- Email: [email protected]
Emerging Trends in Antibiotic Use in Neonates: New or Not-so-New Drugs for New Bugs
Emerging Trends in Antibiotic Use in Neonates: New or Not-so-New Drugs for New Bugs Marie Ambroise, MD, FAAP
Nosocomial sepsis is a major problem in neonatal intensive care units. Bacteria are becoming resistant to antibiotics that once were very effective against sepsis. Multidrug-resistant bacteria are increasing in incidence owing to mutations in their genome or through plasmid encoded genes that confer resistance. This article looks at the problem of resistance and discusses newer resistant bacteria such as extended spectrum βlactamase producing organisms as well as methicillin-resistant bacteria. Also reviewed are antibiotics now used to treat nosocomial infections such as carbapenems, linezolid, and vancomycin. Their mechanisms of action as well as side effects and benefits are discussed. Keywords: Nosocomial sepsis; Carbapenems; Extended spectrum β-lactamases; NICU; Antibiotic resistance; Antibiotic use
Sepsis is a very important problem in hospitals across the country. In fact, the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) has brought this to the forefront by implementing certain programs to bring awareness to this problem. In 2003, JCAHO set up a sentinel event alert whereby deaths associated with hospital-acquired infections are considered and reported as sentinel events. 1 They also organized an infection control panel that served to revise JCAHO infection control standards, which went into effect in 2005.1 These revised standards sought to encourage the development of hospital infection control programs that continually assess risk factors, study the epidemiological data, and enact effective prevention strategies.1 The newborn population is especially susceptible to sepsis because of poorly developed immune systems. Neonates have decreased T-cell function as compared to adults.2 There is decreased cytokine production, decreased natural killer cell cytotoxicity, diminished neutrophil migration, and diminished complement pathway activity.2 Therefore, they are at risk for developing sepsis at any time. Sepsis can occur early (first 3 days of life) and/or late (after 3 days of life). Neonatal intensive care unit (NICU) patients are often given a host of antibiotics to treat both proven and suspected cases of sepsis and other infections. These antibiotics may be started right at admission. Also, the tiniest premature infants may be exposed to several courses of antibiotics during their long hospital stays. Recently, there has been concern over resistant From the Pediatrix Medical Group of Florida, West Palm Beach, FL. E-mail: [email protected]. © 2009 Elsevier Inc. All rights reserved. 1527-3369/08/0901-0287$36.00/0 doi:10.1053/j.nainr.2008.12.008
bacterial strains emerging onto the NICU scene. More and more, NICUs have had to adjust their antibiotic regimens because some of the usual antibiotics used for sepsis treatment are becoming useless as the incidence of resistant bacteria rises. We are all familiar with prescribing ampicillin and an aminoglycoside like gentamicin for initial sepsis workups in the NICU. This combination is still appropriate for initial treatment for suspected neonatal sepsis.3 Ampicillin, as well as carbenicillin (Geocillin, Pfizer, New York, NY), ticarcillin (with clavulanic acid such as Timentin, GlaxoSmithKline, Middlesex, UK), and piperacillin (Pipracil, Wyeth-Ayerst, Madison, NJ), has greater activity against some gram-negative bacteria than penicillin G (PfizerPen, Pfizer).4 Ampicillin also has activity against enterococci, Listeria monocytogenes, Escherichia coli, salmonella species, and group A and B streptococci. It interferes with cell wall synthesis by inhibiting protein synthesis. Side effects include nonspecific rashes, elevated transaminases, creatinine elevation, alteration of intestinal flora, and diarrhea.5 Ampicillin and other penicillins like it are susceptible to destruction by β-lactamases, which are enzymes discussed later on in this paper.4 Aminoglycosides, which are bactericidal, are used for broad spectrum coverage of most gram-negative organisms. They work also by inhibiting protein synthesis. This occurs through ribosomal binding. Aminoglycosides were originally developed from Streptomyces species in the 1940s.4 Gentamicin (Garamycin, Schering-Plough, Kenilworth, NJ), which has been used in neonates since 1970,6 enters the bacterial cell and binds to the 30S subunit of the ribosome. Protein synthesis is inhibited and the bacterium is killed.4 Aminoglycosides work synergistically with penicillins.6 Although gentamicin is often used in NICUs as a first-line drug, it is important to remember that there are differences among the aminoglycosides. For example, amikacin
(Amikin, Bedford Laboratories, Bedford, OH) is a better choice for infections with Serratia sp and tobramycin (Nebcin, Lilly & Co, Indianapolis, IN) has the best antipseudomonal activity.5 Lastly, aminoglycosides achieve CSF concentrations of only 30% of serum levels in infants with meningitis.6 Currently, extended or once-a-day dosing of gentamicin is used in the NICU. Guidelines for this dosing method in neonates were determined from studies in the adult population and available pharmacokinetic data in preterm infants. The main rationale for extended dosing use is decreased toxicity. The two side effects of aminoglycoside therapy are nephrotoxicity and ototoxicity. The incidence of nephrotoxicity in adults ranges from 3% to 25%.6 Although an actual number is unknown, the incidence of ototoxicity can be as high as 25%.6 Aminoglycoside excretion depends on glomerular filtration. Although most is excreted, some of the filtered drug is reabsorbed in the proximal tubule, which then binds to the phospholipid membrane. This results in lysosomal release of cytotoxic material, which injures the nephron.6 Accumulation of aminoglycosides, and therefore drug concentration, is less when one large dose is given. The risk of toxicity is then lessened. Multiple studies have confirmed the improved pharmacokinetics in neonates. Extended dosing also has the advantage of increasing bacterial killing owing to the higher peak levels achieved with one single initial dose. Higher initial doses are needed in preterm infants as compared to term infants because a preterm infant has a higher volume of distribution (Vd). A higher initial dose affords a comparable maximum concentration (Cmax) of drug when compared to a term baby who receives a lower initial dose.6 Furthermore, there is a possible postantibiotic effect whereby persistent suppression of bacterial growth follows exposure to an antibiotic.6 However, no study has had the statistical power to confirm this benefit,5 nor to delineate the duration of the postantibiotic effect.6 Other side effects of aminoglycoside therapy very rarely include neuromuscular blockade.5 Although both ampicillin and gentamicin are still used relatively frequently for treating sepsis, antibiotics are and should be prescribed according to the bacterial prevalence and resistance patterns of each unit. As bacterial resistance to antibiotics becomes more of an issue, it is more important to know the resistance patterns of one's own NICU. Information on pattern resistance can usually be obtained from hospital microbiology laboratories. Bacteria may develop resistance to antibiotics in different ways. For example, aminoglycosides can develop resistance through plasmid-mediated enzyme production, which inactivates the drug.4 Penicillin resistance also follows this pattern where enzymatic inactivation occurs through β-lactam ring disruption.4 Another method of resistance is alteration of the target site, such as mutations in the penicillin-binding proteins (PBPs). This leads to decreased uptake of the drug. Organisms can lack the appropriate receptors needed for antibiotic binding.4 Also, alterations in metabolic pathways can circumvent the chemical reaction that the drug inhibits.4 Lastly, increased efflux can cause active pumping of drug out of cells.
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Resistant organisms may spread from colonized individuals and health care workers to patients because of poor infection control practices and poor hand hygiene. Ultimately, this leads to nosocomial infections. Nosocomial infections may affect more than two million individuals each year7. This is estimated to contribute to approximately 20 000 deaths per year.7 Nosocomial infections lead to increased hospital length of stay and increased morbidity and mortality. Neonatal intensive care units that have low nosocomial infection rates are those that have procedures and policies in place to decrease infection. These include good hand-washing protocols, the use of closed systems for suctioning, and limitations on line days, including peripheral intravenous lines. This contrasts to sites with high infection rates.8 Bacteria such as extended spectrum β-lactamase–producing organisms (ESBL), methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococcus (CONS), and vancomycin-resistant enterococci (VRE) are the most prevalent bacteria implicated in nosocomial infections. These microbes have developed resistance to multiple antibiotic classes. Newer antibiotics and antibiotic regimens must now be used to combat these illnesses. At the same time, strict antibiotic use and infection control measures must be implemented to prevent the newer antibiotics from also developing resistance.
Extended Spectrum β-Lactamases and Treatment As mentioned above, one of the mechanisms of drug resistance is the production of specialized enzymes. Extended spectrum β-lactamases are such enzymes that confer resistance to certain antibiotics. They were first recognized in the early 1980s and have since been increasing in prevalence and incidence. Several bacteria are able to produce ESBLs and they include E coli, Klebsiella pneumoniae, Citrobacter, Proteus, Pseudomonas, Salmonella, Serratia, and Enterobacter species. According to the Centers for Disease Control and Prevention (CDC), approximately 12% of Klebsiella species have ESBLs. Extended spectrum β-lactamases hydrolyze the β-lactam ring of β-lactam drugs, including penicillins, cephalosporins, carbapenems, and monobactams. These β-lactam antibiotics would normally bind to PBPs on the surface of the bacterium to exert their killing activity. There are usually several binding sites per bacterium and each has a different drug affinity that depends on cell wall structure.4 However, the binding of ESBLs to the β-lactam ring disrupts it, which renders the antibiotic ineffective. Extended spectrum β-lactamases are produced from gene expression on chromosomes and plasmids. Chromosomalmediated ESBLs can sometimes be induced with the use of cephalosporins.9 Plasmids, which are extrachromosomal pieces of DNA, can readily transfer between bacterial species and are the most common way of spreading resistance. They are widespread between both gram-positive and -negative organisms. The patient with ESBL gastrointestinal colonization, on a ventilator with prolonged hospitalization, is at high risk for invasive nosocomial ESBL infection because of several factors.
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Again, one factor is poor infection control. Those who are asymptomatic, including health care workers and other patients, act as reservoirs for the disease which can then be transmitted from patient to patient through poor hand hygiene.10 Patients with central catheters and patients who have undergone abdominal surgery are also at increased risk for developing infections with ESBL bacteria. Another factor is the increased use of cephalosporins. Cephalosporin drugs can induce cephalosporinases, which are enzymes that confer resistance. Therefore, the CDC recommends limiting use of cephalosporins as well as implementing infection control measures such as contact isolation in patients with confirmed ESBL.11 Also, it is recommended that when ESBL is detected, all penicillins, cephalosporins, and aztreonam should be considered resistant despite results of in vitro studies. Extended spectrum β-lactamase infections may be treated with antibiotics containing β-lactamase inhibitors such as clavulanic acid and sulbactam. Clavulanic acid is naturally derived from Streptomyces, whereas sulbactam is a semisynthetic drug. The β-lactamase inhibitors are usually paired with penicillins or cephalosporins because alone they have little antimicrobial activity.9 β-Lactamase inhibitors bind to the catalytic site of the β-lactamase enzyme which prevents the inactivation of the β-lactam antibiotics.9 However, the activity of these inhibitors depends on which β-lactam antibiotic is paired with it. For example, although some E coli strains show resistance to certain combinations, they are still quite sensitive to piperacillin/tazobactam (Zosyn, Wyeth Pharmaceuticals, Inc, Philadelphia, PA).9 Carbapenems are also used to treat infections with ESBL bacteria as ESBLs remain susceptible.10 Carbapenems are structurally related to β-lactam antibiotics.4 However, their structure renders them resistant to β-lactamases. They have a very broad range of activity. Carbapenems are effective against streptococci, enterococci, pneumococci, methicillin-sensitive S aureus, gram-negative rods except stenotrophomonas. Two carbapenems are approved for use in neonates and they are imipinem/cilastin (Primaxin, Merck &Co, Inc, Whitehouse Stations, NJ) and meropenem (Merrem IV, AstraZeneca, London, UK). These antibiotics treat both aerobic and anaerobic bacteria. They bind via PBPs and disrupt the bacterial cell wall, which then kills the bacteria. Carbapenems also penetrate well into the cerebrospinal fluid. Clearance is related to renal function. There is limited clinical experience in their use on neonates but there are a few risks and side effects to consider. Primarily, carbapenems can cause diarrhea and vomiting. Allergic rashes, although rare, have been reported. There is also a risk of phlebitis at the site of injection. Imipenem can cause seizures in those with meningitis or those with preexisting central nervous system pathology. 12 Carbapenems can cause laboratory abnormalities, such as increased transaminases, eosinophilia, decreased platelet count, and increased creatinine.13 They can also induce cephalosporinases on gram-negative bacteria including Enterobacter, Pseudomonas, Citrobacter, and Acinetobacter. Lastly, they can increase the risk of superficial or invasive fungal disease because of their broad spectrum of activity.13
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Vancomycin, CONS, and Resistant Organisms Vancomycin (Vancocin, ViroPharma, Inc, Exton, PA) is another antibiotic frequently used in the NICU setting. It is a glycopeptide antibiotic first introduced in the 1960s. It works by inhibiting cell wall synthesis, cell wall permeability, and RNA synthesis. It has activity against gram-positive organisms including staphylococcal species, streptococcal species, enterococci, clostridium dificile, and diphtheroids. It is also active against listeria, actinomyces, and bacillus species.14 It works synergistically with aminoglycosides. Vancomycin is used in some NICUs as a first-line drug in the treatment of nosocomial sepsis especially when there is a high prevalence of resistant coagulase-negative staphylococci. In one study, the use of vancomycin in hospitals increased 20-fold in the years from 1981 to 1991.15 Vancomycin is used for treatment of severe gram-positive infections especially when methicillin resistance is suspected or when endemic. It is also an appropriate initial therapy for sepsis until susceptibility testing leads to adjustment to narrower spectrum antibiotics.
Resistance in Staphylcoccal Species Staphylococcus aureus is an important cause of infection in NICUs. It is the most common cause of nosocomial infection.16 The majority of S aureus strains throughout the world produce β-lactamases.9 More concerning is the growing number of MRSA.7 The method of resistance in that case is related to the transfer of the mecA gene, which codes for a PBP. This PBP acts as a substitute for other staphylococcal enzymes and triggers them to continue cell wall synthesis even when β-lactam antibiotics are in use.2 First reported in the late 1960s,17 the incidence has been increasing, and in some NICUs, MRSA has become endemic. Methicillin-resistant S aureus strains make up 55% of S aureus stains causing nosocomial infection according to 2001 data.17 This bacterium is resistant to all penicillin, cephalosporins, carbapenems, and all β-lactamase inhibitors.17 Infants may be colonized within 24 to 48 hours after birth and may experience infections of the skin, bloodstream, and gastrointestinal tract (necrotizing enterocolitis).17 Vancomycin remains the treatment of choice for MRSA. Coagulase-negative staphylococci are the most common cause of nosocomial infection.7,18 Coagulase-negative staphylococci are common flora of skin, nares, and ear canals.2 Approximately 5% of NICU patients will develop CONS infections.7 Infections can include meningitis, central line infections, and endocarditis. Risk factors for developing infection with CONS are low birth weight, mechanical ventilation, use of central catheters, use of intravenous lipids, and parenteral nutrition.7 This is likely due to widespread CONS colonization. A premature infant's skin is colonized early on in the course of their hospitalization. The CONS then invades their central lines and leads to bloodstream infections.7 Fortunately, such infections are rarely fulminant and the
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mortality rate from CONS is similar to noninfected neonates.19 Most CONS is resistant to penicillin because of penicillinases and, therefore, is considered resistant to cephalosporins as well.2 Because most nosocomial infection in the NICU is caused by CONS, studies and research aim to decrease the incidence. One of the potential ways being studied is through the use of prophylactic vancomycin.20 A meta-analysis in 2008 reviewed the use of antibiotic prophylaxis to reduce blood stream infections. Two studies were analyzed in the final meta-analysis because they were the only two that used prophylactic vancomycin as compared to a third study that used amoxicillin. The meta-analysis showed an 87% decrease in the incidence of sepsis compared with placebo or no treatment.20 The catheter-related infection rate decreased from 23% to 2.4%.20 Duration of catheter days and mortality showed no statistically significant difference in the treatment and nontreatment groups. Although there was an overall decrease in sepsis episodes, the insufficient evidence precludes the authors of that paper from recommending the routine use of prophylactic vancomycin.20,21 Overuse of antibiotics, and in particular vancomycin, is a big concern in light of the fact that resistance is increasing. Since the late 1990s, concern has been increasing over detection of MRSA strains that are insensitive to vancomycin, which have affected certain adult populations.11 Vancomycin-resistant enterococcus (VRE) emerged in the late 1980s. According to the National Nosocomial Infection Surveillance System during the years from 1989 to 1993, the incidence of VRE has increased from 0.3% to 8%.22 There are several phenotypes and the two most common are VanA (resistant to vancomycin and teicoplanin; Targocid, SanofiAventis, Surrey, England) and Van B (resistant to vancomycin alone).11 According to the CDC, the incidence of resistant strains has increased in the time from 1995 to 2004.11 Vancomycin resistance occurs through plasmids or mutations.2 To date, only two antibiotics are licensed for use in neonates to treat VRE. They are linezolid (Zyvox, Pfizer) and quinupristin/ dalfopristin (Synercid, Monarch Pharmaceuticals, Bristol, TN). Linezolid is an oxazolidinone antibiotic whose mechanism of action involves inhibiting bacterial protein translation.23 It binds to the 23S subunit of the bacterial 50s ribosome to block protein translation. It is effective against VRE, S aureus, βstreptococcus, Enterococcus faecalis. It is generally bacteriostatic for staphylococci and enterococci in that it inhibits bacterial growth. However, it is bacteriocidal for streptococcal species.23 It is well distributed in body tissues and its clearance is higher in older children and adults than in neonates. However, clearance increases rapidly in the first postnatal week. Lower doses have been recommended in preterm infants owing to the slower systemic clearance in this age.23 Myelosuppression, demonstrated by anemia, pancytopenia, and thrombocytopenia, can occur as a side effect. It is recommended that complete blood counts be obtained weekly while the infant remains on linezolid. This drug is generally considered a last resort drug and its use is limited to prevent development of resistance. Although approved for use in neonates, there are few clinical studies and data on usage. There
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are reports of treatment success in infants with endocarditis and ventriculitis, and in adults. There are also reports of success in treating MRSA infections.23 Quinupristin is also used to treat VRE. It is a streptogramin antibiotic and is derived from Streptomyces as well. Its combination with dalfopristin targets the 50S subunit of the ribosome. Together they block both an early and late step in protein synthesis which leads to bactericidal activity. Resistance to this drug can happen but is largely uncommon.22 Side effects in the older population include arthritis, liver enzyme abnormalities, rash, and diarrhea.22 Although there are reports of its successful use in infants, there are no large-scale studies in neonates and its safety has not yet been established. In conclusion, what are the future challenges facing patients and caregivers in the NICU setting? Nosocomial infections will likely continue to be a growing concern as they are currently responsible for approximately half of NICU deaths after 2 weeks of age.7 As more bacteria develop resistance to available antibiotics, pharmaceutical companies will have to meet this challenge by developing newer drugs to combat these illnesses. Also, implementing better practices can have a big impact in preventing nosocomial infections. Handwashing, proper nutrition, good skin, respiratory, and vascular access care can potentially decrease infection.7 Lastly, and perhaps most important, it is necessary to develop a sense of teamwork where each health care provider sees a nosocomial infection as one infection too many and works to prevent them.
Appendix A. Case Report A 30 2/7–week premature male infant was born to a 42year-old gravida 4, para 0 mother. Her blood type was O positive, and prenatal laboratory results were negative with the exception of group B Streptococcus, which was unknown. The pregnancy course was complicated by a history of a positive PPD with a negative chest x-ray, insulin-dependent diabetes mellitus of 10 years duration, and a short, incompetent cervix with a cerclage in place. The mother was admitted to the hospital 45 days before delivery for management of her incompetent cervix. At the time of her admission, the fetus was 24 weeks' gestation. It is unknown whether or not the mother received antenatal steroids. She remained hospitalized and her membranes ruptured 15 days before delivery. During that time, she received ampicillin and erythromycin to prevent infection. The antibiotics were stopped 1 day before a caesarean delivery which was performed for nonreassuring fetal status. Apgar scores were 8.9. The baby was admitted to the NICU for further management. On admission, the baby was started on ampicillin and gentamicin for a rule out sepsis. His initial complete blood count (CBC) was significant for 12 segmented neutrophils with 18 band forms, yielding an immature-to-total neutrophil ratio of 0.6. His second CBC obtained approximately 12 hours after birth had 53 segmented neutrophils with 13 band forms for an immature-to-total neutrophil ratio of 0.19. The bandemia resolved by the third CBC.
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However, the mother became febrile with respiratory symptoms shortly after delivery. Her blood culture was reported positive for ESBL Klebsiella and she was treated for both pneumonia and bacteremia. The baby was treated with ampicillin and gentamicin. Zosyn was added when the mother's infection with Klebsiella was reported. In total, the baby was treated with antibiotics for 12 days. His blood culture remained negative and he is preparing for homegoing.
12. 13.
14. 15.
References 1. Gourley D. Joint Commission places infection control under the microscope. FOCUS. J Respir Care Sleep Med. 2004. 2. Ryan K, Kenneth J. Sherris Medical Microbiology An Introduction to Infectious Disease. Norwalk CT: Appleton & Lange; 1994. 3. Isaacs D. Unnatural Selection: reducing antibiotics resistance in neonatal units. Arch Dis Child Fetal Neonatal Ed. 2006;91:F72-F74. 4. Katzung B. Basic and Clinical Pharmacology. Norwalk CT, Appleton & Lange. 1995; 671–692, 699–703. 5. Remington J, Klein J. Wilson & Bakers Infectious Disease of the Fetus and Newborn Infant. 6th ed. Elsevier; 2006. 6. Young T. Aminoglycoside therapy in neonates: with particular reference to gentamicin. Neoreviews. 2002;3:243. 7. Polin RA, Saiman L. Nosocomial Infection in the Neonatal Intensive Care Unit. Neoreviews. 2003;4:e81-e88. 8. Bloom B, Craddock A, Delmore P, et al. Reducing acquired infections in the NICU: observing and implementing meaningful differences in process between high and low acquired infection rate centers. J Perinatol. 2003;23:489-492. 9. Lee NLS, Yuen KY, Kumana CR. Beta lactam antibiotics and beta lactamase inhibitor combinations. JAMA. 2001;285:386-388. 10. Gupta A, Ampofo K, Rubinstein D, Saiman L. Extended spectrum B lactamase-producing Klebsiella pneumoniae
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11.
16. 17. 18.
19.
20.
21.
22.
23.
infections: a review of the literature. J Perinatol. 2003; 23:439-443. Seigel J, Rhinehart E, Jackson M, Chiarello L. Management of Multidrug-Resistant Organisms in Healthcare Settings. CDC; 2006. Young TE, Mangum B. Neofax. Thomson; 2008. Garges H, Alexander KA. Pharmacology review: newer antibiotics: imipenem/cilastin and meropenem. Neoreviews. 2003;4:364. Vancocin package insert Ena J, Dick R, Jones R, Wensel R. The epidemiology of intravenous vancomycin usage in a university hospital: a 10 year study. JAMA. 1993;269:598-602. MMWR. 2004; 53:322–323. Bracher D. Methicillin resistant Staphylococcus aureus in nurseries. Neoreviews. 2005;6:424-430. Sohn A, Garrett DO, Sinkowitz-Cochran R, et al. Prevalence of nosocomial infections in neonatal intensive care unity patients: results from the first national point-prevalence survey. J Pediatr. 2001;139:821-827. Stoll BJ, Hansen N, Fanaroff AA, et al. Late onset sepsis in very low birth weight neonates: the experience of NICHD Neonatal Research Network. Pediatrics. 2002;110:285-291. Lodha A, Furlan AD, Whyte H, Moore AM. Prophylactic antibiotics in the prevention of catheter-associated bloodstream bacterial infection in preterm neonates: a systematic review. J Perinatol. 2008;28:526-533. Clark R, Powers R, White R, Bloom B, Sanchez P, Benjamin Jr DK. Prevention and treatment of nosocomial sepsis in the NICU. J Perinatol. 2004;24:446-453. Manzella J. Quinupristin-dalfopristin: a new antibiotic for severe gram-positive infection. Am Fam Phys. 2001;11:1863. Garges H, Alexander KA. Pharmacology review: newer antibiotics: linezolid. Neoreviews. 2003;4:128.
VOLUME 9, NUMBER 1, www.nainr.com
Nosocomial sepsis is a major problem in neonatal intensive care units. Bacteria are becoming resistant to antibiotics that once were very effective against sepsis. Multidrug-resistant bacteria are increasing in incidence owing to mutations in their genome or through plasmid encoded genes that confer resistance. This article looks at the problem of resistance and discusses newer resistant bacteria such as extended spectrum βlactamase producing organisms as well as methicillin-resistant bacteria. Also reviewed are antibiotics now used to treat nosocomial infections such as carbapenems, linezolid, and vancomycin. Their mechanisms of action as well as side effects and benefits are discussed. Keywords: Nosocomial sepsis; Carbapenems; Extended spectrum β-lactamases; NICU; Antibiotic resistance; Antibiotic use
Sepsis is a very important problem in hospitals across the country. In fact, the Joint Commission on the Accreditation of Healthcare Organizations (JCAHO) has brought this to the forefront by implementing certain programs to bring awareness to this problem. In 2003, JCAHO set up a sentinel event alert whereby deaths associated with hospital-acquired infections are considered and reported as sentinel events. 1 They also organized an infection control panel that served to revise JCAHO infection control standards, which went into effect in 2005.1 These revised standards sought to encourage the development of hospital infection control programs that continually assess risk factors, study the epidemiological data, and enact effective prevention strategies.1 The newborn population is especially susceptible to sepsis because of poorly developed immune systems. Neonates have decreased T-cell function as compared to adults.2 There is decreased cytokine production, decreased natural killer cell cytotoxicity, diminished neutrophil migration, and diminished complement pathway activity.2 Therefore, they are at risk for developing sepsis at any time. Sepsis can occur early (first 3 days of life) and/or late (after 3 days of life). Neonatal intensive care unit (NICU) patients are often given a host of antibiotics to treat both proven and suspected cases of sepsis and other infections. These antibiotics may be started right at admission. Also, the tiniest premature infants may be exposed to several courses of antibiotics during their long hospital stays. Recently, there has been concern over resistant From the Pediatrix Medical Group of Florida, West Palm Beach, FL. E-mail: [email protected]. © 2009 Elsevier Inc. All rights reserved. 1527-3369/08/0901-0287$36.00/0 doi:10.1053/j.nainr.2008.12.008
bacterial strains emerging onto the NICU scene. More and more, NICUs have had to adjust their antibiotic regimens because some of the usual antibiotics used for sepsis treatment are becoming useless as the incidence of resistant bacteria rises. We are all familiar with prescribing ampicillin and an aminoglycoside like gentamicin for initial sepsis workups in the NICU. This combination is still appropriate for initial treatment for suspected neonatal sepsis.3 Ampicillin, as well as carbenicillin (Geocillin, Pfizer, New York, NY), ticarcillin (with clavulanic acid such as Timentin, GlaxoSmithKline, Middlesex, UK), and piperacillin (Pipracil, Wyeth-Ayerst, Madison, NJ), has greater activity against some gram-negative bacteria than penicillin G (PfizerPen, Pfizer).4 Ampicillin also has activity against enterococci, Listeria monocytogenes, Escherichia coli, salmonella species, and group A and B streptococci. It interferes with cell wall synthesis by inhibiting protein synthesis. Side effects include nonspecific rashes, elevated transaminases, creatinine elevation, alteration of intestinal flora, and diarrhea.5 Ampicillin and other penicillins like it are susceptible to destruction by β-lactamases, which are enzymes discussed later on in this paper.4 Aminoglycosides, which are bactericidal, are used for broad spectrum coverage of most gram-negative organisms. They work also by inhibiting protein synthesis. This occurs through ribosomal binding. Aminoglycosides were originally developed from Streptomyces species in the 1940s.4 Gentamicin (Garamycin, Schering-Plough, Kenilworth, NJ), which has been used in neonates since 1970,6 enters the bacterial cell and binds to the 30S subunit of the ribosome. Protein synthesis is inhibited and the bacterium is killed.4 Aminoglycosides work synergistically with penicillins.6 Although gentamicin is often used in NICUs as a first-line drug, it is important to remember that there are differences among the aminoglycosides. For example, amikacin
(Amikin, Bedford Laboratories, Bedford, OH) is a better choice for infections with Serratia sp and tobramycin (Nebcin, Lilly & Co, Indianapolis, IN) has the best antipseudomonal activity.5 Lastly, aminoglycosides achieve CSF concentrations of only 30% of serum levels in infants with meningitis.6 Currently, extended or once-a-day dosing of gentamicin is used in the NICU. Guidelines for this dosing method in neonates were determined from studies in the adult population and available pharmacokinetic data in preterm infants. The main rationale for extended dosing use is decreased toxicity. The two side effects of aminoglycoside therapy are nephrotoxicity and ototoxicity. The incidence of nephrotoxicity in adults ranges from 3% to 25%.6 Although an actual number is unknown, the incidence of ototoxicity can be as high as 25%.6 Aminoglycoside excretion depends on glomerular filtration. Although most is excreted, some of the filtered drug is reabsorbed in the proximal tubule, which then binds to the phospholipid membrane. This results in lysosomal release of cytotoxic material, which injures the nephron.6 Accumulation of aminoglycosides, and therefore drug concentration, is less when one large dose is given. The risk of toxicity is then lessened. Multiple studies have confirmed the improved pharmacokinetics in neonates. Extended dosing also has the advantage of increasing bacterial killing owing to the higher peak levels achieved with one single initial dose. Higher initial doses are needed in preterm infants as compared to term infants because a preterm infant has a higher volume of distribution (Vd). A higher initial dose affords a comparable maximum concentration (Cmax) of drug when compared to a term baby who receives a lower initial dose.6 Furthermore, there is a possible postantibiotic effect whereby persistent suppression of bacterial growth follows exposure to an antibiotic.6 However, no study has had the statistical power to confirm this benefit,5 nor to delineate the duration of the postantibiotic effect.6 Other side effects of aminoglycoside therapy very rarely include neuromuscular blockade.5 Although both ampicillin and gentamicin are still used relatively frequently for treating sepsis, antibiotics are and should be prescribed according to the bacterial prevalence and resistance patterns of each unit. As bacterial resistance to antibiotics becomes more of an issue, it is more important to know the resistance patterns of one's own NICU. Information on pattern resistance can usually be obtained from hospital microbiology laboratories. Bacteria may develop resistance to antibiotics in different ways. For example, aminoglycosides can develop resistance through plasmid-mediated enzyme production, which inactivates the drug.4 Penicillin resistance also follows this pattern where enzymatic inactivation occurs through β-lactam ring disruption.4 Another method of resistance is alteration of the target site, such as mutations in the penicillin-binding proteins (PBPs). This leads to decreased uptake of the drug. Organisms can lack the appropriate receptors needed for antibiotic binding.4 Also, alterations in metabolic pathways can circumvent the chemical reaction that the drug inhibits.4 Lastly, increased efflux can cause active pumping of drug out of cells.
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Resistant organisms may spread from colonized individuals and health care workers to patients because of poor infection control practices and poor hand hygiene. Ultimately, this leads to nosocomial infections. Nosocomial infections may affect more than two million individuals each year7. This is estimated to contribute to approximately 20 000 deaths per year.7 Nosocomial infections lead to increased hospital length of stay and increased morbidity and mortality. Neonatal intensive care units that have low nosocomial infection rates are those that have procedures and policies in place to decrease infection. These include good hand-washing protocols, the use of closed systems for suctioning, and limitations on line days, including peripheral intravenous lines. This contrasts to sites with high infection rates.8 Bacteria such as extended spectrum β-lactamase–producing organisms (ESBL), methicillin-resistant Staphylococcus aureus (MRSA), coagulase-negative staphylococcus (CONS), and vancomycin-resistant enterococci (VRE) are the most prevalent bacteria implicated in nosocomial infections. These microbes have developed resistance to multiple antibiotic classes. Newer antibiotics and antibiotic regimens must now be used to combat these illnesses. At the same time, strict antibiotic use and infection control measures must be implemented to prevent the newer antibiotics from also developing resistance.
Extended Spectrum β-Lactamases and Treatment As mentioned above, one of the mechanisms of drug resistance is the production of specialized enzymes. Extended spectrum β-lactamases are such enzymes that confer resistance to certain antibiotics. They were first recognized in the early 1980s and have since been increasing in prevalence and incidence. Several bacteria are able to produce ESBLs and they include E coli, Klebsiella pneumoniae, Citrobacter, Proteus, Pseudomonas, Salmonella, Serratia, and Enterobacter species. According to the Centers for Disease Control and Prevention (CDC), approximately 12% of Klebsiella species have ESBLs. Extended spectrum β-lactamases hydrolyze the β-lactam ring of β-lactam drugs, including penicillins, cephalosporins, carbapenems, and monobactams. These β-lactam antibiotics would normally bind to PBPs on the surface of the bacterium to exert their killing activity. There are usually several binding sites per bacterium and each has a different drug affinity that depends on cell wall structure.4 However, the binding of ESBLs to the β-lactam ring disrupts it, which renders the antibiotic ineffective. Extended spectrum β-lactamases are produced from gene expression on chromosomes and plasmids. Chromosomalmediated ESBLs can sometimes be induced with the use of cephalosporins.9 Plasmids, which are extrachromosomal pieces of DNA, can readily transfer between bacterial species and are the most common way of spreading resistance. They are widespread between both gram-positive and -negative organisms. The patient with ESBL gastrointestinal colonization, on a ventilator with prolonged hospitalization, is at high risk for invasive nosocomial ESBL infection because of several factors.
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Again, one factor is poor infection control. Those who are asymptomatic, including health care workers and other patients, act as reservoirs for the disease which can then be transmitted from patient to patient through poor hand hygiene.10 Patients with central catheters and patients who have undergone abdominal surgery are also at increased risk for developing infections with ESBL bacteria. Another factor is the increased use of cephalosporins. Cephalosporin drugs can induce cephalosporinases, which are enzymes that confer resistance. Therefore, the CDC recommends limiting use of cephalosporins as well as implementing infection control measures such as contact isolation in patients with confirmed ESBL.11 Also, it is recommended that when ESBL is detected, all penicillins, cephalosporins, and aztreonam should be considered resistant despite results of in vitro studies. Extended spectrum β-lactamase infections may be treated with antibiotics containing β-lactamase inhibitors such as clavulanic acid and sulbactam. Clavulanic acid is naturally derived from Streptomyces, whereas sulbactam is a semisynthetic drug. The β-lactamase inhibitors are usually paired with penicillins or cephalosporins because alone they have little antimicrobial activity.9 β-Lactamase inhibitors bind to the catalytic site of the β-lactamase enzyme which prevents the inactivation of the β-lactam antibiotics.9 However, the activity of these inhibitors depends on which β-lactam antibiotic is paired with it. For example, although some E coli strains show resistance to certain combinations, they are still quite sensitive to piperacillin/tazobactam (Zosyn, Wyeth Pharmaceuticals, Inc, Philadelphia, PA).9 Carbapenems are also used to treat infections with ESBL bacteria as ESBLs remain susceptible.10 Carbapenems are structurally related to β-lactam antibiotics.4 However, their structure renders them resistant to β-lactamases. They have a very broad range of activity. Carbapenems are effective against streptococci, enterococci, pneumococci, methicillin-sensitive S aureus, gram-negative rods except stenotrophomonas. Two carbapenems are approved for use in neonates and they are imipinem/cilastin (Primaxin, Merck &Co, Inc, Whitehouse Stations, NJ) and meropenem (Merrem IV, AstraZeneca, London, UK). These antibiotics treat both aerobic and anaerobic bacteria. They bind via PBPs and disrupt the bacterial cell wall, which then kills the bacteria. Carbapenems also penetrate well into the cerebrospinal fluid. Clearance is related to renal function. There is limited clinical experience in their use on neonates but there are a few risks and side effects to consider. Primarily, carbapenems can cause diarrhea and vomiting. Allergic rashes, although rare, have been reported. There is also a risk of phlebitis at the site of injection. Imipenem can cause seizures in those with meningitis or those with preexisting central nervous system pathology. 12 Carbapenems can cause laboratory abnormalities, such as increased transaminases, eosinophilia, decreased platelet count, and increased creatinine.13 They can also induce cephalosporinases on gram-negative bacteria including Enterobacter, Pseudomonas, Citrobacter, and Acinetobacter. Lastly, they can increase the risk of superficial or invasive fungal disease because of their broad spectrum of activity.13
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Vancomycin, CONS, and Resistant Organisms Vancomycin (Vancocin, ViroPharma, Inc, Exton, PA) is another antibiotic frequently used in the NICU setting. It is a glycopeptide antibiotic first introduced in the 1960s. It works by inhibiting cell wall synthesis, cell wall permeability, and RNA synthesis. It has activity against gram-positive organisms including staphylococcal species, streptococcal species, enterococci, clostridium dificile, and diphtheroids. It is also active against listeria, actinomyces, and bacillus species.14 It works synergistically with aminoglycosides. Vancomycin is used in some NICUs as a first-line drug in the treatment of nosocomial sepsis especially when there is a high prevalence of resistant coagulase-negative staphylococci. In one study, the use of vancomycin in hospitals increased 20-fold in the years from 1981 to 1991.15 Vancomycin is used for treatment of severe gram-positive infections especially when methicillin resistance is suspected or when endemic. It is also an appropriate initial therapy for sepsis until susceptibility testing leads to adjustment to narrower spectrum antibiotics.
Resistance in Staphylcoccal Species Staphylococcus aureus is an important cause of infection in NICUs. It is the most common cause of nosocomial infection.16 The majority of S aureus strains throughout the world produce β-lactamases.9 More concerning is the growing number of MRSA.7 The method of resistance in that case is related to the transfer of the mecA gene, which codes for a PBP. This PBP acts as a substitute for other staphylococcal enzymes and triggers them to continue cell wall synthesis even when β-lactam antibiotics are in use.2 First reported in the late 1960s,17 the incidence has been increasing, and in some NICUs, MRSA has become endemic. Methicillin-resistant S aureus strains make up 55% of S aureus stains causing nosocomial infection according to 2001 data.17 This bacterium is resistant to all penicillin, cephalosporins, carbapenems, and all β-lactamase inhibitors.17 Infants may be colonized within 24 to 48 hours after birth and may experience infections of the skin, bloodstream, and gastrointestinal tract (necrotizing enterocolitis).17 Vancomycin remains the treatment of choice for MRSA. Coagulase-negative staphylococci are the most common cause of nosocomial infection.7,18 Coagulase-negative staphylococci are common flora of skin, nares, and ear canals.2 Approximately 5% of NICU patients will develop CONS infections.7 Infections can include meningitis, central line infections, and endocarditis. Risk factors for developing infection with CONS are low birth weight, mechanical ventilation, use of central catheters, use of intravenous lipids, and parenteral nutrition.7 This is likely due to widespread CONS colonization. A premature infant's skin is colonized early on in the course of their hospitalization. The CONS then invades their central lines and leads to bloodstream infections.7 Fortunately, such infections are rarely fulminant and the
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mortality rate from CONS is similar to noninfected neonates.19 Most CONS is resistant to penicillin because of penicillinases and, therefore, is considered resistant to cephalosporins as well.2 Because most nosocomial infection in the NICU is caused by CONS, studies and research aim to decrease the incidence. One of the potential ways being studied is through the use of prophylactic vancomycin.20 A meta-analysis in 2008 reviewed the use of antibiotic prophylaxis to reduce blood stream infections. Two studies were analyzed in the final meta-analysis because they were the only two that used prophylactic vancomycin as compared to a third study that used amoxicillin. The meta-analysis showed an 87% decrease in the incidence of sepsis compared with placebo or no treatment.20 The catheter-related infection rate decreased from 23% to 2.4%.20 Duration of catheter days and mortality showed no statistically significant difference in the treatment and nontreatment groups. Although there was an overall decrease in sepsis episodes, the insufficient evidence precludes the authors of that paper from recommending the routine use of prophylactic vancomycin.20,21 Overuse of antibiotics, and in particular vancomycin, is a big concern in light of the fact that resistance is increasing. Since the late 1990s, concern has been increasing over detection of MRSA strains that are insensitive to vancomycin, which have affected certain adult populations.11 Vancomycin-resistant enterococcus (VRE) emerged in the late 1980s. According to the National Nosocomial Infection Surveillance System during the years from 1989 to 1993, the incidence of VRE has increased from 0.3% to 8%.22 There are several phenotypes and the two most common are VanA (resistant to vancomycin and teicoplanin; Targocid, SanofiAventis, Surrey, England) and Van B (resistant to vancomycin alone).11 According to the CDC, the incidence of resistant strains has increased in the time from 1995 to 2004.11 Vancomycin resistance occurs through plasmids or mutations.2 To date, only two antibiotics are licensed for use in neonates to treat VRE. They are linezolid (Zyvox, Pfizer) and quinupristin/ dalfopristin (Synercid, Monarch Pharmaceuticals, Bristol, TN). Linezolid is an oxazolidinone antibiotic whose mechanism of action involves inhibiting bacterial protein translation.23 It binds to the 23S subunit of the bacterial 50s ribosome to block protein translation. It is effective against VRE, S aureus, βstreptococcus, Enterococcus faecalis. It is generally bacteriostatic for staphylococci and enterococci in that it inhibits bacterial growth. However, it is bacteriocidal for streptococcal species.23 It is well distributed in body tissues and its clearance is higher in older children and adults than in neonates. However, clearance increases rapidly in the first postnatal week. Lower doses have been recommended in preterm infants owing to the slower systemic clearance in this age.23 Myelosuppression, demonstrated by anemia, pancytopenia, and thrombocytopenia, can occur as a side effect. It is recommended that complete blood counts be obtained weekly while the infant remains on linezolid. This drug is generally considered a last resort drug and its use is limited to prevent development of resistance. Although approved for use in neonates, there are few clinical studies and data on usage. There
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are reports of treatment success in infants with endocarditis and ventriculitis, and in adults. There are also reports of success in treating MRSA infections.23 Quinupristin is also used to treat VRE. It is a streptogramin antibiotic and is derived from Streptomyces as well. Its combination with dalfopristin targets the 50S subunit of the ribosome. Together they block both an early and late step in protein synthesis which leads to bactericidal activity. Resistance to this drug can happen but is largely uncommon.22 Side effects in the older population include arthritis, liver enzyme abnormalities, rash, and diarrhea.22 Although there are reports of its successful use in infants, there are no large-scale studies in neonates and its safety has not yet been established. In conclusion, what are the future challenges facing patients and caregivers in the NICU setting? Nosocomial infections will likely continue to be a growing concern as they are currently responsible for approximately half of NICU deaths after 2 weeks of age.7 As more bacteria develop resistance to available antibiotics, pharmaceutical companies will have to meet this challenge by developing newer drugs to combat these illnesses. Also, implementing better practices can have a big impact in preventing nosocomial infections. Handwashing, proper nutrition, good skin, respiratory, and vascular access care can potentially decrease infection.7 Lastly, and perhaps most important, it is necessary to develop a sense of teamwork where each health care provider sees a nosocomial infection as one infection too many and works to prevent them.
Appendix A. Case Report A 30 2/7–week premature male infant was born to a 42year-old gravida 4, para 0 mother. Her blood type was O positive, and prenatal laboratory results were negative with the exception of group B Streptococcus, which was unknown. The pregnancy course was complicated by a history of a positive PPD with a negative chest x-ray, insulin-dependent diabetes mellitus of 10 years duration, and a short, incompetent cervix with a cerclage in place. The mother was admitted to the hospital 45 days before delivery for management of her incompetent cervix. At the time of her admission, the fetus was 24 weeks' gestation. It is unknown whether or not the mother received antenatal steroids. She remained hospitalized and her membranes ruptured 15 days before delivery. During that time, she received ampicillin and erythromycin to prevent infection. The antibiotics were stopped 1 day before a caesarean delivery which was performed for nonreassuring fetal status. Apgar scores were 8.9. The baby was admitted to the NICU for further management. On admission, the baby was started on ampicillin and gentamicin for a rule out sepsis. His initial complete blood count (CBC) was significant for 12 segmented neutrophils with 18 band forms, yielding an immature-to-total neutrophil ratio of 0.6. His second CBC obtained approximately 12 hours after birth had 53 segmented neutrophils with 13 band forms for an immature-to-total neutrophil ratio of 0.19. The bandemia resolved by the third CBC.
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However, the mother became febrile with respiratory symptoms shortly after delivery. Her blood culture was reported positive for ESBL Klebsiella and she was treated for both pneumonia and bacteremia. The baby was treated with ampicillin and gentamicin. Zosyn was added when the mother's infection with Klebsiella was reported. In total, the baby was treated with antibiotics for 12 days. His blood culture remained negative and he is preparing for homegoing.
12. 13.
14. 15.
References 1. Gourley D. Joint Commission places infection control under the microscope. FOCUS. J Respir Care Sleep Med. 2004. 2. Ryan K, Kenneth J. Sherris Medical Microbiology An Introduction to Infectious Disease. Norwalk CT: Appleton & Lange; 1994. 3. Isaacs D. Unnatural Selection: reducing antibiotics resistance in neonatal units. Arch Dis Child Fetal Neonatal Ed. 2006;91:F72-F74. 4. Katzung B. Basic and Clinical Pharmacology. Norwalk CT, Appleton & Lange. 1995; 671–692, 699–703. 5. Remington J, Klein J. Wilson & Bakers Infectious Disease of the Fetus and Newborn Infant. 6th ed. Elsevier; 2006. 6. Young T. Aminoglycoside therapy in neonates: with particular reference to gentamicin. Neoreviews. 2002;3:243. 7. Polin RA, Saiman L. Nosocomial Infection in the Neonatal Intensive Care Unit. Neoreviews. 2003;4:e81-e88. 8. Bloom B, Craddock A, Delmore P, et al. Reducing acquired infections in the NICU: observing and implementing meaningful differences in process between high and low acquired infection rate centers. J Perinatol. 2003;23:489-492. 9. Lee NLS, Yuen KY, Kumana CR. Beta lactam antibiotics and beta lactamase inhibitor combinations. JAMA. 2001;285:386-388. 10. Gupta A, Ampofo K, Rubinstein D, Saiman L. Extended spectrum B lactamase-producing Klebsiella pneumoniae
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infections: a review of the literature. J Perinatol. 2003; 23:439-443. Seigel J, Rhinehart E, Jackson M, Chiarello L. Management of Multidrug-Resistant Organisms in Healthcare Settings. CDC; 2006. Young TE, Mangum B. Neofax. Thomson; 2008. Garges H, Alexander KA. Pharmacology review: newer antibiotics: imipenem/cilastin and meropenem. Neoreviews. 2003;4:364. Vancocin package insert Ena J, Dick R, Jones R, Wensel R. The epidemiology of intravenous vancomycin usage in a university hospital: a 10 year study. JAMA. 1993;269:598-602. MMWR. 2004; 53:322–323. Bracher D. Methicillin resistant Staphylococcus aureus in nurseries. Neoreviews. 2005;6:424-430. Sohn A, Garrett DO, Sinkowitz-Cochran R, et al. Prevalence of nosocomial infections in neonatal intensive care unity patients: results from the first national point-prevalence survey. J Pediatr. 2001;139:821-827. Stoll BJ, Hansen N, Fanaroff AA, et al. Late onset sepsis in very low birth weight neonates: the experience of NICHD Neonatal Research Network. Pediatrics. 2002;110:285-291. Lodha A, Furlan AD, Whyte H, Moore AM. Prophylactic antibiotics in the prevention of catheter-associated bloodstream bacterial infection in preterm neonates: a systematic review. J Perinatol. 2008;28:526-533. Clark R, Powers R, White R, Bloom B, Sanchez P, Benjamin Jr DK. Prevention and treatment of nosocomial sepsis in the NICU. J Perinatol. 2004;24:446-453. Manzella J. Quinupristin-dalfopristin: a new antibiotic for severe gram-positive infection. Am Fam Phys. 2001;11:1863. Garges H, Alexander KA. Pharmacology review: newer antibiotics: linezolid. Neoreviews. 2003;4:128.
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