Critical Care Antimicrobials in the Neonate

I. Introduction

In choosing the appropriate antimicrobial agent for a given infection, a number of important factors must be considered:

1. The identity of the infecting organism must be known, or at least it must be possible to arrive at a reasonable statistical guess as to its identity on the basis of clinical information.
2. Determination of the antimicrobial susceptibility (or potential susceptibility) of the infecting organism must be as accurate as possible.
3. Series of host factors must be taken into consideration to arrive at the optimal choice of antimicrobial agent.
4. The ability of the drug to enter the local environment of infection.

II. Identification of the infecting organism

Several methods of rapid identification of pathogenic bacteria in clinical specimens are available. A gram stain preparation is the simplest and most useful of all the “rapid methods” of identification of bacterial pathogens (sometimes fungal). On occasion gram staining of the buffy coat preparation of blood reveals phagocytosed organisms in the polymorphonuclear leukocytes in patients with bacteremia. Similar preparations of sputum can be useful in revealing the nature of the infecting organism in patients with bacterial pneumonia. Gram staining of the manure may also produce useful information. In addition, the presence of polymorphonuclear leukocytes in the stool provides a helpful clue to the cause of certain cases of diarrhea. Polymorphonuclear leukocytes are not found in normal stool and usually suggest the possibility of a bacterial gastroenteritis such as salmonella or invasive Escherichia coli.

Immunologic methods for antigen detection (such as enzyme- linked immunoadsorbent assay [ELISA] or latex agglutination) may also provide clues for rapid identification of the infecting pathogen. Polymerase chain reaction (PCR) allows for rapid and highly specific diagnosis of infectious diseases, including those caused by bacteria or viruses. PCR also permits identification of non-cultivatable or slow-growing microorganisms such as mycobacteria, anaerobic bacteria, or viruses from tissue culture assays and animal models. The basis for PCR diagnostic applications in microbiology is the detection of infectious agents and the discrimination of non-pathogenic from pathogenic strains by virtue of specific genes. In most cases, it may be impossible to determine the exact nature of the infecting organisms before institution of antimicrobial therapy. In these cases bacteriologic statistics may be helpful. “Bacteriologic statistics” refers to the application of knowledge of the organism most likely to cause infection in a given clinical setting. For example a horse with abnormal host defense mechanism that develops cellulitis of the leg after a minor abrasion most likely has an infection due to Staphylococcus spp. and antimicrobial therapy should be tailored accordingly, even though there is no material available for examination with Gram stain.

III. Determination of antimicrobial susceptibility of infecting organisms¹

Because organisms vary in their susceptibility to antimicrobial agents, it is imperative that we determine the antimicrobial susceptibility of the actual (or presumed) infecting organism or organisms. If the pathogen is isolated from culture it can be subjected to direct susceptibility testing using either the Kirby-Bauer or microwell dilution methods. The lowest concentration of antimicrobial agent that prevents visible growth after an 18- 24-hour incubation period is the minimal inhibitory concentration (MIC).

With the widespread clinical and agricultural use of antibiotics since the 1930’s and 1940’s, many strains of bacteria resistant to one or more antimicrobial agents have emerged. Therefore susceptibility testing is important in regards to determining the emergence of resistant organisms. In certain cases routine susceptibility testing need not be done, but these cases make up an ever-diminishing list. All Group A and other ß-hemolytic streptococci remain susceptible to the penicillins and cephalosporins; virtually all anaerobes except Bacteroides spp. are susceptible to penicillin G. Thus testing these organisms against agents listed need not be carried out routinely at the present time.

IV. Host factors

Age

The age of the patient is a major factor to consider in the choice of antimicrobial agents. A foal is not just a small horse when it comes to considering drug therapy, particularly concerning the use of orally administered drugs in the neonatal foal. Within the first 2-3 weeks of life, most drugs that are absorbed orally in small animals can be used effectively in foals. Somewhere after 3 weeks of age the hindgut fermentation capabilities of the foal can be viewed as an adult for the purposes of drug administration.

Liver and renal function account for most of the differences in neonatal physiology. Thus, the serum half-lives of drugs that are primarily excreted by the kidneys may be considerably increased in neonates. Foals, calves and pigs have considerable excretory renal function at birth while puppies and kittens require about 2 to 3 weeks to approach adult values.^2,3

In addition to the toxicity that may result from impaired renal excretion in neonates and elderly patients, other adverse effects of antimicrobial agents may also be age related. In other species the hepatic function of the neonate is underdeveloped compared to adult standards. This can result in difficulties if such patients are administered drugs that are normally excreted or inactivated by the liver. Chloramphenicol is inactivated by conjugation to the glucuronide form in the liver. However, in the neonate hepatic levels of glucuronyl transferase are relatively insufficient. Thus when neonates are given large doses of chloramphenicol, high serum levels of unconjugated chloramphenicol results. Such high levels of unconjugated chloramphenicol are toxic and can result in shock, cardiovascular collapse, and death. The foal is somewhat of an exception in regards to liver function. Although born naïve the foal rapidly develops drug metabolic capability over the first 1 to 3 days of its life such that it functions as an adult after 3 days of age. Other species typically require 4 to 5 weeks to reach drug metabolic maturity.

The sulfonamides compete with bilirubin for binding sites on serum albumin. When given to neonates, they produce increased serum levels of unbound bilirubin that may predispose the foal to kernicterus.

The quinolone (enrofloxacin, ciprofloxacin) antimicrobials have been shown to cause cartilage damage and arthropathy in young animals. As a result, they are not considered a first line drug for use in young animals.

Finally, hypersensitivity reactions to antimicrobial agents also appear to be more common in elderly than in younger patients. This seems to be due to the fact that older patients are more likely to have been previously exposed and, thus sensitized to these agents.

Pregnancy

During pregnancy there is a large increase in aldosterone production (3-fold in women) that leads to increased sodium and water retention. As a result, blood volume may increase 30-50%. In accordance with the Frank-Starling law, cardiac output increases approximately 30-40%. Plasma protein concentrations are typically lower than normal during pregnancy, in part due to dilution from the increased blood volume and there may be a decreased binding affinity of drugs for those proteins. With increased cardiac output, an increase in GFR also occurs and creatinine clearance may increase by as much as 50%.

Because of the increased blood volume during pregnancy, the volume of distribution (Vd) for many drugs is substantially increased. The Vd may also be increased due to lower plasma protein concentrations and associated binding, thereby allowing more drug to enter peripheral tissues. For example, the dose of gentamicin in the pregnant woman may be twice that required in the nonpregnant woman. In general, one should tend toward the higher end of a dosage range when treating the pregnant animal.

You probably remember memorizing in veterinary school the types of placentation different species. While those differences may have anatomical and immune implications, they don’t have much effect on the passage of drugs. For the most part anything the mother has in her central circulation will be passed to the fetus, albeit at different concentrations. There are, of course, exceptions. Predicting which side of the placenta where a drug may concentrate on is based on pH partitioning. Since the pH of the fetus is slightly acidic relative to the dam, weak bases accumulate on the fetal side while weak acids stay predominantly on the maternal side.

A great deal of concern in treating a pregnant animal is directed at avoiding teratogens. While all variables play a role it is generally conceded that time of administration relative to development is much more important than the dose administered. Fetal growth is divided into four stages: blastogenesis, embryogenesis, metamorphosis, and fetal growth. Early in gestation during pre-differentiation the blastocyst is relatively resistant to the induction of congenital malformations, through exposure. Exposure during this stage may interfere with implantation and terminate the pregnancy. It is during differentiation within the embryonic stage and organogenesis during metamorphosis that most abnormalities occur. From the end of metamorphosis until birth, when most growth occurs, the fetus becomes progressively less susceptible to teratogenic effects.  [...]