How to Inject Penicillin: A Step-by-Step Guide

Penicillin injections are given intramuscularly, meaning the medication is delivered deep into a large muscle rather than into a vein or under the skin. The thick, suspension-based formulations used for long-acting penicillin make proper technique critical: the wrong site, the wrong depth, or the wrong route can cause complications ranging from extreme pain to tissue death. Whether you are a healthcare worker preparing for your first benzathine penicillin injection or a patient who wants to understand what the procedure involves, the process follows a consistent sequence of steps, and each one exists to prevent a specific problem.

Why Penicillin Is Injected and Which Formulations Are Used

Not all penicillin is injectable. Oral penicillin V handles many infections perfectly well. The injectable forms exist for situations where a single deep-muscle shot can deliver weeks of antibiotic coverage, most commonly for treating strep throat, syphilis, and preventing recurrences of rheumatic fever. The formulations you will encounter are benzathine penicillin G (often sold as Bicillin L-A), which releases penicillin slowly over two to four weeks, and procaine penicillin G, which provides a shorter burst of higher blood levels over about 24 hours. Some products combine the two. A preparation containing 900,000 units of benzathine penicillin G plus 300,000 units of procaine penicillin G in a single 2-mL injection has been shown to produce the same clinical response as higher-volume alternatives, with all patients recovering within 36 to 48 hours in a trial of 400 children with strep throat.¹

These formulations are thick, white suspensions, not clear liquids. That physical property is what makes them effective as long-acting depot injections, but it also makes them harder to push through a needle and more painful at the injection site. Combining benzathine penicillin G with procaine penicillin G was originally developed to reduce local reactions, bringing the rate of significant pain and swelling down to roughly 5 to 10 percent.¹ Understanding what you are injecting helps explain why every step of the technique matters.

Choosing the Right Injection Site

Site selection is probably the single most consequential decision in the entire process. You need a large muscle with good blood supply, enough depth to keep the medication out of the subcutaneous fat layer, and enough distance from major nerves and blood vessels to avoid catastrophic injury.

For adults, the ventrogluteal site (the upper-outer hip area, over the gluteus medius muscle) is the preferred location. A study of older adults using ultrasound measurements found the ventrogluteal site had thicker muscle tissue (about 40 mm on average) and thinner subcutaneous fat (about 20 mm) compared to the dorsogluteal site, where fat was thicker and muscle thinner.² A meta-analysis pooling data from multiple trials confirmed the clinical difference: ventrogluteal injections produced less pain, less bleeding, and fewer hematomas compared to dorsogluteal injections.³ The ventrogluteal site also carries a lower risk of hitting the sciatic nerve, which runs through the dorsogluteal region and can cause paralysis if damaged.⁴

For infants and young children, the vastus lateralis muscle on the outer thigh is preferred. The thigh muscle is well-developed even in very small children, and it sits far from major nerves. This recommendation holds across clinical settings, and research specifically highlights the vastus lateralis as the best option in resource-limited environments where ultrasound or other imaging is not available.⁵

One additional detail worth knowing: subcutaneous fat is significantly thicker at both injection sites in women compared to men, with no difference in muscle thickness between sexes.⁶ This means needle length may need to be adjusted based on the patient’s body composition to ensure the medication reaches the muscle rather than pooling in fat.

Preparing the Syringe and Needle

Benzathine penicillin G comes as a pre-filled syringe or a vial containing a white, opaque suspension. Before drawing up the dose, the vial needs to be gently rolled between the palms or rotated end-over-end to re-suspend the particles evenly. Shaking vigorously can create foam and worsen clumping. Quality testing of benzathine penicillin G from multiple countries has found that a modest proportion of batches contain aggregated particles larger than 400 micrometers, which can block the needle during injection.⁷ Allowing the syringe to warm to room temperature for a few minutes before injecting can reduce the viscosity of the suspension and make it flow more easily through the needle.

Needle selection matters. For adults receiving a ventrogluteal injection, a 21-gauge needle that is 1 to 1.5 inches long is standard. A thinner gauge makes the injection less painful but can make it nearly impossible to push the thick suspension through. Some clinicians use one needle to draw up the medication and then switch to a fresh needle for the actual injection, which avoids dulling the tip and prevents any medication residue on the outside of the needle from contacting the skin and subcutaneous tissue.

The Injection Process Step by Step

Once the site is chosen and the syringe is ready, the injection follows a deliberate sequence. Each step has a reason behind it.

• Position the patient: For ventrogluteal injection, the patient should lie on their side or slightly tilted, with the hip and leg relaxed. Tensed muscles hurt more and resist the needle.
• Locate the site: Place the heel of your hand on the greater trochanter (the bony prominence at the top of the thigh bone), point your index finger toward the anterior iliac spine, and spread your middle finger toward the iliac crest. The injection goes into the V formed between your two fingers.
• Clean the skin: Swab with an alcohol wipe using a circular motion from the center outward. Let it dry completely; injecting through wet alcohol stings.
• Use the Z-track method: Pull the skin and subcutaneous tissue laterally (to one side) with your non-dominant hand before inserting the needle. After the injection, releasing the skin allows the tissue layers to slide back into their normal position, sealing the needle track and preventing the medication from leaking back up into the subcutaneous tissue. Studies confirm that Z-track technique reduces drug leakage compared to standard injection, cutting visible leakage by roughly a third.⁸
• Insert the needle: Use a smooth, dart-like motion at a 90-degree angle to the skin surface. Hesitating or going slowly increases pain.
• Inject slowly: Push the plunger at a steady rate, roughly 1 mL per 10 seconds. Penicillin suspensions are viscous and require firm, consistent pressure. Rushing creates excessive pressure in the tissue and increases pain.
• Withdraw and release: Pull the needle out at the same angle it went in, then release the Z-track displacement. Apply gentle pressure with gauze. Do not massage the site, as this can push medication into subcutaneous tissue.

The Aspiration Question

Aspiration means pulling back on the plunger briefly before injecting to check whether blood enters the syringe, which would indicate the needle is in a blood vessel rather than muscle. This was long taught as a mandatory step for every intramuscular injection. The evidence no longer supports that practice for most sites. A systematic review concluded that aspiration is unnecessary at the deltoid, ventrogluteal, and vastus lateralis sites, where major blood vessels are not in the needle’s path.⁹ A more recent meta-analysis found that aspiration increases pain and lengthens the procedure without reducing complication rates.¹⁰

The one exception is the dorsogluteal site, where the gluteal artery runs nearby. If you are using this site (which is discouraged for the reasons described earlier), aspiration is still recommended.⁹ For penicillin injections specifically, given that accidental intravenous administration can be fatal, some clinicians choose to aspirate regardless of site as an added precaution, even though the evidence at the ventrogluteal site does not require it.

Reducing Pain During the Injection

Penicillin injections have a well-earned reputation for being painful. The suspension itself is irritating to tissue, the volume is relatively large (usually 2 mL for an adult dose), and the viscosity means it enters the muscle slowly under pressure. Several strategies can help.

Adding lidocaine as a diluent is one of the most effective approaches. A randomized, double-blind crossover study in children receiving benzathine penicillin G for rheumatic heart disease found that co-administering lidocaine cut pain scores by more than half at five minutes after injection, with a median pain score of 2 out of 10 in the lidocaine group compared to 5 out of 10 with sterile water as the diluent.¹¹ No adverse events were observed. The pain difference evened out by 60 minutes, but the acute period right after the injection is when patients report the worst experience, so that early window matters.

Other practical techniques include allowing the medication to reach room temperature before injection, injecting slowly, using the Z-track method (which reduces leakage of the irritating medication into superficial tissue), and applying a cold pack to the area before the injection to numb the skin. Distraction techniques, especially for children, also help. The cumulative effect of combining several of these measures can make a meaningful difference for patients who need monthly injections for rheumatic fever prophylaxis.

Why Penicillin Must Never Be Given Intravenously

This is the most critical safety point for anyone handling injectable penicillin formulations. Benzathine penicillin G and procaine penicillin G are formulated exclusively for intramuscular use. If they enter a vein, the thick suspension can cause immediate vascular blockage, leading to cardiorespiratory arrest and death.¹² This is not a theoretical concern. Case reports document fatal outcomes from accidental intravenous injection.

The risk exists because these are particulate suspensions, not solutions. When dissolved penicillin G (the standard intravenous formulation) is given into a vein, it distributes harmlessly through the bloodstream. When a particulate suspension designed for slow release in muscle instead enters the bloodstream, the particles can occlude small blood vessels in the lungs and heart. Labeling on benzathine penicillin products includes boxed warnings about this hazard. Anyone administering these injections should verify they are using the correct product for the correct route every time, and should never attempt to administer them through an IV line, IV port, or any intravenous access.

Nicolau Syndrome and Serious Local Complications

Nicolau syndrome is a rare but devastating complication of intramuscular injection that is particularly associated with penicillin preparations. It begins with sudden, severe pain at the injection site, followed rapidly by skin discoloration, swelling, and eventually tissue death extending through the skin, fat, and muscle.¹³ The exact mechanism is still debated. Proposed explanations include accidental injection into or near an artery causing clotting and downstream tissue death, sympathetic nerve spasm restricting blood flow, and direct mechanical or inflammatory damage to blood vessels.¹⁴

The consequences can extend well beyond the injection site. Published case reports describe patients developing paralysis of the lower limb, kidney failure from the release of proteins from dead muscle tissue, bone infection, and in the most severe cases, death.¹⁵ About a third of patients experience neurological complications, most often temporary numbness or weakness.¹⁴

Nicolau syndrome is rare enough that most clinicians will never see a case. But it underscores why proper site selection and technique exist: choosing the ventrogluteal site over the dorsogluteal site reduces proximity to large arteries, using the correct needle length ensures the medication reaches muscle rather than being deposited too superficially, and injecting slowly reduces the hydraulic pressure that could force medication into a vessel wall. When a patient reports sudden, explosive pain during or immediately after a penicillin injection, accompanied by skin color changes at or near the injection site, it should be treated as a potential emergency.

Sciatic Nerve Injury From Gluteal Injections

Separate from Nicolau syndrome, direct damage to the sciatic nerve is another well-documented complication of gluteal injections. The sciatic nerve is the largest nerve in the body, running from the lower spine through the buttock and down the back of each leg. When an injection is placed too low or too medially in the buttock, the needle can contact or penetrate the nerve, causing immediate burning pain radiating down the leg, weakness, or paralysis.

This complication is overwhelmingly associated with the dorsogluteal site. A review of sciatic nerve injection injuries confirmed that the ventrogluteal region has a more favorable safety profile because the nerve runs well below and behind the recommended injection zone.⁴ The risk is highest in thin patients, where less tissue separates the skin surface from the nerve, and in young children, where anatomical landmarks are smaller and harder to identify. This is one of the reasons pediatric guidelines direct clinicians to the vastus lateralis rather than any gluteal site in infants.⁵

Penicillin Allergy and Pre-Injection Screening

Before any penicillin injection, the patient should be asked about previous reactions to penicillin or other beta-lactam antibiotics. About 10 percent of the general population reports a penicillin allergy, though the actual rate of confirmed, clinically significant allergy is much lower. Most reported allergies are based on childhood rashes that may not have been true immune-mediated reactions.

Still, genuine penicillin allergy can cause anaphylaxis, and an intramuscular injection delivers the drug in a way that cannot be easily reversed. Unlike an IV infusion that can be stopped immediately, an IM depot injection continues releasing penicillin for days to weeks. For patients with a convincing history of anaphylaxis or severe allergic reaction, penicillin skin testing is available to help determine whether the allergy is still present. Patients with confirmed allergy should not receive injectable penicillin, and alternative antibiotics should be used.

Whenever penicillin injections are given, emergency equipment for treating anaphylaxis (including injectable epinephrine, airway management tools, and the ability to call for emergency medical support) should be available. Patients are typically observed for 15 to 30 minutes after the injection, as anaphylactic reactions most often begin within minutes.

Penicillin Injections in Veterinary Medicine

Many people encounter injectable penicillin not in a hospital but in a barn or pasture. Procaine penicillin G is one of the most commonly used antibiotics in livestock, administered intramuscularly to cattle, horses, sheep, and goats for bacterial infections. The principles of injection are broadly similar to human medicine: the medication goes into a large muscle, the site should be chosen to avoid nerves and blood vessels, and proper technique reduces tissue damage.

One key difference is that tissue damage at the injection site has economic consequences in food animals, because the affected muscle cannot be used for meat. Research in cows found that intramuscular injections of antimicrobials, including penicillin formulations, caused significant increases in serum creatine kinase activity (a marker of acute muscle damage), with peaks occurring within 3 to 12 hours. Histological examination of injection sites revealed degeneration, necrosis, and inflammatory cell infiltration.¹⁶ For this reason, current livestock guidelines often recommend injecting in the neck rather than the hindquarters, because neck muscle is less commercially valuable than the large cuts from the hip and loin.

Withdrawal periods also apply. After the last injection, a set number of days must pass before the animal’s meat or milk can enter the food supply, allowing the drug to clear from tissues. These periods vary by species, formulation, and country, and are printed on the product label. Livestock producers who administer penicillin injections are legally responsible for observing these intervals.