How to use antibiotics in suspected Bacterial
Infections in Neonates?

Antibiotics are among our most valuable resources. When they first became available 50 years ago they probably made little difference to overall mortality in the neonatal period but with the advent of prolonged intubation and intravascular catheterization, babies are now at much greater risk of secondary bacterial infection. Modern neonatal intensive care would be impossible without antibiotics. Their effectiveness can only be preserved if they are used rationally and with great care. Irresponsible use can quickly lead to the selective appearance of organisms that are resistant to most forms of treatment.

Septic babies rarely present with clear, well-defined, clinical features, and often deteriorate rapidly if not treated promptly. Laboratory markers of sepsis are not always present. Even complex “Septic screens” utilizing immature (band) neutrophils to total cell count ratios, measurement of c-reactive protein and micro ESR, miss nearly 7% of babies with sepsis. It is hard to justify the cost of such tests therefore, and generally accepted that antibiotics should be started whenever there is clinical suspicion of sepsis, regardless of laboratory results.
following important general principles need to be followed, however, to limit the emergence of resistant organisms:

• Start early, stop early: If systemic cultures are negative, antibiotics can always be stopped safety after 48-72 hours (or even earlier if the symptoms provoking treatment do not persist).

• Use C-RP to monitor duration of antibiotic therapy in culture-negative septicemic babies. Though still controversial, quantitative serial estimation of C-RP can be used to keep track the progress of a septicemic baby in which blood culture has come negative.

• Treat sepsis, not colonisation: Antibiotics are not indicated every time a potential pathogen is grown from a peripheral culture (e.g. from an endotracheal aspirate). Treat babies, not colonizing organisms.

• Use a narrow spectrum antibiotic: The antibiotics chosen initially need to cover all the likely organisms, but a narrow spectrum antibiotic is best once the organism is known.

• Don’t use prophylactic antibiotics: Using an antibiotics to prevent infection, rather then treat it is seldom of any proven value. Such an approach can easily do more harm than good.

• Rotate them frequently: Make an antibiotic policy for the unit and try to rotate the often-used empiric agents after a specified period. Certain agents showing good sensitivity few weeks earlier might have lost their edge and vice-a-versa.

• Know your micro flora: It is a good policy to send frequent culture from your NICU equipments and walls to know prevailing/existing bacterial flora, if any. Plan your ‘empiric antibiotic policy’ based on these results. Mind you, it is 10-times more difficult to treat a neonate with ‘nosocomial sepsis’ than sepsis acquired through other sources!

• Limit your cephalosporins usage! Cross-resistance from one cephalosporin to other is quite common and it does spread quite quickly from one generation to another.

• Be fanatical about ‘asepsis routine’! Ensure strict hand hygiene, use disposables quite amply and freely, employ regular disinfections of floor and walls, and regular fumigation make your unit an unfriendly place for the most microbes.

• Make a habit to audit ‘antibiograms’ at regular intervals! This help in deciding ‘antibiotic policy’ for your unit.

• Anticipation and prompt action are the key words! Waiting for a clinical entity to be evolved and then react may prove to be a very hazardous approach while dealing preemies in your NICUs.

• Supportive care is all that matters: Mind you, in the management of neonatal sepsis, the supportive care is what makes all the difference in survival and death of neonates, not the antibiotics. First make neonate survives the time till antibiotics start acting!

Antibiotics are potentially toxic substances and the risk of toxicity is increased when other drugs are used simultaneously. Anyone using an antibiotic must make themselves aware of these potential drug interactions. Toxicity is often increased in babies with impaired renal function, as may be the case after asphyxia or extremely preterm delivery. Dose, and dose interval, may need to be modified in the light of renal function, and according to gestational and postnatal, or postconceptional age. Prolonged use makes fungal infection likely. Inexperienced staff should seek a second opinion before initiating treatment to minimize excessive use.
Rational treatment is extremely difficult if the organism cannot be isolated. Even 0.5ml of blood will usually identify the organism if collected with due care to prevent skin contamination because large numbers of bacteria are generally present in the blood stream. Taking an endotracheal aspirate before starting treatment in any baby requiring intubation on the first day of life will identify most cases of ascending intrapartum infection. Meningitis will sometimes be missed if lumber puncture is omitted (and about 15% have a sterile blood culture at presentation) but it may be advisable to secure the airway, start treatment and initiate respiratory support before doing this. Other components of the traditional septic work up (ear swabs, gastric aspirate, etc.) are seldom of help.

Antibiotics on their own will only suffice to save a few septicemic babies. Many will require ventilation and circulatory support. Hypoglycemia may require attention, and pain relief may be required. Other supportive measure are under investigation. Units need a clear policy for the management of suspected infection by an, as yet unidentified agent. A combination of penicillin/aminopenicillin and an aminoglycoside (such an Amikacin) remains the best treatment for babies becoming symptomatic in the first 48 hours of life. Use cloxacillin and an aminoglycoside in babies with signs of late onset bacterial infection and Vancomycin, where there are grounds for suspecting catheter-related infection with ‘Coagulase Negative Staphylococci’.
Frequent B –lactamase antibiotic use seriously increases the risk of colonization and of infection with resistant Enterobacter, Klebsiella and Serratia species.

Antimicriobial Choice:
Selection considerations
Increasingly sophisticated and powerful agents have been developed in recent years for treating bacterial, viral, fungal, and parasitic infections and the choice of available agents may appear bewildering. In addition, microbial resistance is increasing in prevalence, leading in some cases to organisms that are resistant to all commonly used antimicrobical therapies. This has led to the development of novel antimicrobials, many of which remain experimental, particularly in children. Nevertheless, most childhood infections can still be treated successfully with only a few agents. Limiting the number of antimicrobials used has two main advantages:
  * It allows the clinician to become familiar with these agents
  * It allows other antimicrobials to be held in reserve for difficult or more complex problems.

Considerations in antibiotic or other antimicrobial therapy
Decisions regarding appropriate antibiotic choices require answers to the
following interrelated questions:

• Is therapy indicated by the clinical findings?

• Have appropriate specimens been obtained?

• What is the most likely causative organism?

• Is the patient immunologically normal?

• Is there any reason to avoid certain agents? Due to allergy, renal or hepatic dysfunction, etc?

• What is the best route of administration?

• What is the appropriate dose?

• Will initial therapy require later modification?

• What is the optimal duration of therapy?

• Is a combination of antibiotics appropriate?

An Antibiogram Audit
On analyzing almost more than 100 positive blood culture and sensitivity reports performed over a period of last 18 months by Bactec rapid culture technique from a level III NICU of the region, following key findings have emerged:

• Gram negative bacteria were isolated in more than 95% of cases;

• E.coli (78%), Klebsiella (14%), Enterobactor spp (5%) and Pseudomonas (7%) were the most common pathogens. Co-infection with more than one bacteria was seen in 4 instances.

• Gram-positive bacteria (mainly Staphylococcus aureus) caused sepsis very infrequently in neonates.

• Infection with Candida spp was seen in 5 cases.

• Sensitivity pattern: Amikacin was the only aminoglycoside that showed very good sensitivity quite consistently. Overall, amikacin was sensitive in >88% cases.

• Ceftazidime is almost rendered ineffective by increasing antimicrobial resistance due to indiscriminate use. Even Cefotaxime was showing better sensitivity than this agent (45% Vs 22%).

• Ceftriaxone was found to be sensitive in more than 50% of isolates.

• The combination of Cefoperazone with Sulbactum scored over all the other 3rd generation cephalosporins being found to be sensitive in 78% of cases.

• Newer 4th generation extended spectrum cephalosporins, Cefepime and Cefpirome, showed good sensitivity being effective in 80% and 82% isolates, respectively.

• Newer molecules like Meropenem, Piperacillin-Tazobactum, and Aztreonam all showed quite high (>85%) sensitivity against cultured organisms.

• Piperacillin-Tazobactum (though not yet approved for use in neonates) was the most sensitive antibiotic against pseudomonas, being sensitive in all the 7 isolates of the agent.

• The sensitivity patterns of Aztreonam (86%) and Amikacin were quite comparable.

• Meropenem showed a very high sensitivity (>95%) against all the cultured organisms being most effective against Kebsiella.

• Isolates of Staph. aureus were found to be sensitive to Teicoplanin, Vancomycin and Linezolid.

• Most fluroquinolones apart from Gatifloxacin (not recommended in pediatric age group) were found to be resistant in >50% of isolates. Gatifloxacin showed a very high sensitivity of 82% against all the cultured pathogens.
   

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