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Antimicrobial Resistance Among Neonatal Pathogens in Developing Countries

Thaver, Durrane MBBS, MSc; Ali, Syed Asad MBBS, MPH; Zaidi, Anita K. M. MBBS, SM

Pediatric Infectious Disease Journal: January 2009 - Volume 28 - Issue 1 - pp S19-S21
doi: 10.1097/INF.0b013e3181958780
Supplement

Introduction: Knowledge of antimicrobial resistance and trends in resistance patterns among major pathogens causing infections in young infants (up to 90 days of life) is an important component of developing community-based management strategies. Hospital-based data suggest alarming rates of resistance to ampicillin and gentamicin, the first-line antimicrobial agents recommended by WHO for treatment of serious infections in young infants.

Methods: We searched the literature published since 1990 for studies from developing countries reporting resistance among serious community-acquired infections (including sepsis, pneumonia, and meningitis) in young infants.

Results: Only 10 relevant reports were retrieved. Among the 3 major pathogens studied (Escherichia coli, Staphyloccoccus aureus, and Klebsiella species), a high proportion of E. coli were ampicillin (72%) and cotrimoxazole (78%) resistant; 19% were resistant to third generation cephalosporins. Among Klebsiella species, almost all were resistant to ampicillin, 45% to cotrimoxazole, and 66% to third generation cephalosporins. Resistance to gentamicin was low among E. coli (13%), but much higher among Klebsiella species (60%). Methicillin resistance S. aureus (MRSA) was rare (1 of 33 isolates) but 46% were resistant to cotrimoxazole.

Conclusions: Antimicrobial resistance data for infections in young infants from community-based studies were extremely limited. Significant resistance, in particular to cotrimoxazole among all pathogens, and to gentamicin and third generation cephalosporins among Klebsiella and emerging resistance in E. coli is cause for concern. Limited data pose a challenge in devising simple community-based management strategies. Further studies from different developing country regions are needed to determine prevalence of resistant strains, as well as assess regional and time trends.

From the Department of Pediatrics and Child Health, Aga Khan University, Karachi, Pakistan.

Address for correspondence: Anita K. M. Zaidi, Department of Paediatrics and Child Health, Aga Khan University, Karachi, Pakistan. E-mail: anita.zaidi@aku.edu.

Information regarding antimicrobial resistance among bacteria-causing infections in communities is essential for developing appropriate management strategies. In addition, the sustainability of community-based management strategies depends on monitoring changes in the etiology as well as resistance patterns of serious infections over time. Unfortunately, there is a paucity of information on resistance patterns of community-acquired infections in neonates and young infants in developing countries, owing to lack of appropriate laboratory and susceptibility testing facilities and challenges of conducting studies of etiology of serious infections in community settings.1,2

Hospital-based data show alarming rates of resistance to ampicillin and gentamicin among common pathogens causing neonatal sepsis (71% of Klebsiella and 50% of Escherichia coli are reportedly resistant to gentamicin), suggesting that the WHO recommended ampicillin and gentamicin combination for treatment of neonatal sepsis may no longer be effective in treating many newborns with sepsis.3

This review summarizes available data on antimicrobial resistance among common pathogens causing infections in neonates and young infants seen in community settings in developing countries–namely Klebsiella species, E. coli, and S. aureus.

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METHODS

To identify studies documenting antimicrobial resistance in pathogens causing early onset or community-acquired neonatal sepsis, we searched PubMed database (date of last search May 7, 2007) from 1990 onward, using the words infant*, newborn*, neonat*, with resistance, resistant, susceptibility, sensitiv*, and infection*, bacter*, sepsis, septic*, meningitis, pneumonia, along with communit* or early. In addition, antimicrobial resistance or antibiotic resistance along with neonate was used. The search was combined with the names of all middle and low income countries, as defined by the World Bank.4 Titles, abstracts, and/or full texts of studies obtained were screened. The search was supplemented with studies identified in other searches for this review series, as well as articles in the author's collection. Erroneous or inconsistent data were excluded. The analysis was restricted to the post 1990 period, owing to expected changes in resistance patterns over time making older data irrelevant. Resistance data for pathogens causing early onset sepsis (ie, within the first week of life) were included where available, as infections occurring during this period are commonly considered to be of maternal origin.5

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RESULTS

Only 10 reports, including 2 unpublished works6–13; (Bhutta ZA 2005, unpublished data; Zaidi AKM 2008, unpublished data) contributed resistance data. Characteristics of these studies are presented in Table 1 6–13; (Bhutta ZA 2005, unpublished data; Zaidi AKM 2008, unpublished data). Two studies provided resistance data for early onset sepsis or meningitis.7,10 Five other reports used criteria to screen community-acquired infections8,9,12; (Bhutta ZA 2005, unpublished data; Zaidi AKM 2008, unpublished data), and only 2 of these reports were known to include data from predominantly home-born babies12; (Zaidi 2008, unpublished data).

The time trends in resistance rates are difficult to interpret, since data available for 1991 to 1995 were particularly limited (Table 2). Overall, methicillin resistant S. aureus (MRSA) did not appear to be a problem in these limited data (1 MRSA among 33 isolates in total). In data obtained from 1996 to 2007, nearly half of S. aureus isolates were resistant to cotrimoxazole. Nearly 90% of these isolates were obtained from a single African study done in the out-patient setting.11 However, a similar proportion was also found to be resistant to cotrimoxazole among remaining isolates from other regions [12 from Pakistan (Zaidi 2008, unpublished data; Bhutta ZA 2005, unpublished data) and 1 from Philippines12].

Available data (Table 2) suggest that a high proportion of E. coli isolates were resistant to cotrimoxazole (78%) and ampicillin. Among 12 E. coli isolates reported during the period of 1991 to 1995, only 1 was ampicillin-resistant (8%), but among 105 isolates from the 1996 to 2007 period, 76 (72%) exhibited resistance to ampicillin. Resistance to gentamicin was low (13%) among E. coli. However, 72 of 121 isolates (60%) Klebsiella were gentamicin resistant. Most Klebsiella (66%) were also resistant to third generation cephalosporins and emerging resistance among E. coli (19%) was also noted.

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DISCUSSION AND CONCLUSIONS

The review underscores the paucity of data regarding resistance patterns among major pathogens causing infections in newborns and young infants in community settings in developing countries. Most studies on microbial etiology report pathogens but do not report resistance patterns. Such limited data preclude firm conclusions, and indicate the urgent need for further studies as well as establishment of infection surveillance and antimicrobial resistance monitoring and reporting systems in developing countries.

The data available suggest, however, that in contrast to hospital settings, resistance rates may not be as high in community-acquired infections. Resistance to gentamicin is much lower than that reported from hospital-based studies,3 and the rare occurrence of MRSA among community-acquired infections is notable and in stark contrast to hospital-based studies from developing countries, where MRSA is now a major concern.3 E. coli resistance to third generation cephalosporins was also less common compared with figures reported from hospital-based studies.3

Cotrimoxazole is an oral agent in widespread use in the management of acute respiratory infections in national pneumonia control programs in many developing countries. As the data here show, high-level resistance is now common among community isolates of E. coli and S. aureus. Overall, 45% of Klebsiella isolates were resistant to cotrimoxazole; however, recent community-based data from Pakistan (Zaidi AKM 2008, unpublished data) show rates as high as 83%.

Of particular concern is the high level of resistance reported among Klebsiella, 60% of the isolates showing resistance to gentamicin. Since Klebsiella are uniformly resistant to ampicillin, regimens containing ampicillin and gentamicin would not provide adequate coverage against most Klebsiella species.

Increasing resistance to third generation cephalosporins among Klebsiella and E. coli is also notable. Klebsiella and E. coli resistance is usually acquired via plasmid-mediated extended spectrum beta-lactamase (ESBL) production.14,15 Owing to the presence of other resistance-conferring genes on these transferable plasmids, such organisms are also often resistant to other drugs, including aminoglycoside antibiotics.15 Risk factors for acquiring ESBL organisms include heavy antibiotic use, including use of third generation cephalosporins.14,15 In a facility-based study of neonatal sepsis in India, 50% of babies with early onset gram negative sepsis were infected with ESBL producing bacteria16; however, the possibility of these being nosocomial, rather than maternally acquired infections cannot be ruled out. Further investigations are required to determine prevalence of ESBL and multidrug resistant Klebsiella and E. coli in young infants in community settings. Indeed, several studies of community-acquired urinary tract infections report that ESBL-mediated resistance among E. coli is now widespread.17–22

Although data are limited, antimicrobial resistance among community-acquired pathogens was higher than expected, especially the high level of ampicillin (72%) and ceftriaxone (19%) resistance reported in E. coli, and 60% gentamicin resistance among Klebsiella. However, the possibility that some isolates from early onset sepsis among hospital-born babies were in fact hospital rather than maternally-acquired, cannot be excluded. Additionally, many studies report microbiologic data without reporting clinical information on treatment and outcomes, which makes interpretation difficult.

The scarcity of data from community sources poses considerable challenges in devising optimal community-based antibiotic treatment guidelines for infections in young infants in developing countries. Moreover, ensuring rational antibiotic use, and preventing the spread of antimicrobial resistance is an important concern in implementing community-based antibiotic management strategies for serious infections in newborns and young infants. The critical gap in knowledge on newborn pathogens causing infections in home-born babies and their antimicrobial resistance patterns should be addressed soon if case-management guidelines for community management of serious infections in young infants are to be implemented at scale in developing countries where hospitalization of sick infants is often not feasible.

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Keywords:

neonatal infections; antimicrobial resistance; developing country; community

© 2009 Lippincott Williams & Wilkins, Inc.