Injectable Antibiotics for Newborn Sepsis

PRODUCT PROFILE

Potential Lives Saved/Year: In India alone, 75% intervention coverage would save 65,000 newborns a year1

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Problem and Proposed Intervention

(Centre)Children at Amari Yewbesh Kebele in Oromia State of Ethiopia, July 2013.
© UNICEF/ Ose

Globally, neonatal sepsis accounts for over 500,000 newborn deaths annually.2 Newborn infection has a rapid onset, and urgent diagnosis and presumptive treatment is needed. Case-fatality rates for severe bacterial infections in developing countries are high, in part due to late or inadequate administration of the necessary antibiotics.3 And yet, relatively low-cost treatments exist that could have an important impact on neonatal mortality if care providers are properly trained to administer them. A review of evidence of home-based and first-level facility treatment of neonatal bacterial infections4 found substantial reductions in neonatal mortality in a nonrandomized controlled study in rural India (62% reduction, P 0.001) and in a cluster randomized trial in rural Bangladesh (34% reduction, 95% CI: 7%–53%). The WHO has listed three injectable antibiotics for the treatment of neonatal sepsis on the Essential Medicines List for Children: procaine benzylpenicillin, gentamicin, and ceftriaxone. As so poignantly stated in the WHO Neonatal Sepsis – a major killer to be tackled in communities, “if we are to improve rates of child survival, it is no longer possible to overlook the importance of addressing neonatal deaths from infections. There is a clear need for investment in expanded surveillance activities and in more research on diagnosis, etiology, and treatment of neonatal sepsis at all levels of the health system, and especially at the community level.” 5

Injectable antibiotics product characteristics:

Drug: Procaine Benzylpenicillin (PBP) Gentamicin Ceftriaxone
Indication: neonatal sepsis, first-line neonatal sepsis, second-line
Formulation: Powder for injection: 1 g (=1 mill IU); 3 g (=3 mill IU) in vial6 Injection: 10 mg; 40 mg (as sulfate)/ml in 2-ml vial6 powder for injection 250 mg and 1 g7
Dose: intramuscular injections 50 mg/kg of ampicillin (or comparable, such as PBP) every 6 to 8 hours—depending on age – divided 2x/day for at least 10 days6 intramuscular injection 7.5 mg/kg of gentamicin (or comparable aminoglycoside) in addition to the benzylpenicillin injections – divided 2x/day for at least 10 days 6 50 mg/kg once daily for all newborns (<1 week, <2 kg) 75 mg/kg once daily for ten days (>1 week, >2 kg).8
Avg. Cost: ~$0.13-0.16/treatment (depending wt and # days trt) ~$0.17-$2.03/treatment (depending wt and # days trt) ~$0.50-0.90/treatment (depending wt & # days trt)

Initial Findings from Product Case Study Working Paper

* Note: The strengths and challenges outlined below are initial findings from a longer working paper developed to analyze the current global situation of each product. The findings are presented below to catalyze further thinking and discussion in order to finalize a list of issues and recommendations. The full working paper texts are forthcoming.

Strengths Challenges
Policy and Regulation
Global * WHO recommends antibiotic treatment with benzylpenicillin and gentamicin as first-line therapy in newborns at risk of bacterial infection. Recommend ceftriaxone delivered alone as a second-line therapy.* WHO EML6 [i] and Priority Medicines for Mothers and Children 20117 provide specifications for use of specific antibiotics for neonatal sepsis.

* Current WHO guidelines for case management exist, and WHO IMCI guidelines provide specific guidelines for when referral is not possible.9

* There is no clear cohesion among policymakers on the optimal antibiotic treatment for community scenarios.
National, Regional * Some countries have these medicines on their national essential medicines lists.  Most use the WHO EML as the base document for their policies regarding these drugs. * Little is known about national policies, availability, and use of these drugs at various levels of the health care system.* Divergence in policy, practice, and need for a community-based strategy and case management of neonatal sepsis in many countries.10
Product specification & characteristics * Formulations of PBP, gentamicin, and ceftriaxone are standardized per US Pharmacopeia and British Pharmacopoeia and are governed GMP.* Gentamicin has been widely used to treat neonatal infections as a first-line therapy and is a commonly used antibiotic medication.

* Ceftriaxone has been widely used in treating neonatal infections in both developed and developing countries.8,11

* Innovations: Two different doses of gentamicin in Uniject® prefilled injection system have been produced, and early upstream development of microneedle patches is being tested.

* PBP and ceftriaxone do not require refrigeration when stored as dry powder. Nor does Gentamicin.

* WHO expert committee strongly recommends that further safety and efficacy studies be conducted in neonates in order to support the use of PBP. It further suggested that studies be conducted to better assess the safety and efficacy community health worker case management.12* Gentamicin should be monitored closely, as there are risks related to toxicity (hearing and kidney damage).

* Resistance to ceftriaxone develops very rapidly.

* It is difficult to develop alternative delivery mechanisms for PBP and ceftriaxone powders. They must be reconstituted with sterile water.

* In both Asia and sub-Saharan Africa, formulations at appropriate dosage may not be readily available.

* Once reconstituted, PBP and Ceftriaxone must be refrigerated and used within a very short time.

Financing, Procurement & Supply * Over 50 different companies throughout Asia and South Asia, Europe, the Middle East, and North America manufacture these drugs.* These drugs are most likely being procured locally.

* Both PBP and gentamicin are relatively low-cost antibiotics, making them excellent options for public procurement.

* Few data are available about the supplier manufacturing base in low-resource settings.* These drugs are often not readily available or subject to stock-outs in weaker health systems.

*Manufacturers have cited insufficient demand as a reason for low supply of PBP in some cases.

* The relative expense of ceftriaxone may make it less affordable for public procurement.

Service Provision (Rational Use) * Innovations in drug delivery technology (e.g. Uniject and microneedle patches) have the potential to ease some of the delivery/service provision issues associated with injectable antibiotics for neonatal sepsis treatment. * Gentamicin and PBP cannot be mixed in the same syringe (requires separate injections).* Diagnosing neonatal sepsis is difficult in even the most sophisticated settings. Deaths are often due to under-recognition of illness, lack of access to appropriate treatment and trained health workers, delay in initiation of treatment, and inability to pay.

* Current IMCI guidelines9 recommend referral, but there is also a need for treatment at the community level if referral is not possible. Some country contexts lack trained staff for case management.

* The reported lack of willingness to use gentamicin may be linked to problems with a lack of pediatric syringes, and the challenge of filling other syringes with the small dose needed.

  • USAID, PATH. A Health Tech Report: Rapid assessment of economic value for Gentamicin in the Uniject prefilled injection device. Seattle: PATH; 2010, pg. 9.
  • Black RE, Cousens S, Johnson HL, Lawn JE, et al. Global, regional and national causes of mortality in 2008: a systematic analysis. Lancet 2010; 375:1969-1987.
  • Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatric Infectious Disease Journal. 2009;28(S1):S3–S9.
  • Bhutta ZA, Zaidi AK, Thaver D. et al. Management of newborn infections in primary care settings. A Review of the Evidence and Implications for Policy? The Pediatric Infectious Disease Journal. 2009; 28( 1):S22–S30.
  • WHO. (2012). Neonatal Sepsis – a major killer to be tackled in communities. http://www.who.int/maternal_child_adolescent/news_events/news/2009/19_01/en/index.html. Accessed March 19, 2012
  • WHO. WHO Model List of Essential Medicines (March 2011), 17th edition. Available at: http://whqlibdoc.who.int/hq/2011/a95053_eng.pdf. Accessed March 26,2011
  • WHO. Priority Medicines for Mothers and Children 2011, 3rd edition. http://www.who.int/medicines/publications/A4prioritymedicines.pdf (Accessed March 2012).
  • Saez-Llorens X, McCracken GH. Clinical pharmacology of antibacterial agents. In: Remington JS, Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia: W.B. Saunders Company; 2001: 1419–1466. (19)
  • WHO, UNICEF. Handbook: IMCI Integrated Management of Childhood Illness. Geneva: WHO; 2005. Available at: http://whqlibdoc.who.int/publications/2005/9241546441.pdf. Accessed February 16, 2012.
  • WHO, UNICEF, Save the Children, United States Agency for International Development (USAID). Meeting Report. From: Expert Consultation on Community-Based Approaches for Neonatal Sepsis Management, 2007; London, England.
  • Van Reempts PJ, Van Overmeire B, Mahieu LM, et al. Clinical experience with ceftriaxone treatment in the neonate.Chemotherapy. 1995;41(4):316–322.
  • WHO. Procaine Benzylpenicillin in Neonates. Report from the Second Meeting of the Subcommittee on the Selection and Use of Essential Medicines. September 29-October 3, 2009.