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1.  Coagulase-negative staphylococcal infections in a neonatal intensive care unit: In vivo response to cloxacillin 
Paediatrics & Child Health  2006;11(10):659-663.
Following the introduction of cloxacillin and gentamicin as the first line of treatment for possible late-onset sepsis (LOS) in the authors’ neonatal intensive care unit (NICU), it was subsequently noted that very low birth weight (VLBW) infants improved clinically, despite subsequently positive blood cultures for oxacillin-resistant, coagulase-negative Staphylococcus (CONS). The results of the management of VLBW infants with CONS sepsis during one calendar year, based on clinical rather than laboratory findings, are presented.
VLBW infants with LOS were identified through the neonatal database, and the charts of those with CONS were reviewed for antibiotic usage, antibiotic resistance pattern, clearance of CONS from the blood and NICU discharge status. Oxacillin sensitivity was determined by the presence of the mecA gene.
From January 1 to December 31, 2002, 27 VLBW infants, treated in the authors’ NICU for LOS due to CONS, were identified. The mean age of LOS infants with CONS was 15 days (median 12 days; range three to 54 days), the mean birth weight (± SD) was 904±247 g, and the mean gestational age at birth (± SD) was 27±2 weeks. All infants were started on cloxacillin and gentamicin, and improved clinically over the first 48 h. Six isolates were sensitive to cloxacillin. Twenty-three infants grew oxacillin-resistant CONS, eight of whom had persistence of CONS on repeat culture secondary to central lines. Two infants grew two strains of CONS. Eighteen of 22 infants (82%) with in vitro oxacillin-resistant CONS had clearance of bacteremia with cloxacillin and gentamicin. Ten infants (37%) received vancomycin, based on the authors’ guidelines. There were no cases of prolonged bacteremia requiring rifampicin. Three infants died, but none of the deaths could be attributed to CONS.
The authors describe clinical improvement with clearance of CONS using cloxacillin and gentamicin, despite laboratory results suggesting oxacillin resistance. The authors’ unit policy was based on clinical response and permitted the continuation of cloxacillin, provided that a repeat blood culture was negative. Vancomycin use was suggested for clinical deterioration or persistence of CONS. These results question the in vitro tests of resistance. Clearance of oxacillin-resistant CONS from the blood points to in vivo sensitivity, while the laboratory testing suggests in vitro resistance. The absence of subsequent positive blood cultures for CONS confirms clearance of this organism.
It was demonstrated that cloxacillin (150 mg/kg/day dose), along with gentamicin, can clear CONS from the blood within 48 h. The relationship between in vivo and in vitro sensitivities also needs to be further studied both in the laboratory and in a prospective trial.
PMCID: PMC2528592  PMID: 19030249
Antibiotic sensitivities; Coagulase-negative staphylococcal bacteremia; Very low birth weight
2.  A ten year, multicentre study of coagulase negative staphylococcal infections in Australasian neonatal units 
Objective: To study late onset systemic infections with coagulase negative staphylococci.
Methods: Prospective longitudinal study of coagulase negative staphylococcal infection in 18 Australasian neonatal nurseries.
Results: From 1991 to 2000 inclusive, there were 1281 cases of coagulase negative staphylococcal (CoNS) sepsis, comprising 57.1% of all late onset infections. The male/female ratio was 1.27:1 (p < 0.05). The incidence of CoNS sepsis was 3.46 episodes per 1000 live births. Most infected babies (71%) were 24–29 weeks gestation at birth (mode 26 weeks). The first positive culture was day 7–14 in 49% of babies (mode 10 days). Five cases of meningitis were reported, an incidence of 0.4% of all CoNS infections. Twenty nine babies (2.3%) had concurrent necrotising enterocolitis and CoNS septicaemia. Four babies (0.3%) died from CoNS infection, but CoNS infection possibly contributed to the death of an additional 20 babies (1.6%). The mortality directly attributable to CoNS infection was significantly lower than that from late onset infections with Staphylococcus aureus (13.1%; relative risk (RR) = 36.1 (95% confidence interval (CI) 13.0 to 100.2) or with Gram negative bacilli (14.2%; RR = 45.5 (95% CI 16.8 to 123.3)).
Conclusions: CoNS are currently responsible for most late onset neonatal infections. Most infected babies are < 30 weeks gestation at birth, and usually present between 7 and 14 days of age. CoNS infections may be associated with necrotising enterocolitis, although causality is unproven. Neonatal CoNS infections are relatively benign: meningitis is rare and mortality low compared with infection from other organisms. Over-vigorous attempts to reduce the incidence of CoNS infections using prophylactic antibiotics are not advisable.
PMCID: PMC1721527  PMID: 12598493
3.  Cloxacillin versus vancomycin for presumed late-onset sepsis in the Neonatal Intensive Care Unit and the impact upon outcome of coagulase negative staphylococcal bacteremia: a retrospective cohort study 
BMC Pediatrics  2005;5:49.
Coagulase negative staphylococcus (CONS) is the main cause of late-onset sepsis in Neonatal Intensive Care Units (NICU). Although CONS rarely causes fulminant sepsis, vancomycin is frequently used as empiric therapy. Indiscriminate use of vancomycin has been linked to the emergence of vancomycin resistant organisms. The objective of this study was to compare duration of CONS sepsis and mortality before and after implementation of a policy of selective vancomycin use and compare use of vancomycin between the 2 time periods.
A retrospective study was conducted of infants ≥4 days old, experiencing signs of sepsis with a first positive blood culture for CONS, during two 12-month periods. Late-onset sepsis was treated empirically with vancomycin and gentamicin during period 1, and cloxacillin and gentamicin during period 2. The confidence interval method was used to assess non-inferiority of the outcomes between the two study groups.
There were 45 episodes of CONS sepsis during period 1 and 37 during period 2. Duration of sepsis was similar between periods (hazard ratio of 1.00, 95%CI: 0.64, 1.57). One death during period 2 was possibly related to CONS sepsis versus none in period 1. Vancomycin was used in 97.8% of episodes in period 1 versus 81.1% of episodes in period 2.
Although we failed to show non-inferiority of duration of sepsis in the cloxacillin and gentamicin group compared to the vancomycin and gentamicin group, duration of sepsis was clinically similar. Restricting vancomycin for confirmed cases of CONS sepsis resistant to oxacillin appears effective and safe, and significantly reduces vancomycin use in the NICU.
PMCID: PMC1343548  PMID: 16375769
4.  Serious infection in a neonatal intensive care unit: a two-year survey. 
The Journal of Hygiene  1985;95(2):289-297.
Over a two-year period 160 episodes of serious infection occurred in 139 infants admitted to a regional neonatal intensive-care unit. Eighty-seven (26%) of very low birth weight (VLBW) neonates and 52 (8%) of infants of birth weight greater than 1500 g were infected. The majority (84%) had bacteraemia alone. Though the clinical features of infection were not distinctive, in 94% of episodes the peripheral white blood cell or band counts were abnormal. Thirty-three (21%) of the infections occurred in infants under 48 h old and 15 of these followed prolonged rupture of membranes (greater than 48 h). All of the infections due to group B streptococci (5), Streptococcus viridans (2) and Haemophilus influenzae (3) occurred in this group. Coagulase-negative staphylococci (CONS) accounted for 49% of the infections and there was a marked increase in incidence of such infections during the survey. Infections with CONS were not necessarily associated with parenteral nutrition, the presence of intra-arterial catheters or mechanical ventilation but the rise in incidence was coincident with change in skin disinfectant usage and the general use of a third-generation cephalosporin to which the CONS were resistant. Although VLBW infants with meningitis were more likely to die than those of higher birthweight, the risk for those with bacteriaemia was the same in both groups. Infants with CONS sepsis were less likely to die than those with infections due to Gram-negative bacteria and the time from onset of infection to death was significantly longer for the former.
PMCID: PMC2129542  PMID: 4067290
5.  Molecular Epidemiology of Coagulase-Negative Staphylococci Causing Sepsis in a Neonatal Intensive Care Unit over an 11-Year Period 
Journal of Clinical Microbiology  2004;42(3):992-995.
Coagulase-negative staphylococci (CoNS) are the major causative microorganisms in neonatal nosocomial sepsis. Previous studies have shown that CoNS sepsis in the neonatal intensive care unit (NICU) is caused by predominant molecular types that are widely distributed among both neonates and staff. Some of these molecular types may persist in the NICU for years. The purpose of the present study was to determine the dynamic behavior of CoNS strains causing sepsis over a prolonged period of time by determining the molecular types of all blood isolates from septicemic infants over a period of 11 years (1991 to 2001). The results show that neonatal CoNS sepsis is increasingly caused by a few predominant molecular clusters. The most striking finding was that in recent years one molecular cluster emerged as the predominant cause of neonatal CoNS sepsis, responsible for no less than 31% (20 of 65) of blood isolates in 2001. Antibiotic resistance, particularly beta-lactam resistance, is probably an important selective force considering the high mecA gene carriage of CoNS blood isolates (70 to 92%). We conclude that neonatal CoNS sepsis is increasingly caused by a limited number of predominant molecular CoNS types and that antibiotic resistance is probably a major selective force.
PMCID: PMC356815  PMID: 15004043
6.  Coagulase-Negative Staphylococcal Skin Carriage among Neonatal Intensive Care Unit Personnel: from Population to Infection▿  
Journal of Clinical Microbiology  2010;48(11):3876-3881.
Coagulase-negative staphylococci (CoNS) are a major cause of sepsis in neonatal intensive care units (NICU) worldwide. Infecting strains of these commensal bacteria may originate from NICU personnel. Therefore, we studied the characteristics of CoNS isolates from NICU personnel and compared them to those of isolates from the general population and from sepsis patients. Furthermore, we studied the epidemiological effect on CoNS carriage of NICU personnel after a period of absence. In our study, we isolated CoNS from the thumbs of NICU personnel every 2 weeks during the summer of 2005 and sampled personnel returning from vacation and a control group from the general population. Furthermore, we collected sepsis isolates from this period. Isolates were tested for antibiotic resistance, mecA and icaA carriage, biofilm production, and genetic relatedness. We found that mecA and icaA carriage as well as penicillin, oxacillin, and gentamicin resistance were significantly more prevalent in CoNS strains from NICU personnel than in community isolates. Similar trends were observed when postvacation strains were compared to prevacation strains. Furthermore, genetic analysis showed that 90% of the blood isolates were closely related to strains found on the hands of NICU personnel. Our findings revealed that CoNS carried by NICU personnel differ from those in the general population. Hospital strains are replaced by community CoNS after a period of absence. NICU personnel are a likely cause for the cross-contamination of virulent CoNS that originate from the NICU to patients.
PMCID: PMC3020886  PMID: 20826641
7.  The ica Operon and Biofilm Production in Coagulase-Negative Staphylococci Associated with Carriage and Disease in a Neonatal Intensive Care Unit 
Journal of Clinical Microbiology  2002;40(2):382-388.
Coagulase-negative staphylococci (CoNS) are a major cause of sepsis in the neonatal intensive care unit (NICU). We evaluated the hypothesis that the ica operon and biofilm production are associated with CoNS disease in this setting. CoNS associated with bacteremia or blood culture contamination and from the skin of infants with CoNS bacteremia or healthy controls were obtained during a prospective case-control study on a busy NICU. A total of 180 strains were identified, of which 122 (68%) were Staphylococcus epidermidis and the remainder were S. capitis (n = 29), S. haemolyticus (n = 11), S. hominis (n = 9), S. warneri (n = 8), and S. auricularis (n = 1). The presence of the genes icaA, icaB, icaC, and icaD was determined by PCR, and biofilm production was examined using qualitative (Congo red agar [CRA]) and quantitative (microtiter plate) techniques. There were no significant differences in the presence of the ica operon or CRA positivity among the four groups of strains. However, quantitative biofilm production was significantly greater in strains isolated from either the blood or the skin of neonates with S. epidermidis bacteremia. We conclude that the quantity of biofilm produced may be associated with the ability to cause CoNS infection. This conclusion suggests that the regulation of biofilm expression may play a central role in the disease process.
PMCID: PMC153361  PMID: 11825946
8.  Persistence of Clones of Coagulase-Negative Staphylococci among Premature Neonates in Neonatal Intensive Care Units: Two-Center Study of Bacterial Genotyping and Patient Risk Factors 
Journal of Clinical Microbiology  1998;36(9):2485-2490.
From 1 January 1995 until 1 January 1996, we studied the molecular epidemiology of blood isolates of coagulase-negative staphylococci (CoNS) in the Neonatal Intensive Care Units (NICUs) of the Sophia Children’s Hospital (SCH; Rotterdam, The Netherlands) and the Wilhelmina Children’s Hospital (WCH; Utrecht, The Netherlands). The main goal of the present study was to detect putatively endemic clones of CoNS persisting in these NICUs. Pulsed-field gel electrophoresis was used to detect the possible presence of endemic clones of clinical significance. In addition, clinical data of patients in the SCH were analyzed retrospectively to identify risk factors for the acquisition of positive blood cultures. In both centers, endemic CoNS clones were persistently present. Thirty-three percent of the bacterial isolates derived from blood cultures in the SCH belonged to a single genotype. In the WCH, 45% of all bacterial strains belonged to a single clone. These clones were clearly different from each other, which implies that site specificity is involved. Interestingly, we observe that the clonal type in the SCH differed significantly from the incidentally occurring strains with respect to both the average pH and partial CO2 pressure of the patient’s blood at the time of bacterial culture. We found that the use of intravascular catheters, low gestational age, and a long hospital stay were important risk factors for the development of a putative CoNS infection. When the antibiotic susceptibility of the bacterial isolates was assessed, a clear correlation between the nature of the antibiotics most frequently used as a first line of defense versus the resistance profile was observed. We conclude that the intensive use of antibiotics in an NICU setting with highly susceptible patients causes selection of multiresistant clones of CoNS which subsequently become endemic.
PMCID: PMC105149  PMID: 9705379
9.  Trends of Staphylococcus aureus bloodstream infections in a neonatal intensive care unit from 2000-2009 
BMC Pediatrics  2014;14:121.
Invasive methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-sensitive Staphylococcus aureus (MSSA) infections are major causes of numerous neonatal intensive care unit (NICU) outbreaks. There have been increasing reports of MRSA outbreaks in various neonatal intensive care units (NICUs) over the last decade. Our objective was to review the experience of Staphylococcus aureus sepsis in our NICU in the last decade and describe the trends in the incidence of Staphylococcus aureus blood stream infections from 2000 to 2009.
A retrospective perinatal database review of all neonates admitted to our NICU with blood cultures positive for Staphylococcus aureus from (Jan 1st 2000 to December 31st 2009) was conducted. Infants were identified from the database and data were collected regarding their clinical characteristics and co-morbidities, including shock with sepsis and mortality. Period A represents patients admitted in 2000-2003. Period B represents patients seen in 2004-2009.
During the study period, 156/11111 infants were identified with Staphylococcus aureus blood stream infection: 41/4486 (0.91%) infants in Period A and 115/6625 (1.73%) in Period B (p < 0.0004). Mean gestation at birth was 26 weeks for infants in both periods. There were more MRSA infections in Period B (24% vs. 55% p < 0.05) and they were associated with more severe outcomes. In comparing the cases of MRSA infections observed in the two periods, infants in period B notably had significantly more pneumonia cases (2.4% vs. 27%, p = 0.0005) and a significantly higher mortality rate (0% vs. 15.7%, p = 0.0038). The incidences of skin and soft tissue infections and of necrotizing enterocolitis were not significantly changed in the two periods.
There was an increase in the incidence of Staphylococcus aureus infection among neonates after 2004. Although MSSA continues to be a problem in the NICU, MRSA infections were more prevalent in the past 6 years in our NICU. Increased severity of staphylococcal infections and associated rising mortality are possibly related to the increasing MRSA infections with a more virulent community-associated strain.
PMCID: PMC4024190  PMID: 24886471
Staphylococcus aureus; Methicillin-sensitive; Methicillin-resistant; Bloodstream; Pneumonia; Sepsis
10.  Risk Factors for Infection with Coagulase-Negative Staphylococci in Newborns from the Neonatal Unit of a Brazilian University Hospital 
Coagulase-negative staphylococci (CoNS) are one of the most frequent causative agents of neonatal nosocomial infections, especially in premature and low-weight newborns. Risk factors for infection include extracellular polysaccharide production and consequent biofilm formation that permit adhesion to the smooth surface of catheters and other medical devices. The objective of this study was to identify CoNS strains isolated from 105 newborns admitted to the Neonatal Unit of our hospital, and to evaluate the association of biofilm production and host risk factors with the occurrence of infection.
CoNS isolates were identified and classified as significant or contaminant based on clinical and laboratory data of the newborn medical records. Perinatal risk factors for infection, neonatal clinical evolution, and antibiotic treatment were analysed. In addition, the presence of genes (icaA, icaC and icaD) responsible for biofilm production in CoNS was investigated.
Among the 130 CoNS strains studied, 66 (50.8%) were classified as clinically significant and 64 (49.2%) as contaminant. There was no difference in the detection of biofilm-specific genes between CoNS strains isolated from newborns with (81.8%) and without infection (84.3%), although 11 (91.7%) of the 12 children whose death was related to CoNS were infected with strains that were positive for these genes. Forty-five (83.3%) of the 54 newborns infected with CoNS were premature and 33 (61.1%) had a birth weight ≤ 1,500 g. Most newborns infected with CoNS had been submitted to invasive procedures, including catheter use (85.2%), parenteral nutrition (61.1%), and mechanical ventilation (57.4%). S. epidermidis was the most frequently isolated species (81.5%) and was more related to infection (86.3%) than to contamination (76.5%).
Most newborns infected with CoNS presented factors that contributed to the colonization and development of infection with these microorganisms, including a birth weight ≤ 1,500 g, catheter complications, use of a drain, and previous antibiotic treatment. The fact that most children who died of CoNS-related infection carried strains positive for biofilm-specific genes indicates the importance of this virulence factor for the outcome of staphylococcal infections.
PMCID: PMC3620778  PMID: 23641161
biofilm; Staphylococcus; coagulase-negative; risk factors; infection; phenotyping methods; PCR
11.  Molecular epidemiology of coagulase-negative Staphylococcus carriage in neonates admitted to an intensive care unit in Brazil 
BMC Infectious Diseases  2013;13:572.
Nasal colonization with coagulase-negative Staphylococcus (CoNS) has been described as a risk factor for subsequent systemic infection. In this study, we evaluated the genetic profile of CoNS isolates colonizing the nares of children admitted to a neonatal intensive care unit (NICU).
We assessed CoNS carriage at admittance and discharge among newborns admitted to a NICU from July 2007 through May 2008 in one of the major municipalities of Brazil. Isolates were screened on mannitol salt agar and tryptic soy broth and tested for susceptibility to antimicrobials using the disc diffusion method. Polymerase chain reaction (PCR) was used to determine the species, the presence of the mecA gene, and to perform SCCmec typing. S. epidermidis and S. haemolyticus isolated from the same child at both admission and discharge were characterized by PFGE.
Among 429 neonates admitted to the NICU, 392 (91.4%) had nasal swabs collected at both admission and discharge. The incidence of CoNS during the hospitalization period was 55.9% (95% confidence interval [CI]: 50.9-60.7). The most frequently isolated species were S. haemolyticus (38.3%) and S.epidermidis (38.0%). Multidrug resistance (MDR) was detected in 2.2% and 29.9% of the CoNS isolates, respectively at admittance and discharge (p = 0.053). The mecA gene was more prevalent among strains isolated at discharge (83.6%) than those isolated at admission (60%); overall, SCCmec type I was isolated most frequently. The length of hospitalization was associated with colonization by MDR isolates (p < 0.005). Great genetic diversity was observed among S. epidermidis and S. haemolyticus.
NICU represents an environment of risk for colonization by MDR CoNS. Neonates admitted to the NICU can become a reservoir of CoNS strains with the potential to spread MDR strains into the community.
PMCID: PMC4028975  PMID: 24308773
Coagulase-negative Staphylococcus; mecA; SCCmec; Neonatal intensive care units; Neonates
12.  Use of rifampin in persistent coagulase negative staphylococcal bacteremia in neonates 
BMC Pediatrics  2010;10:84.
Coagulase negative staphylococci (CoNS) are the most common cause of neonatal sepsis in the Neonatal Intensive Care Unit (NICU). A minority of neonates does not respond to vancomycin therapy and develops persistent bacteremia, which may be treated with rifampin. We evaluated the use of rifampin in persistent CoNS bacteremia.
Retrospective study of 137 neonates with CoNS bacteremia during admission to a tertiary NICU between July 2006 and July 2009. Main outcome measures were total duration of bacteremia and the adequacy of vancomycin and rifampin therapy.
137/1696 (8.0%) neonates developed a CoNS bacteremia. Eighteen were treated with rifampin because of persistent bacteremia (3 positive blood cultures at least 48 hours apart with clinical symptoms) or (a serious suspicion of) an intravascular thrombus. Duration of bacteremia prior to rifampin therapy (8.0 ± 3.6 days) was positively correlated (p < 0.001) to the total duration of bacteremia (10.3 ± 3.7 days). After starting rifampin therapy C-reactive protein (CRP) levels of all neonates declined and blood cultures became sterile after 2.3 ± 1.6 days. Vancomycin levels were not consistently measured in all neonates, resulting in late detection of subtherapeutic trough levels.
Rifampin may be effective in the treatment of persistent CoNS infections in neonates. Outcome may be improved by adequate monitoring of vancomycin trough levels.
PMCID: PMC2994847  PMID: 21092087
13.  Pregnancy and Infant Outcomes among HIV-Infected Women Taking Long-Term ART with and without Tenofovir in the DART Trial 
PLoS Medicine  2012;9(5):e1001217.
Diana Gibb and colleagues investigate the effect of in utero tenofovir exposure by analyzing the pregnancy and infant outcomes of HIV-infected women enrolled in the DART trial.
Few data have described long-term outcomes for infants born to HIV-infected African women taking antiretroviral therapy (ART) in pregnancy. This is particularly true for World Health Organization (WHO)–recommended tenofovir-containing first-line regimens, which are increasingly used and known to cause renal and bone toxicities; concerns have been raised about potential toxicity in babies due to in utero tenofovir exposure.
Methods and Findings
Pregnancy outcome and maternal/infant ART were collected in Ugandan/Zimbabwean HIV-infected women initiating ART during The Development of AntiRetroviral Therapy in Africa (DART) trial, which compared routine laboratory monitoring (CD4; toxicity) versus clinically driven monitoring. Women were followed 15 January 2003 to 28 September 2009. Infant feeding, clinical status, and biochemistry/haematology results were collected in a separate infant study. Effect of in utero ART exposure on infant growth was analysed using random effects models.
382 pregnancies occurred in 302/1,867 (16%) women (4.4/100 woman-years [95% CI 4.0–4.9]). 226/390 (58%) outcomes were live-births, 27 (7%) stillbirths (≥22 wk), and 137 (35%) terminations/miscarriages (<22 wk). Of 226 live-births, seven (3%) infants died <2 wk from perinatal causes and there were seven (3%) congenital abnormalities, with no effect of in utero tenofovir exposure (p>0.4). Of 219 surviving infants, 182 (83%) enrolled in the follow-up study; median (interquartile range [IQR]) age at last visit was 25 (12–38) months. From mothers' ART, 62/9/111 infants had no/20%–89%/≥90% in utero tenofovir exposure; most were also zidovudine/lamivudine exposed. All 172 infants tested were HIV-negative (ten untested). Only 73/182(40%) infants were breast-fed for median 94 (IQR 75–212) days. Overall, 14 infants died at median (IQR) age 9 (3–23) months, giving 5% 12-month mortality; six of 14 were HIV-uninfected; eight untested infants died of respiratory infection (three), sepsis (two), burns (one), measles (one), unknown (one). During follow-up, no bone fractures were reported to have occurred; 12/368 creatinines and seven out of 305 phosphates were grade one (16) or two (three) in 14 children with no effect of in utero tenofovir (p>0.1). There was no evidence that in utero tenofovir affected growth after 2 years (p = 0.38). Attained height- and weight for age were similar to general (HIV-uninfected) Ugandan populations. Study limitations included relatively small size and lack of randomisation to maternal ART regimens.
Overall 1-year 5% infant mortality was similar to the 2%–4% post-neonatal mortality observed in this region. No increase in congenital, renal, or growth abnormalities was observed with in utero tenofovir exposure. Although some infants died untested, absence of recorded HIV infection with combination ART in pregnancy is encouraging. Detailed safety of tenofovir for pre-exposure prophylaxis will need confirmation from longer term follow-up of larger numbers of exposed children.
Trial registration ISRCTN13968779
Please see later in the article for the Editors' Summary
Editors' Summary
Currently, about 34 million people (mostly in low- and middle-income countries) are infected with HIV, the virus that causes AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now about half of all people living with HIV/AIDS are women, most of who became infected through unprotected sex with an infected partner. In sub-Saharan Africa alone, 12 million women are HIV-positive. Worldwide, HIV/AIDS is the leading cause of death among women of child-bearing age. Moreover, most of the 400,000 children who become infected with HIV every year acquire the virus from their mother during pregnancy or birth, or through breastfeeding, so-called mother-to-child transmission (MTCT). Combination antiretroviral therapy (ART)—treatment with cocktails of powerful antiretroviral drugs—reduces HIV-related illness and death among women, and ART given to HIV-positive mothers during pregnancy and delivery and to their newborn babies greatly reduces MTCT.
Why Was This Study Done?
Because of ongoing international efforts to increase ART coverage, more HIV-positive women in Africa have access to ART now than ever before. However, little is known about pregnancy outcomes among HIV-infected African women taking ART throughout pregnancy for their own health or about the long-term outcomes of their offspring. In particular, few studies have examined the effect of taking tenofovir (an antiretroviral drug that is now recommended as part of first-line ART) throughout pregnancy. Tenofovir readily crosses from mother to child during pregnancy and, in animal experiments, high doses of tenofovir given during pregnancy caused bone demineralization (which weakens bones), kidney problems, and impaired growth among offspring. In this study, the researchers analyze data collected on pregnancy and infant outcomes among Ugandan and Zimbabwean HIV-positive women who took ART throughout pregnancy in the Development of AntiRetroviral Therapy in Africa (DART) trial. This trial was designed to test whether ART could be safely and effectively delivered in Africa without access to the expensive laboratory tests that are routinely used to monitor ART toxicity and efficacy in developed countries.
What Did the Researchers Do and Find?
The pregnancy outcomes of 302 women who became pregnant during the DART trial and information on birth defects among their babies were collected as part of the DART protocol; information on the survival, growth, and development of the infants born to these women was collected in a separate infant study. Most of the women who became pregnant were taking tenofovir-containing ART before and throughout their pregnancies. 58% of the pregnancies resulted in a live birth, 7% resulted in a stillbirth (birth of a dead baby at any time from 22 weeks gestation to the end of pregnancy), and 35% resulted in a termination or miscarriage (before 22 weeks gestation). Of the 226 live births, seven infants died within 2 weeks and seven had birth defects. Similar proportions of the infants exposed and not exposed to tenofovir during pregnancy died soon after birth or had birth defects. Of the 182 surviving infants who were enrolled in the infant study, 14 subsequently died at an average age of 9 months, giving a 1-year mortality of 5%. None of the surviving children who were tested (172 infants) were HIV infected. No bone fractures or major kidney problems occurred during follow-up and prebirth exposure to tenofovir in utero had no effect on growth or weight gain at 2 years (in contrast to a previous US study).
What Do These Findings Mean?
By showing that prebirth tenofovir exposure does not affect pregnancy outcomes or increase birth defects, growth abnormalities, or kidney problems, these findings support the use of tenofovir-containing ART during pregnancy among HIV-positive African women, and suggest that it could also be used to prevent women of child-bearing age acquiring HIV-infection heterosexually. Notably, the observed 5% 1-year infant mortality is similar to the 2%–4% infant mortality normally seen in the region. The absence of HIV infection among the infants born to the DART participants is also encouraging. However, this is a small study (only 111 infants were exposed to tenofovir throughout pregnancy) and women were not randomly assigned to receive tenofovir-containing ART. Consequently, more studies are needed to confirm that tenofovir exposure during pregnancy does not affect pregnancy outcomes or have any long-term effects on infants. Such studies are essential because the use of tenofovir as a treatment for women who are HIV-positive is likely to increase and tenofovir may also be used in the future to prevent HIV acquisition in HIV-uninfected women.
Additional Information
Please access these Web sites via the online version of this summary at
Information is available from the US National Institute of Allergy and infectious diseases on all aspects of HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment (in several languages)
Information is available from Avert, an international AIDS nonprofit on many aspects of HIV/AIDS, including detailed information on HIV/AIDS treatment and care, women, HIV and AIDS, children, HIV and AIDS, and on HIV/AIDS and pregnancy (some information in English and Spanish); personal stories of women living with HIV are available
More information about the DART trial is available
Additional patient stories about living with HIV/AIDS are available through the nonprofit website Healthtalkonline
PMCID: PMC3352861  PMID: 22615543
14.  Incidence of Late Onset Neonatal Sepsis in Very Low Birth Weight Infants in a Tertiary Hospital 
Late onset neonatal septicaemia (LONS) is one of the major causes of morbidity and mortality in very low birth weight (VLBW) infants. The main objective of this study was to investigate the rate of LONS in the Neonatal Intensive Care Unit (NICU) of King Khalid University Hospital (KKUH) in Riyadh, Saudi Arabia over a three year period and compare it to international standards.
To determine the incidence of LONS, a retrospective study was undertaken and premature infants with a birth weight less than 1250 g were included, giving a total of 273 infants. Their bacterial profile and the antimicrobial susceptibility of the isolates were investigated, and the changes in trends over the study period studied.
91.5% of included infants (217/237) had 1 or more blood cultures obtained beyond the second day of life. 41% (98/237) of included infants had at least one episode of proven sepsis. The majority (71.4%) of first episode sepsis was caused by Gram-positive organisms. Coagulase negative Staphylococcus accounted for around 80% of all Gram-positive infections. Gram-negative pathogens accounted for 24.5% of the late onset infections while fungal organisms were responsible for 4%.
The rate of LONS was high and exceeded internationally reported rates in our tertiary care NICU. Gram-positive organisms continue to be major causative isolates. High priority should be placed on preventative steps to control nosocomial sepsis.
PMCID: PMC3074715  PMID: 21509234
Very low birth weight infants; Sepsis; Epidemiology
15.  Change in Pathogens Causing Late-onset Sepsis in Neonatal Intensive Care Unit in Izmir, Turkey 
Iranian Journal of Pediatrics  2010;20(4):451-458.
Neonatal sepsis is a common cause of morbidity and mortality among newborns in the developing world. We have investigated the causative agents and their antimicrobial susceptibility of late-onset sepsis (>72 h post-delivery), and determined the possible association between various risk factors and the mortality due to neonatal sepsis in 2008. To view the changes in years, we compared them with the data which we gained in 2004.
Medical records of all neonates with late-onset sepsis were reviewed for demographic characteristics (birth weight, gestational age, gender, type of delivery, and mortality rate), positive cultures and risk factors of mortality.
One hundred and forty-seven and 227 neonates had been diagnosed as late-onset sepsis in 2004 and 2008, respectively. Coagulase-negative staphylococcus was the most frequent microorganisms. Gram-negative bacilli, particularly Pseudomonas aeruginosa showed a significant increase in years. The mortality rate was 11.5% and 19% in 2004 and 2008, respectively. Birth weight, gestational age, and infection with Klebsiella spp. isolates were found to have significant association with sepsis mortality in our neonatal intensive care unit (NICU).
The present study emphasizes the importance of periodic surveys of sepsis encountered in particular neonatal setting to recognize the trend. Increased Gram-negative bacilli rate was possibly related to the widespread use of antibiotics in our NICU.
PMCID: PMC3446087  PMID: 23056745
Sepsis; Risk factors; Neonatal intensive care unit; Neonate; Infection; Antibiotics
16.  Nosocomial Spread of a Staphylococcus capitis Strain with Heteroresistance to Vancomycin in a Neonatal Intensive Care Unit 
Journal of Clinical Microbiology  2002;40(7):2520-2525.
A premature infant in a neonatal intensive care unit (NICU) developed a bloodstream infection caused by coagulase-negative staphylococci (CoNS) sensitive to vancomycin. The infection persisted for 3 weeks, despite therapy with vancomycin and replacement of all intravenous catheters. The neonate died due to necrotizing enterocolitis which developed during the ongoing sepsis. We screened this strain and 216 other strains of CoNS from cultures of blood obtained from neonates between 1997 and 2000 for heteroresistance to vancomycin. Forty-eight isolates, including the strain that caused ongoing sepsis, proved heteroresistant. All isolates were identified as Staphylococcus capitis and were identical, just as their resistant stable subcolonies were, when they were genetically fingerprinted by amplified-fragment length polymorphism analysis. The heteroresistant phenotype of this endemic strain was confirmed by population analysis. We conclude that heteroresistance to vancomycin occurs in S. capitis and might be the cause of therapeutic failures in NICUs. Moreover, heteroresistant strains can become endemic in such units.
PMCID: PMC120592  PMID: 12089273
17.  Sepsis in Young Infants with Congenital Heart Disease 
Early human development  2012;88(Suppl 2):S92-S97.
We sought to describe the incidence, pathogen distribution, and mortality associated with blood culture-proven sepsis in young infants with congenital heart disease (CHD) admitted to a neonatal intensive care unit (NICU).
Cohort study of all blood cultures obtained from infants with CHD between 4 and 120 days of age cared for in250 NICUs managed by the Pediatrix Medical Group in the United States between 1996 and 2007.
Of 11,638 infants with CHD, 656 (6%) had 821 episodes of sepsis: a cumulative incidence of 71/1000 admissions. Gram-positive organisms were the most common cause (64%), and coagulase-negative Staphylococcus and Staphylococcus aureus were the most frequently isolated species. On multivariable regression, infants with sepsis were more likely to die compared to infants with sterile blood cultures (odds ratio [OR] = 1.53 [95% confidence interval: 1.09, 2.13]). Infants with gram-negative bacteremia and candidemia were more likely to die than infants with sterile blood cultures (OR = 2.01 [1.20, 3.37], and OR = 3.18 [1.60, 6.34], respectively).
Infants with CHD have a high incidence of culture-proven sepsis, especially with staphylococcal organisms. Gram-negative bacteremia and candidemia are strongly associated with increased mortality in this group of young infants.
PMCID: PMC3513769  PMID: 22633525
infant; sepsis; infection; congenital heart disease; epidemiology; outcomes
18.  Epidemiology and Diagnosis of Hospital-Acquired Conjunctivitis Among Neonatal Intensive Care Unit Patients 
Few recent reports describe the epidemiology and risk factors for health care-associated conjunctivitis among neonatal intensive care unit (NICU) patients in developed countries. Reporting may be inaccurate in this population given that the National Nosocomial Infection Surveillance System (NNIS) definition is largely dependent on a positive culture, whereas clinical practice often consists of empiric treatment.
We describe the epidemiology of conjunctivitis among neonates in 2 level III–IV NICUs and compare the NNIS definition with our study definition: eye drainage and empiric treatment with or without a culture.
Patient demographics, clinical, device usage and conjunctivitis data collected prospectively from March 2001 through January 2003 were analyzed.
Conjunctivitis occurred in 5% (n = 154/2935) of infants, of whom 51% (n =79) were in NICU 1 and 49% (n =75) in NICU 2. Predominant pathogens included coagulase-negative staphylococci (25%), Staphylococcus aureus (19%) and Klebsiella spp. (10%). Significant predictors of conjunctivitis included low birth weight, use of ventilator or nasal cannula continuous positive airway pressure and study year. Ophthalmologic examination was an additional predictor of infection in NICU 1. Eye examination data were unavailable for NICU 2. Only 62% of cases that met the study definition for conjunctivitis met the NNIS definition, because many infants received empiric treatment.
Clinical conjunctivitis was associated with low birth weight and patient care factors that could lead to contamination of the eye with respiratory tract secretions. The NNIS definition failed to detect 38% of clinical infections. Consideration should be given to revising the definition of conjunctivitis for the NICU population.
PMCID: PMC2045635  PMID: 15998997
conjunctivitis; neonatal intensive care unit; low birth weight; premature infants
19.  Early and Late Onset Sepsis in Very-Low-Birth-Weight Infants from a Large Group of Neonatal Intensive Care Units 
Early human development  2012;88(Suppl 2):S69-S74.
Very-low-birth-weight (VLBW, <1500 g birth weight) infants are at high risk for both early- and late-onset sepsis. Prior studies have observed a predominance of gram-negative organisms as a cause of early-onset sepsis and gram-positive organisms as a cause of late-onset sepsis. These reports are limited to large, academic neonatal intensive care units (NICUs) and may not reflect findings in other units. The purpose of this study was to determine the risk factors for sepsis, the causative organisms, and mortality following infection in a large and diverse sample of NICUs.
We analyzed the results of all cultures obtained from VLBW infants admitted to 313 NICUs from 1997 to 2010.
Over 108,000 VLBW infants were admitted during the study period. Early-onset sepsis occurred in 1032 infants, and late-onset sepsis occurred in 12,204 infants. Gram-negative organisms were the most commonly isolated pathogens in early-onset sepsis, and gram-positive organisms were most commonly isolated in late-onset sepsis. Early- and late-onset sepsis were associated with increased risk of death controlling for other confounders (odds ratio 1.45 [95% confidence interval 1.21, 1.73], and OR 1.30 [95% CI 1.21, 1.40], respectively).
This is the largest report of sepsis in VLBW infants to date. Incidence for early-onset sepsis and late-onset sepsis has changed little over this 14-year period, and overall mortality in VLBW infants with early- and late-onset sepsis is higher than in infants with negative cultures.
PMCID: PMC3513766  PMID: 22633519
early-onset sepsis; late-onset sepsis; very-low-birth-weight infants
20.  Nonperinatal Nosocomial Transmission of Candida albicans in a Neonatal Intensive Care Unit: Prospective Study 
Journal of Clinical Microbiology  1998;36(5):1255-1259.
Nosocomial Candida albicans infections have become a major cause of morbidity and mortality in neonates in neonatal intensive care units (NICUs). To determine the possible modes of acquisition of C. albicans in hospitalized neonates, we conducted a prospective study at Grady Memorial Hospital, Atlanta, Ga. Clinical samples for fungal surveillance cultures were obtained at birth from infants (mouth, umbilicus, and groin) and their mothers (mouth and vagina) and were obtained from infants weekly until they were discharged. All infants were culture negative for C. albicans at birth. Six infants acquired C. albicans during their NICU stay. Thirty-four (53%) of 64 mothers were C. albicans positive (positive at the mouth, n = 26; positive at the vagina, n = 18; positive at both sites, n = 10) at the time of the infant’s delivery. A total of 49 C. albicans isolates were analyzed by restriction endonuclease analysis and restriction fragment length polymorphism analysis by using genomic blots hybridized with the CARE-2 probe. Of the mothers positive for C. albicans, 3 of 10 were colonized with identical strains at two different body sites, whereas 7 of 10 harbored nonidentical strains at the two different body sites. Four of six infants who acquired C. albicans colonization in the NICU had C. albicans-positive mothers; specimens from all mother-infant pairs had different restriction endonuclease and CARE-2 hybridization profiles. One C. albicans-colonized infant developed candidemia; the colonizing and infecting strains had identical banding patterns. Our study indicates that nonperinatal nosocomial transmission of C. albicans is the predominant mode of acquisition by neonates in NICUs at this hospital; mothers may be colonized with multiple strains of C. albicans simultaneously; colonizing C. albicans strains can cause invasive disease in neonates; and molecular biology-based techniques are necessary to determine the epidemiologic relatedness of maternal and infant C. albicans isolates and to facilitate determination of the mode of transmission.
PMCID: PMC104810  PMID: 9574687
21.  Coagulase-negative staphylococci strains resistant to oxacillin isolated from neonatal blood cultures 
Memórias do Instituto Oswaldo Cruz  2013;108(7):939-942.
Coagulase-negative staphylococci (CoNS) are the microorganisms most frequently isolated from clinical samples and are commonly found in neonatal blood cultures. Oxacillin is an alternative treatment of choice for CoNS infections; however, resistance to oxacillin can have a substantial impact on healthcare by adversely affecting morbidity and mortality. The objective of this study was to detect and characterise oxacillin-resistant CoNS strains in blood cultures of newborns hospitalised at the neonatal ward of the University Hospital of the Faculty of Medicine of Botucatu. One hundred CoNS strains were isolated and the mecA gene was detected in 69 of the CoNS strains, including 73.2% of Staphylococcus epidermidis strains, 85.7% of Staphylococcus haemolyticus strains, 28.6% of Staphylococcus hominis strains and 50% of Staphylococcus lugdunensis strains. Among these oxacillin-resistant CoNS strains, staphylococcal cassette chromosome mec (SCCmec) type I was identified in 24.6%, type II in 4.3%, type III in 56.5% and type IV in 14.5% of the strains. The data revealed an increase in the percentage of CoNS strains isolated from blood cultures from 1991-2009. Furthermore, a predominant SCCmec profile of the oxacillin-resistant CoNS strains isolated from neonatal intensive care units was identified with a prevalence of SCCmec types found in hospital-acquired strains.
PMCID: PMC3970650  PMID: 24141968
coagulase; negative staphylococci; mecA; SCCmec
22.  Comparisons of mortality and pre-discharge respiratory outcomes in small-for-gestational-age and appropriate-for-gestational-age premature infants 
BMC Pediatrics  2004;4:9.
There are differences in the literature regarding outcomes of premature small-for-gestational-age (SGA) and appropriate-for gestational-age (AGA) infants, possibly due to failure to take into account gestational age at birth.
To compare mortality and respiratory morbidity of SGA and AGA premature newborn infants.
A retrospective study was done of the 2,487 infants born without congenital anomalies at ≤36 weeks of gestation and admitted to the neonatal intensive care unit (NICU) at John Dempsey Hospital, between Jan. 1992 and Dec. 1999. Recent (1994–96) U.S. birth weight percentiles for gestational age (GA), race and gender were used to classify neonates as SGA (<10th percentile for GA) or AGA (10th–90th percentile for GA). Using multivariate logistic regression and survival analyses to control for GA, SGA and AGA infants were compared for mortality and respiratory morbidity.
Controlling for GA, premature SGA infants were at a higher risk for mortality (Odds ratio 3.1, P = 0.001) and at lower risk of respiratory distress syndrome (OR = 0.71, p = 0.02) than AGA infants. However multivariate logistic regression modeling found that the odds of having respiratory distress syndrome (RDS) varied between SGA and AGA infants by GA. There was no change in RDS risk in SGA infants at GA ≤ 32 wk (OR = 1.27, 95% CI 0.32 – 1.98) but significantly decreased risk for RDS at GA > 32 wk (OR = 0.41, 95% CI 0.27 – 0.63; p < 0.01). After controlling for GA, SGA infants were observed to be at a significantly higher risk for developing chronic lung disease as compared to AGA infants (OR = 2.2, 95% CI = 1.2 – 3.9, P = 0.01). There was no significant difference between SGA and AGA infants in total days on ventilator. Among infants who survived, mean length of hospital stay was significantly higher in SGA infants born between 26–36 wks GA than AGA infants.
Premature SGA infants have significantly higher mortality, significantly higher risk of developing chronic lung disease and longer hospital stay as compared to premature AGA infants. Even the reduced risk of RDS in infants born at ≥32 wk GA, (conferred possibly by intra-uterine stress leading to accelerated lung maturation) appears to be of transient effect and is counterbalanced by adverse effects of poor intrauterine growth on long term pulmonary outcomes such as chronic lung disease.
PMCID: PMC434508  PMID: 15186501
23.  Catheter-related bloodstream infections in neonatal intensive care units 
Korean Journal of Pediatrics  2011;54(9):363-367.
Central venous catheters (CVCs) are regularly used in intensive care units, and catheter-related bloodstream infection (CRBSI) remains a leading cause of healthcare-associated infections, particularly in preterm infants. Increased survival rate of extremely-low-birth-weight infants can be partly attributed to routine practice of CVC placement. The most common types of CVCs used in neonatal intensive care units (NICUs) include umbilical venous catheters, peripherally inserted central catheters, and tunneled catheters. CRBSI is defined as a laboratory-confirmed bloodstream infection (BSI) with either a positive catheter tip culture or a positive blood culture drawn from the CVC. BSIs most frequently result from pathogens such as gram-positive cocci, coagulase-negative staphylococci, and sometimes gram-negative organisms. CRBSIs are usually associated with several risk factors, including prolonged catheter placement, femoral access, low birth weight, and young gestational age. Most NICUs have a strategy for catheter insertion and maintenance designed to decrease CRBSIs. Specific interventions slightly differ between NICUs, particularly with regard to the types of disinfectants used for hand hygiene and appropriate skin care for the infant. In conclusion, infection rates can be reduced by the application of strict protocols for the placement and maintenance of CVCs and the education of NICU physicians and nurses.
PMCID: PMC3250601  PMID: 22232628
Catheter; Bacteremia; Intensive care units; Newborn
24.  Variations in mortality rates among Canadian neonatal intensive care units 
Most previous reports of variations in mortality rates for infants admitted to neonatal intensive care units (NICUs) have involved small groups of subpopulations, such as infants with very low birth weight. Our aim was to examine the incidence and causes of death and the risk-adjusted variation in mortality rates for a large group of infants of all birth weights admitted to Canadian NICUs.
We examined the deaths that occurred among all 19 265 infants admitted to 17 tertiary-level Canadian NICUs from January 1996 to October 1997. We used multivariate analysis to examine the risk factors associated with death and the variations in mortality rates, adjusting for risks in the baseline population, severity of illness on admission and whether the infant was outborn (born at a different hospital from the one where the NICU was located).
The overall mortality rate was 4% (795 infants died). Forty percent of the deaths (n = 318) occurred within 2 days of NICU admission, 50% (n = 397) within 3 days and 75% (n = 596) within 12 days. The major conditions associated with death were gestational age less than 24 weeks (59 deaths [7%]), gestational age 24–28 weeks (325 deaths [41%]), outborn status (340 deaths [42%]), congenital anomalies (270 deaths [34%]), surgery (141 deaths [18%]), infection (108 deaths [14%]), hypoxic–ischemic encephalopathy (128 deaths [16%]) and small for gestational age (i.e., less than the third percentile) (77 deaths [10%]). There was significant variation in the risk-adjusted mortality rates (range 1.6% to 5.5%) among the 17 NICUs.
Most NICU deaths occurred within the first few days after admission. Preterm birth, outborn status and congenital anomalies were the conditions most frequently associated with death in the NICU. The significant variation in risk-adjusted mortality rates emphasizes the importance of risk adjustment for valid comparison of NICU outcomes.
PMCID: PMC99269  PMID: 11826939
25.  Multiresistant coagulase-negative staphylococci disseminate frequently between intubated patients in a multidisciplinary intensive care unit 
Critical Care  2003;8(1):R42-R47.
The intensive care unit is burdened with a high frequency of nosocomial infections often caused by multiresistant nosocomial pathogens. Coagulase-negative staphylococci (CoNS) are reported to be the third causative agent of nosocomial infections and the most frequent cause of nosocomial bloodstream infections. CoNS are a part of the normal microflora of skin but can also colonize the nasal mucosa, the lower airways and invasive devices. The main aim of the present study was to investigate colonization and the rate of cross-transmissions of CoNS between intubated patients in a multidisciplinary intensive care unit.
Materials and methods
Twenty consecutive patients, ventilated for at least 3 days, were included. Samples were collected from the upper and lower airways. All samples were cultured quantitatively and CoNS were identified by morphology and biochemical tests. A total of 199 CoNS isolates from 17 patients were genetically fingerprinted by pulsed-field gel electrophoresis in order to identify clones and to monitor dissemination within and between patients.
An unexpected high number of transmission events were detected. Five genotypes were each isolated from two or more patients, and 14/20 patients were involved in at least one and up to eight probable transmission events.
A frequent transmission of CoNS was found between patients in the intensive care unit. Although transmission of bacteria does not necessarily lead to infection, it is nevertheless an indication that infection control measures can be improved.
PMCID: PMC420068  PMID: 14975054
coagulase-negative staphylococci; colonization; cross-transmission; infection control measures; intensive care unit

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