Europe/Middle East Spain 1979-1981 1978-1981 1983-1984 1987 1984-1986 1984-1986 1989 Switzerland 1976-1977 1984-1985 West Germany, 1979-1980 France 1980-1986 1987-1989 1990 Belgium. 1983-1988 Poland 1969-1970 1975 Hungary. 1988-1989 Romania. I991 England 1977t 1981 1987 1987-1988 1988-1989 Northern Ireland, 1986 Iceland 1989 1990 1991 Israel. 1981-1982 Africa South Africa 1977 1977-1978 1981 1983-1986 1986 1990 Zambia. 1986 Asia Japan 1974-1975 1979-1982 1984-1989 1991
No. of isolates resistant*/no. tested (% resistant)
79
Pneumococcal Drug Resistance: Overview
ClD 1992: 15 (July)
Table 1. (Continued) Location. year(s)
Source of isolates
Reference
5/249 (2.0)
Clinical
[52]
7/79 (8.9) 8/87 (9.2) 6/51(11.8)
Clinical Clinical Clinical
[53] [54] [55]
39/178 (21.9) 25/150 ( 16.7)
Clinical Clinical. carriers
[56] [57]
2/200 (1.0) 19/131 (14.5) 6/50 (12.0) 1/50 (2.0) 3j169 (1.8) 1/98 ( 1.0) 6/243 (2.5) 16/103 (15.5) 16/523 (3.1) 9/62(14.5) 13/222 (5.9) 9/215 (4.2) 5/200 (2.5) 21/258 (8.1)
Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Clinical Carriers Clinical Clinical Clinical Clinical
[2] [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] [70]
10/294 (3.4) 17/139 (12.2) 22/197 {I 1.2) 15/284 (5.3) 40/155 (25.8) 280/5,479 (5. I) 20/487 (4.1)
Clinical, carriers Clinical Clinical Clinical Carriers Clinical Clinical
[71 ] [72] [73] [74] [74] [75] [76]
143/6.000 (2.4) 4/117 (3.4) 6/468 (1.3)
Clinical Not given Clinical
[77] [16]
[78]
* MIC, ~O.I /oLg/mL. : Includes Scotland as well.
inent in New Guinea, Israel, Poland, Spain, and South Africa as well as in the U.S. states of New Mexico, Oklahoma, Massachusetts, Colorado, and Alaska [16-78]. Published surveys of pneumococcal resistance to penicillin are summarized in table 1 and figure 1. Reports of penicillin-resistant pneumococci from African countries other than South Africa (e.g., Nigeria, Kenya, and Zambia) are scanty [47, 79, 80, 82], and more data are required before prevalence and distribution can be accurately defined. In Japan the incidence of penicillin-resistant pneumococci increased from ~l.o% during 1974-1982 to 5.9%27.8% during 1984-1991 [48-51]. Resistance to penicillin in S. pneumoniae has also been described in Malaysia, Pakistan, and Bangladesh [52-55]. Data from other Asian countries are inadequate. In Europe, Spain is the focus of penicillin-resistant pneu-
mococcal strains, with patterns mirroring those in South Africa [18-24]. The incidence of penicillin-resistant pneumococci in Spain rose from 6%in 1979 to 44% in 1989 [24]. A similar increase in the rate of resistance-from 0.3% in 1980-1986 to 5.3% in 1987-1989 and 12.5%in 1990-was observed in France [28, 29]. Moreover, the incidence of penicillin-resistant pneumococci in Iceland rose from 2.5% in 1989 to 9.6% in 1991 [40]. Recent reports of penicillin resistance in more than 50% of pneumococcal strains from Hungary [33] and in 25%of strains from Romania [34] may indicate foci of resistance in those countries and possibly in other countries of Eastern Europe and the former Soviet Union. Early anecdotal reports of penicillin resistance from Poland and Romania [31, 32, 81] support the existence of such foci. The first published report of penicillin-resistant pneumococci in South America came from Chile in 1987 [56]; a
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Asia (Continuedy Malaysia. 1984-1985 Pakistan 1989 1986-1989 Bangladesh. 1989-1991 South America Chile. 1983-1985 Brazil. 1989-1990 United States Boston. 1964-1965 New Mexico. 1972 Boston. 1972-1973 U.S.. 1976-1977 Pittsburgh, 1978 Denve~ 1975-1979 Madison. WI. 1978 Oklahoma City. 1977-1978 Detroit. 1978-1980 Denver. 1980 Houston. 1981 Denver. 1981 Atlanta. 1981 Dallas. 1981-1983 Veterans Administration hospitals. 1981-1984 Denver. 1984 Alaska. 1980-1984 Alaska. 1980-1986 Alaska. 1987 U.S .. 1979-1987 U.S.. 1987-1988 Canada Alberta. 1974-1976 Montreal, 1977-1978 Canad~ 1984-1986
No. of isolates resistant* /no. tested (% resistant)
80
Appelbaum
CID 1992; 15 (July)
subsequent report from Brazil [57] documented a similarly high rate of penicillin resistance in that country. The prevalence of antibiotic-resistant pneumococci in other South American countries is unknown at present. The level of resistance to penicillin among pneumococcal strains in Canada remains low [16, 77, 78]. In the United States, nationwide rates of penicillin resistance were reported as 4.1%-5.1% for 1987-1988 [75, 76]. Of all U.S. states, Alaska has had the highest rate of pneumococcal resistance to penicillin (25.8%) [73. 74]. It is extremely important in the examination of data from surveillance reports such as those detailed above to realize that strains have been isolated from different sources, different hospitals, and different cities in the same country. Thus the data are representative only of a specific population group.
Pneumococcal Resistance to Multiple Drugs Pneumococcal resistance to penicillin may occur either on its own or in combination with resistance to other antimicrobial agents. Resistance to antibiotics of at least three different groups has been defined as multiple resistance [15, 82]. In South Africa multiple resistance soon followed the original description of resistance to penicillin and chlorampheni-
col in 1977 [14, 15]. The first multiresistant strain-isolated from the sputum ofa patient with pneumonia-was resistant to penicillin, tetracycline, erythromycin, clindarnycin, trimethoprim-sulfamethoxazole, and chloramphenicol [15, 83]. In an investigation at six Johannesburg hospitals, 56% of 315 pneumococci isolated from carriers were multiresistant, as were 15% of 180 strains from carriers in Durban [42]. Although the prevalence of multiple resistance among pneumococcal isolates from hospitalized carriers in South Africa remains high, infections caused by these isolates are relatively uncommon [44, 82]. After the emergence of multiresistant pneumococci in South Africa, a high prevalence of these organisms was documented in Spain (table 1). The epidemiological pattern of multiresistant pneumococci in South Africa and Spain was initially similar (i.e., occurrence among hospitalized children receiving antibiotics); however, disease caused by multiresistant S. pneumoniae is now a significant problem in both children and adults in Spain [84]. Strains resistant to penicillin, tetracycline, and chloramphenicol have been described in Britain, and strains whose multiple resistance includes trirnethoprim-sulfamethoxazole and erythromycin have been isolated from carriers as well as from patients in that country [38, 85-87]. Multiresistant strains have been reported to the Central Public Health Labo-
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Figure 1. Worldwide prevalence and distribution of penicillin-resistant S. pneurnoniae. White areas represent countries in which prevalence is unknown. Information on countries not listed in table I and most other data are from [82].
CID 1992; 15 (July)
Pneumococcal Drug Resistance: Overview
Africa, Asia, Eastern Europe, the former Soviet Union, and South America.
COCCI III
References I. Eriksen KR. Studies on induced resistance to penicillin in a pneumococcus type I. Acta Pathol Microbiol Scand 1945;22:398-405. 2. Kislak JW. Razavi LMB, Daly AK, Finland M. Susceptibility ofpneumococci to nine antibiotics. Am J Med Sci 1965;250:261-8. 3. Hansman D. Bullen MM. A resistant pneumococcus [letter]. Lancet
1967;2:264-5. 4. Hansman D. Glasgow H. Sturt J. Devitt HL. Douglas R. Increased resistance to penicillin of pneumococci isolated from man. N Engl J Med 1971;284: 175-7. 5. Hansman D. Type distribution and antibiotic sensitivity of pneumococci from carriers in Kiriwina, Trobriand Islands (New Guinea). Med J Aust 1972;2:771-3. 6. Hansman D. Devitt L. Miles H. Riley I. Pneumococci relatively insensitive to penicillin in Australia and New Guinea. Med J Aust
1974;2:353-6. 7. Gratten M. Naraqi S. Hansman D. High prevalence of penicillin-insensitive pneumococci in Port Moresby. Papua New Guinea. Lancet
1980;2: 192-5.
Serotypes of Resistant Pneumococcal Strains The three countries with the highest reported incidence of penicillin-resistant pneumococci are South Africa, Spain, and Hungary. South African isolates belong predominantly to serotypes 6, 14, 19, and 23 [46]. In Spain serotypes 6,9, 19, and 23 are the commonest isolates from blood cultures; resistant isolates from the CSF are mainly of serotypes 6, 9, and 23; and isolates from the lungs are most often of serotypes 6,9, 14, 19, and 23 [96]. In Hungary resistant isolates belong to serotypes 19A, 6B, and 23F [97]. In France, where the problem of penicillin-resistant pneumococci has become severe during the past few years, serotypes 19, 23, 14, and 6 predominate [29]. Molecular studies have shown that the resistant serotype 23F probably spread from Spain to France and the United States [29, 98].
Conclusions Resistance to penicillin among strains of S. pneumoniae is now widespread and is rapidly increasing all over the world. Serotyping and analyses of other epidemiological markers reveal that a specific strain of resistant S. pneumoniae may spread from country to country and even from one continent to another. Recognition of this problem mandates susceptibility testing of pneumococcal isolates from blood, CSF, and other normally sterile body fluids; isolates from the ears and eyes may also need to be tested. Epidemiological investigations and measures designed to lower rates of carriage are necessary in areas with high rates of pneumococcal resistance to penicillin. The optimal choice of therapy for infections caused by penicillin-resistant pneumococci depends on the strain's specific susceptibility pattern. More information is necessary on the prevalence of penicillin-resistant pneumo-
8. Naraqi S. Kirkpatrick GP. Kabins S. Relapsing pneumococcal meningitis: isolation ofan organism with decreased susceptibility to penicillin G. J Pediatr 1974:85:671-3. 9. Howes VJ. Mitchell RG. Meningitis due to relatively penicillin-resistant pneumococcus. BMJ 1976; I :996. 10. Paredes A Taber LH. Yow MD. Clark D. Nathan W. Prolonged pneumococcal meningitis due to an organism with increased resistance to penicillin. Pediatrics 1976;58:378-81. II. Mace JW. Janik OS. Sauer RL. Quilligan JJ Jr. Penicillin-resistant pneumococcal meningitis in an immunocompromised infant [letter]. J Pediatr 1977:91 :506-57. 12. Cates KL. Gerrard JM. Giebink GS. et al. A penicillin-resistant pneumococcus. J Pediatr 1978:93:624-6. 13. lyer PV. Kahler JH. Jacobs NM. Penicillin-resistant pneumococcal meningitis [letter]. Pediatrics 1978;61: 157-8. 14. Appelbaum Pc. Bhamjee A Scragg IN. Hallett AF. Bowen AJ. Cooper RC. Streptococcus pneumoniae resistant to penicillin and chloramphenicol. Lancet 1977;2:995-7. 15. Jacobs MR, Koornhof HJ. Robins-Browne RM. et al. Emergence of multiply resistant pneumococci. N Engl J Med 1978:299:735-40. 16. Ahronheim GA. Reich B, Marks MI. Penicillin-insensitive pneumococci: case report and review. Am J Dis Child 1979: 133:187-91. 17. Heffernan H. Antimicrobial susceptibility of clinically-significant Streptococcus pneumoniae isolates. N Z Med J 1987:100:327. 18. Casal J. Antimicrobial susceptibility of Streptococcus pneunioniae: serotype distribution of penicillin-resistant strains in Spain. Antimicrob Agents Chemother 1982:22:222-5. 19. Linares J. Garau J, Dominguez C. Perez JL. Antibiotic resistance and serotypes of Streptococcus pneumoniae from patients with community-acquired pneumococcal disease. Antimicrob Agents Chemother
1983:23:545-7. 20. Latorre C. Juncosa T, Sanfeliu I. Antibiotic resistance and serotypes of 100 Streptococcus pneumoniae strains isolated in a children's hospital in Barcelona. Spain. Antimicrob Agents Chemother 1985:28:357-9. 21. Perez JL. Linares J. Bosch J, Lopez de Goicoechea MJ. Martin R. Antibiotic resistance of Streptococcus pneumoniae in childhood carriers [letter]. J Antimicrob Chemother 1987: 19:278-80. 22. Pallares R, Gudiol F. Linares .I. Viladrich PF. Bacteremic pneumonia caused by penicillin-resistant pneumococci [letter]. N Engl .I Med
1988;318: 124.
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ratory in London from 14 of 15 health regions in England, Wales, Scotland, and Ireland [87]. The number ofpneumococcal strains resistant to three or more antimicrobial agents increased from two in 1984to 40 in 1987 [87]. The predominant group in whom multiresistant pneumococci are found in the United Kingdom consists of elderly hospitalized patients receiving multiple antibiotics for acute exacerbations of chronic bronchitis [86, 88]. Four of 200 pneumococcal strains isolated in Italy during 1982 were resistant to three different antibiotic groups [89]. Multiresistant strains have also been isolated in France [28, 29, 90-92] and Belgium [30]. Recent findings suggest a problem with multiple antibiotic resistance in Hungary [33], Romania [34], and Pakistan [53, 54]. In the United States multiresistant pneumococci were responsible for an outbreak of community-acquired pneumonia in Denver in 1981 [66]. Subsequently, multiresistant strains were isolated in Ohio [93], Vermont [94], and New York [71]. The first multiresistant Canadian isolate was described in 1983 [95].
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Pneumococcal Drug Resistance: Overview
